A Novel Two-Step Hierarchial Quantitative Structure-Activity ...

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Background: Accurate prediction of in vivo toxicity from in vitro testing is a challenging problem. Large public–private consortia have been formed with the goal of improving chemical safety assessment by the means of high-throughput screening. Methods and results: A database containing experimental cytotoxicity values for in vitro half-maximal inhibitory concentration (IC50) and in vivo rodent median lethal dose (LD50) for more than 300 chemicals was compiled by Zentralstelle zur Erfassung und Bewertung von Ersatz- und Ergaenzungsmethoden zum Tierversuch (ZEBET ; National Center for Documentation and Evaluation of Alternative Methods to Animal Experiments) . The application of conventional quantitative structure–activity relationship (QSAR) modeling approaches to predict mouse or rat acute LD50 values from chemical descriptors of ZEBET compounds yielded no statistically significant models. The analysis of these data showed no significant correlation between IC50 and LD50. However, a linear IC50 versus LD50 correlation could be established for a fraction of compounds. To capitalize on this observation, we developed a novel two-step modeling approach as follows. First, all chemicals are partitioned into two groups based on the relationship between IC50 and LD50 values: One group comprises compounds with linear IC50 versus LD50 relationships, and another group comprises the remaining compounds. Second, we built conventional binary classification QSAR models t

Cytotoxicity evaluation of a new set of 2-aminobenzo[de]iso-quinoline-1,3-diones.

PubMed

Al-Salahi, Rashad; Alswaidan, Ibrahim; Marzouk, Mohamed

2014-12-04

A new series of 2-amino-benzo[de]isoquinoline-1,3-diones was synthesized and fully characterized in our previous paper. Here, their cytotoxic effects have been evaluated in vitro in relation to colon HCT-116, hepatocellular Hep-G2 and breast MCF-7 cancer cell lines, using a crystal violet viability assay. The IC50-values of the target compounds are reported in µg/mL, using doxorubicin as a reference drug. The findings revealed that compounds 14, 15, 16, 21 and 22 had significant cytotoxic effects against HCT-116, MCF-7 and Hep-G2 cell lines. Their IC50 values ranged between 1.3 and 8.3 μg/mL in relation to doxorubicin (IC50 ≈ 0.45-0.89 μg/mL). Therefore, these compounds could be used as templates for furthering the development and design of more potent antitumor agents through structural modification.

Cytotoxicity of compounds from Xylopia aethiopica towards multi-factorial drug-resistant cancer cells.

PubMed

Kuete, Victor; Sandjo, Louis P; Mbaveng, Armelle T; Zeino, Maen; Efferth, Thomas

2015-12-15

Multidrug resistance (MDR) in cancer represent a major hurdle in chemotherapy. Previously, the methanol extract of the medicinal spice Xylopia aethiopica displayed considerable cytotoxicity against multidrug resistant (MDR) cancer cell lines. The present study was designed to assess the cytotoxicity of compounds, 16α-hydroxy-ent-kauran-19-oic acid (2), 3,4',5-trihydroxy-6″,6″-dimethylpyrano[2,3-g]flavone (3), isotetrandrine (5) and trans-tiliroside (6) derived from the methanol crude extract of Xylopia aethiopica against 9 drug-sensitive and -resistant cancer cell lines. The resazurin reduction assay was used to evaluate the cytotoxicity of these compounds, whilst caspase-Glo assay was used to detect caspase activation. Cell cycle, mitochondrial membrane potential (MMP) and levels of reactive oxygen species (ROS) were all analyzed via flow cytometry. Flavonoid 3 and alkaloid 5 also displayed IC50 values ranging from 2.61 µM (towards leukemia CCRF-CEM cells) to 18.60 µM (towards gliobastoma multiforme U87MG.ΔEGFR cells) and from 1.45 µM (towards HepG2 cells) to 7.28 µM (towards MDA-MB-231-pcDNA cells), respectively. IC50 values ranged from 0.20 µM (against CCRF-CEM cells) to 195.12 µM (against CEM/ADR5000 cells) for doxorubicin. Compound 3 induced apoptosis in leukemia CCRF-CEM cells mediated by the disruption of the MMP, whilst 5 induced apoptosis mediated by ROS production. Compounds 2 and 5 represent potential cytotoxic phytochemicals that deserve more investigations to develop novel antineoplastic drugs against multifactorial drug-resistant cancers. Copyright © 2015 Elsevier GmbH. All rights reserved.

Antimicrobial and antiprotozoal activities of secondary metabolites from the fungus Eurotium repens

PubMed Central

Gao, Jiangtao; Radwan, Mohamed M.; León, Francisco; Wang, Xiaoning; Jacob, Melissa R.; Tekwani, Babu L.; Khan, Shabana I.; Lupien, Shari; Hill, Robert A.; Dugan, Frank M.; Cutler, Horace G.

2011-01-01

In this study, we examined in vitro antibacterial, antifungal, antimalarial, and antileishmanial activities of secondary metabolites (1–8) isolated from the fungus Eurotium repens. All compounds showed mild to moderate antibacterial or antifungal or both activities except 7. The activity of compound 6 was the best of the group tested. The in vitro antimalarial evaluation of these compounds revealed that compounds 1–3, 5, and 6 showed antimalarial activities against both chloroquine-sensitive and chloroquine-resistant strains of Plasmodium falciparum with IC50 values in the range of 1.1–3.0 μg/ml without showing any cytotoxicity to the mammalian cells. Compound 5 displayed the highest antimalarial activity. Antileishmanial activity against Leishmania donovani promastigotes was observed for compounds 1–6 with IC50 values ranging from 6.2 to 23 μg/ml. Antileishmanial activity of compounds 5 and 6 (IC50 values of 7.5 and 6.2 μg/ml, respectively) was more potent than 1–4 (IC50 values ranging from 19–23 μg/ml). Compounds 7 and 8 did not show any antiprotozoal effect. Preliminary structure and activity relationship studies indicated that antibacterial, antifungal, antimalarial, and antileishmanial activities associated with phenol derivates (1–6) seem to be dependent on the number of double bonds in the side chain, which would be important for lead optimization in the future. PMID:23024574

Cytotoxicity of Aporphine, Protoberberine, and Protopine Alkaloids from Dicranostigma leptopodum (Maxim.) Fedde.

PubMed

Sun, Ruiqi; Jiang, Haiyan; Zhang, Wenjuan; Yang, Kai; Wang, Chengfang; Fan, Li; He, Qing; Feng, Jiangbin; Du, Shushan; Deng, Zhiwei; Geng, Zhufeng

2014-01-01

Nine alkaloids with three different structural skeletons were isolated from Dicranostigma leptopodum (Maxim.) Fedde (Papaveraceae) by repeated silica gel column chromatography. Their chemical structures were identified on the basic of physicochemical and spectroscopic data. Among them, 10-O-methylhernovine (1), nantenine (2), corytuberine (3), lagesianine A (4), and dihydrocryptopine (9) were first isolated from this plant. With a series of cytotoxic tests, compounds 2, 3, and 7 displayed cytotoxicity against SMMC-7721 with IC50 values of 70.08 ± 4.63, 73.22 ± 2.35, and 27.77 ± 2.29 μ M, respectively.

Fluorescent rhodanine-3-acetic acids visualize neurofibrillary tangles in Alzheimer's disease brains.

PubMed

Anumala, Upendra Rao; Gu, Jiamin; Lo Monte, Fabio; Kramer, Thomas; Heyny-von Haußen, Roland; Hölzer, Jana; Goetschy-Meyer, Valerie; Schön, Christian; Mall, Gerhard; Hilger, Ingrid; Czech, Christian; Herms, Jochen; Schmidt, Boris

2013-09-01

There is a high demand for the development of an imaging agent for neurofibrillary tangles (NFTs) detection in Alzheimer's diagnosis. In the present study, a series of rhodanine-3-acetic acids was synthesized and evaluated for fluorescence imaging of NFTs in brain tissues of AD patients. Five out of seven probes have shown excellent binding affinity to NFTs over amyloid plaques in the Thiazine red R displacement assay. However, the selectivity in this in vitro assay is not confirmed by the histopathological evaluation, which indicates significant differences in the binding sites in the assays. Probe 6 showed binding affinity (IC50=19nM) to tau aggregates which is the highest among this series. Probes 2, 3, 4 and 5 display IC50 values of lower than 100nM to tau aggregates to displace Thiazine red R. Evaluation of the cytotoxicity of these five probes with human liver carcinoma cells revealed that these compounds excert negligible cytotoxicity. The in vivo studies with zebrafish embryos confirmed negligible cytotoxicity at 24 and 72h post fertilization. Copyright © 2013 Elsevier Ltd. All rights reserved.

Cytotoxicity of Aporphine, Protoberberine, and Protopine Alkaloids from Dicranostigma leptopodum (Maxim.) Fedde

PubMed Central

Jiang, Haiyan; Zhang, Wenjuan; Yang, Kai; Wang, Chengfang; Fan, Li; Feng, Jiangbin; Du, Shushan; Deng, Zhiwei; Geng, Zhufeng

2014-01-01

Nine alkaloids with three different structural skeletons were isolated from Dicranostigma leptopodum (Maxim.) Fedde (Papaveraceae) by repeated silica gel column chromatography. Their chemical structures were identified on the basic of physicochemical and spectroscopic data. Among them, 10-O-methylhernovine (1), nantenine (2), corytuberine (3), lagesianine A (4), and dihydrocryptopine (9) were first isolated from this plant. With a series of cytotoxic tests, compounds 2, 3, and 7 displayed cytotoxicity against SMMC-7721 with IC50 values of 70.08 ± 4.63, 73.22 ± 2.35, and 27.77 ± 2.29 μM, respectively. PMID:24963327

Cytotoxic deoxybenzoins and diphenylethylenes from Arundina graminifolia.

PubMed

Hu, Qiu-Fen; Zhou, Bin; Ye, Yan-Qing; Jiang, Zhi-Yong; Huang, Xiang-Zhong; Li, Yin-Ke; Du, Gang; Yang, Guang-Yu; Gao, Xue-Mei

2013-10-25

Eight new C-4-alkylated deoxybenzoins (1-8), three new diphenylethylenes (9-11), and five known diphenylethylenes were isolated from Arundina graminifolia. The structures of 1-11 were elucidated by spectroscopic methods including extensive 1D and 2D NMR techniques. Compounds 9-11 are the first naturally occurring diphenylethylenes possessing a hydroxyethyl unit. Compounds 1-11 were evaluated for cytotoxicity against five human tumor cell lines. Compounds 4, 5, and 9-11 showed significant cytotoxicity against five cancer cell lines, with IC50 values ranging from 1.8 to 8.7 μM.

Protective effect of Aronia melanocarpa fruit juice in a model of cisplatin-induced cytotoxicity in vitro.

PubMed

Valcheva-Kuzmanova, Stefka V; Beronova, Anna B; Momekov, Georgi Tz

2013-01-01

The aim of the present study was to investigate the protective potential of Aronia melanocarpa fruit juice in a model of cisplatin-induced cytotoxicity in the human embryonal kidney cell line HEK293T. The cellular viability was assessed using the MTT-dye reduction assay based on the reduction of the yellow tetrazolium dye MTT to a violet formazan product via the mitochondrial succinate dehydrogenase in viable cells. Cisplatin was applied in various concentrations either alone or after a 24-hour pretreatment of the cells with Aronia melanocarpa fruit juice at 0.1 and 0.05 mg/ml. The half maximal inhibitory concentrations (IC50 values) were derived from the concentration-response curves to cisplatin. Applied alone, the anticancer drug caused a prominent decrease of cellular viability with IC50 8.3 +/- 1.1 microM. The juice proved to significantly ameliorate the in vitro cytotoxicity of the platinum drug, in a concentration-dependent manner. The pretreatment of the cells with Aronia melanocarpa fruit juice resulted in a significant increase (p < 0.001) of IC50 for cisplatin to 25.1 +/- 2.7 microM (at 0.05 mg/ml) and 34.4 +/- 3.4 microM (at 0.1 mg/ml), respectively. The protective effect of Aronia melanocarpa fruit juice observed in this study is most probably due to its well appreciated antioxidant activity as oxidative stress plays a central role in the toxic effects of cisplatin.

Extracts of Morus nigra L. Leaves Standardized in Chlorogenic Acid, Rutin and Isoquercitrin: Tyrosinase Inhibition and Cytotoxicity

PubMed Central

Fontes, Pedro Ribeiro; Souza, Paula Monteiro; William Fagg, Christopher; Neves Silva Guerra, Eliete; de Medeiros Nóbrega, Yanna Karla; Silveira, Damaris; Fonseca-Bazzo, Yris; Simeoni, Luiz Alberto; Homem-de-Mello, Maurício; Oliveira Magalhães, Pérola

2016-01-01

Melanogenesis is a process responsible for melanin production, which is stored in melanocytes containing tyrosinase. Inhibition of this enzyme is a target in the cosmetics industry, since it controls undesirable skin conditions such as hyperpigmentation due to the overproduction of melanin. Species of the Morus genus are known for the beneficial uses offered in different parts of its plants, including tyrosinase inhibition. Thus, this project aimed to study the inhibitory activity of tyrosinase by extracts from Morus nigra leaves as well as the characterization of its chromatographic profile and cytotoxicity in order to become a new therapeutic option from a natural source. M. nigra leaves were collected, pulverized, equally divided into five batches and the standardized extract was obtained by passive maceration. There was no significant difference between batches for total solids content, yield and moisture content, which shows good reproducibility of the extraction process. Tyrosinase enzymatic activity was determined for each batch, providing the percentage of enzyme inhibition and IC50 values obtained by constructing dose-response curves and compared to kojic acid, a well-known tyrosinase inhibitor. High inhibition of tyrosinase activity was observed (above 90% at 15.625 μg/mL). The obtained IC50 values ranged from 5.00 μg/mL ± 0.23 to 8.49 μg/mL ± 0.59 and were compared to kojic acid (3.37 μg/mL ± 0.65). High Performance Liquid Chromatography analysis revealed the presence of chlorogenic acid, rutin and, its major compound, isoquercitrin. The chromatographic method employed was validated according to ICH guidelines and the extract was standardized using these polyphenols as markers. Cytotoxicity, assessed by MTT assay, was not observed on murine melanomas, human keratinocytes and mouse fibroblasts in tyrosinase IC50 values. This study demonstrated the potential of M. nigra leaf extract as a promising whitening agent of natural source against skin hyperpigmentation. PMID:27655047

Betulinyl Sulfamates as Anticancer Agents and Radiosensitizers in Human Breast Cancer Cells

PubMed Central

Bache, Matthias; Münch, Christin; Güttler, Antje; Wichmann, Henri; Theuerkorn, Katharina; Emmerich, Daniel; Paschke, Reinhard; Vordermark, Dirk

2015-01-01

Betulinic acid (BA), a natural compound of birch bark, is cytotoxic for many tumors. Recently, a betulinyl sulfamate was described that inhibits carbonic anhydrases (CA), such as CAIX, an attractive target for tumor-selective therapy strategies in hypoxic cancer cells. Data on combined CAIX inhibition with radiotherapy are rare. In the human breast cancer cell lines MDA-MB231 and MCF7, the effects of BA and betulinyl sulfamates on cellular and radiobiological behavior under normoxia and hypoxia were evaluated. The two most effective betulinyl sulfamates CAI 1 and CAI 3 demonstrated a 1.8–2.8-fold higher cytotoxicity than BA under normoxia in breast cancer cells, with IC50 values between 11.1 and 18.1 µM. BA exhibits its strongest cytotoxicity with IC50 values of 8.2 and 16.4 µM under hypoxia. All three substances show a dose-dependent increase in apoptosis, inhibition of migration, and inhibition of hypoxia-induced gene expression. In combination with irradiation, betulinyl sulfamates act as radiosensitizers, with DMF10 values of 1.47 (CAI 1) and 1.75 (CAI 3) under hypoxia in MDA-MB231 cells. BA showed additive effects in combination with irradiation. Taken together; our results suggest that BA and betulinyl sulfamates seem to be attractive substances to combine with radiotherapy; particularly for hypoxic breast cancer. PMID:26540049

Betulinyl Sulfamates as Anticancer Agents and Radiosensitizers in Human Breast Cancer Cells.

PubMed

Bache, Matthias; Münch, Christin; Güttler, Antje; Wichmann, Henri; Theuerkorn, Katharina; Emmerich, Daniel; Paschke, Reinhard; Vordermark, Dirk

2015-11-03

Betulinic acid (BA), a natural compound of birch bark, is cytotoxic for many tumors. Recently, a betulinyl sulfamate was described that inhibits carbonic anhydrases (CA), such as CAIX, an attractive target for tumor-selective therapy strategies in hypoxic cancer cells. Data on combined CAIX inhibition with radiotherapy are rare. In the human breast cancer cell lines MDA-MB231 and MCF7, the effects of BA and betulinyl sulfamates on cellular and radiobiological behavior under normoxia and hypoxia were evaluated. The two most effective betulinyl sulfamates CAI 1 and CAI 3 demonstrated a 1.8-2.8-fold higher cytotoxicity than BA under normoxia in breast cancer cells, with IC50 values between 11.1 and 18.1 µM. BA exhibits its strongest cytotoxicity with IC50 values of 8.2 and 16.4 µM under hypoxia. All three substances show a dose-dependent increase in apoptosis, inhibition of migration, and inhibition of hypoxia-induced gene expression. In combination with irradiation, betulinyl sulfamates act as radiosensitizers, with DMF10 values of 1.47 (CAI 1) and 1.75 (CAI 3) under hypoxia in MDA-MB231 cells. BA showed additive effects in combination with irradiation. Taken together; our results suggest that BA and betulinyl sulfamates seem to be attractive substances to combine with radiotherapy; particularly for hypoxic breast cancer.

Three new triterpene esters from pumpkin (Cucurbita maxima) seeds.

PubMed

Kikuchi, Takashi; Ueda, Shinsuke; Kanazawa, Jokaku; Naoe, Hiroki; Yamada, Takeshi; Tanaka, Reiko

2014-04-16

Three new multiflorane-type triterpene esters, i.e. 7α-hydroxymultiflor-8-ene-3α,29-diol 3-acetate-29-benzoate (1), 7α-methoxymultiflor-8-ene-3α,29-diol 3,29-dibenzoate (2), and 7β-methoxymultiflor-8-ene-3α,29-diol 3,29-dibenzoate (3), were isolated from seeds of Cucurbita maxima, along with the known compound, multiflora-7,9(11)-diene-3α,29-diol 3,29-dibenzoate (4). Compound 1 exhibited melanogenesis inhibitory activities comparable with those of arbutin. In cytotoxicity assays, compounds 1 and 3 exhibited weak cytotoxicity, with IC50 values of 34.5-93.7 μM against HL-60 and P388 cells.

Evaluation of antioxidant, in vitro cytotoxicity of micropropagated and naturally grown plants of Leptadenia reticulata (Retz.) Wight & Arn.-an endangered medicinal plant.

PubMed

Mohanty, Sudipta Kumar; Malappa, Kumaraswamy; Godavarthi, Ashok; Subbanarasiman, Balasubramanya; Maniyam, Anuradha

2014-09-01

To evaluate the antioxidant and anti proliferative potential of different solvent extract of micropropagated and naturally grown plants of Leptadenia reticulata against various cancer cell lines. In this study different extract were tested for cytotoxicity against human breast adenocarcinoma cell line MCF-7, human colon adenocarcinoma grade II cell line HT-29 and non cancer skeletal muscle cell line L6 through 3-(4, 5-dimethyl thiazol-2-yl)-5-diphenyl tetrazolium bromide assay. The total antioxidant potential was estimated by three different antioxidant model diphenylpicrylhydrazyl free radical scavenging activity, H2O2 scavenging activity and FeCl3 reducing activity. The ethyl acetate extract of both naturally grown plant and tissue cultured plant exhibited significant cytotoxicity with IC50 values of 21 µg/mL, 26 µg/mL and 22 µg/mL; 20 µg/mL, 30 µg/mL and 18 µg/mL respectively against three cell lines. The diphenylpicrylhydrazyl free radical scavenging activity was found to be highest with IC50 value of 267.13 µg/mL in ethyl acetate extract. The methanolic extract exhibited moderate antioxidant activity with IC50 value of 510.15 µg/mL. A highly positive correlation was observed between the antioxidant potential and cytotoxic activity of the plant. The strong cytotoxicity of ethyl acetate extract revealed anti carcinogenic potential of the plant which supports its traditional use as medicine. The present investigation is new to literature till date and will provide better scientific basis for future pharmacological, in vivo studies and novel source of pure bioactive compounds having anti cancer properties in this plant. Copyright © 2014 Hainan Medical College. Published by Elsevier B.V. All rights reserved.

Moringa oleifera leaf extracts inhibit 6β-hydroxylation of testosterone by CYP3A4

PubMed Central

Monera, Tsitsi G.; Wolfe, Alan R.; Maponga, Charles C.; Benet, Leslie Z.; Guglielmo, Joseph

2017-01-01

Background Moringa oleifera is a tropical tree often used as a herbal medicine, including by people who test positive for HIV. Since herbal constituents may interact with drugs via inhibition of metabolizing enzymes, we investigated the effects of extracts of M. oleifera on the CYP3A4-mediated 6ß-hydroxylation of testosterone. Methods Methanolic and aqueous leaf and root of extracts of M. oleifera with concentrations between 0.01 and 10 mg/ml were incubated with testosterone and mixed-sex human liver microsomes in the presence of NADPH. Metabolite concentrations were determined by HPLC. The cytotoxicity of the extracts was tested with HepG2 cells using the MTT formazan assay. Results Significant CYP3A4 inhibitory effects were found, with IC50 values of 0.5 and 2.5 mg/ml for leaf-methanol and leaf-water extracts, respectively. Root extracts were less active. Cytotoxicity was observed only with the leaf-water extract (IC50 = 6 mg/ml). Conclusions Further investigation is warranted to elucidate the potential of M. oleifera for clinically significant interactions with antiretroviral and other drugs. PMID:19745507

Moringa oleifera leaf extracts inhibit 6beta-hydroxylation of testosterone by CYP3A4.

PubMed

Monera, Tsitsi G; Wolfe, Alan R; Maponga, Charles C; Benet, Leslie Z; Guglielmo, Joseph

2008-10-01

Moringa oleifera is a tropical tree often used as a herbal medicine, including by people who test positive for HIV. Since herbal constituents may interact with drugs via inhibition of metabolizing enzymes, we investigated the effects of extracts of M. oleifera on the CYP3A4-mediated 6beta-hydroxylation of testosterone. Methanolic and aqueous leaf and root of extracts of M. oleifera with concentrations between 0.01 and 10 mg/ml were incubated with testosterone and mixed-sex human liver microsomes in the presence of NADPH. Metabolite concentrations were determined by HPLC. The cytotoxicity of the extracts was tested with HepG2 cells using the MTT formazan assay. Significant CYP3A4 inhibitory effects were found, with IC50 values of 0.5 and 2.5 mg/ml for leaf-methanol and leaf-water extracts, respectively. Root extracts were less active. Cytotoxicity was observed only with the leaf-water extract (IC50 = 6 mg/ml). Further investigation is warranted to elucidate the potential of M. oleifera for clinically significant interactions with antiretroviral and other drugs.

Evaluation of Phenolic Content Variability along with Antioxidant, Antimicrobial, and Cytotoxic Potential of Selected Traditional Medicinal Plants from India

PubMed Central

Singh, Garima; Passsari, Ajit K.; Leo, Vincent V.; Mishra, Vineet K.; Subbarayan, Sarathbabu; Singh, Bhim P.; Kumar, Brijesh; Kumar, Sunil; Gupta, Vijai K.; Lalhlenmawia, Hauzel; Nachimuthu, Senthil K.

2016-01-01

Plants have been used since ancient times as an important source of biologically active substances. The aim of the present study was to investigate the phytochemical constituents (flavonoids and phenolics), antioxidant potential, cytotoxicity against HepG2 (human hepato carcinoma) cancer cell lines, and the antimicrobial activity of the methanol extract of selected traditional medicinal plants collected from Mizoram, India. A number of phenolic compounds were detected using HPLC-DAD-ESI-TOF-MS, mainly Luteolin, Kaempferol, Myricetin, Gallic Acid, Quercetin and Rutin, some of which have been described for the first time in the selected plants. The total phenolic and flavonoid contents showed high variation ranging from 4.44 to 181.91 μg of Gallic Acid equivalent per milligram DW (GAE/mg DW) and 3.17 to 102.2 μg of Quercetin/mg, respectively. The antioxidant capacity was determined by DPPH (IC50 values ranges from 34.22 to 131.4 μg/mL), ABTS (IC50 values ranges from 24.08 to 513.4 μg/mL), and reducing power assays. Antimicrobial activity was assayed against gram positive (Staphylococcus aureus), gram negative (Escherichia coli, Pseudomonas aeruginosa), and yeast (Candida albicans) demonstrating that the methanol extracts of some plants were efficacious antimicrobial agents. Additionally, cytotoxicity was assessed on human hepato carcinoma (HepG2) cancer cell lines and found that the extracts of Albizia lebbeck, Dillenia indica, and Bombax ceiba significantly decreased the cell viability at low concentrations with IC50 values of 24.03, 25.09, and 29.66 μg/mL, respectively. This is the first report of detection of phenolic compounds along with antimicrobial, antioxidant and cytotoxic potential of selected medicinal plants from India, which indicates that these plants might be valuable source for human and animal health. PMID:27066046

Syzygium cumini (L.) Skeels essential oil and its major constituent α-pinene exhibit anti-Leishmania activity through immunomodulation in vitro.

PubMed

Rodrigues, Klinger Antonio da Franca; Amorim, Layane Valéria; Dias, Clarice Noleto; Moraes, Denise Fernandes Coutinho; Carneiro, Sabrina Maria Portela; Carvalho, Fernando Aécio de Amorim

2015-02-03

Syzygium cumini (L.) Skeels (Myrtaceae), commonly known as "jambolão" in Brazil is widely used in folk medicine against leishmaniasis, inflammation, chronic diarrhea, and ulcers. It is one of the most commonly used plants for the treatment of diabetes worldwide. In previous studies, Syzygium cumini was shown to possess antihyperlipidemic and anti-allergic properties, and to exhibit good performance as an antimicrobial agent against bacteria, fungi, and protozoa parasites of the genus Leishmania and Trypanosoma. This study was aimed at evaluating the effects of S. cumini essential oil (ScEO) and its major component α-pinene on Leishmania (Leishmania) amazonensis, as well as their cytotoxicity and possible mechanisms of action. To evaluate the anti-proliferative effect on Leishmania, effects on promastigote and axenic amastigote forms were assessed using tetrazolium salt (MTT) assay. The intramacrophagic amastigotes were exposed to ScEO and α-pinene to determine the survival index. To gain insight into the mechanism of action involved in the effect on the samples, we evaluated the modulation of macrophage activation state by observing structural (phagocytic and lysosomal activities) and cellular (nitric oxide increase) changes. To assess the safety profile of ScEO and α-pinene, murine macrophages and human red blood cells were treated with ScEO and α-pinene and the selectivity index was calculated for each treatment. α-Pinene was effective against Leishmania amazonensis promastigote forms, with a half-maximal inhibitory concentration (IC50) value of 19.7µg/mL. α-Pinene was more active (IC50 values of 16.1 and 15.6µg/mL against axenic and intracellular amastigotes, respectively) than ScEO (IC50 values of 43.9 and 38.1µg/mL against axenic and intracellular amastigotes, respectively). Our results showed that the anti-Leishmania effects were mediated by immunomodulatory activity, as evidenced by the observed increases in both phagocytic and lysosomal activity, and the elevated NO levels. ScEO and α-pinene exhibited low cytotoxicity against murine macrophages and human erythrocytes. The 50% cytotoxicity concentration (CC50) values for the macrophages in the MTT assay were 614.1 and 425.2µg/mL for ScEO and α-pinene, respectively, while the corresponding half-maximal hemolytic concentration (HC50) values were 874.3 and 233.3µg/mL. Taken together, the results demonstrate that ScEO and its major constituent α-pinene have significant anti-Leishmania activity, modulated by macrophage activation, with acceptable levels of cytotoxicity in murine macrophages and human erythrocytes. Further work is warranted, involving more in-depth mechanistic studies and in vivo investigations. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Intracellular delivery of etoposide loaded biodegradable nanoparticles: cytotoxicity and cellular uptake studies.

PubMed

Yadav, Khushwant S; Jacob, Sheeba; Sachdeva, Geetanjali; Sawant, Krutika K

2011-08-01

The preferred delivery systems for anticancer drugs would be the one which would have selective and effective destruction of cancer cells. In the present study etoposide (ETO) loaded nanoparticles (NP) were prepared using PLGA (ETO-PLGA NP), PLGA-MPEG block copolymer (ETO-PLGA-MPEG NP) and PLGA-Pluronic copolymer (ETO-PLGA-PLU NP) and they were evaluated for cytotoxicity and cellular uptake studies using two cancer cell lines, L1210 and DU145. The IC50 values for L1210 cells were 18.0, 6.2, 4.8 and 5.4 microM and for DU145 cells the IC50 values were 98.4, 75.1, 60.1 and 71.3 microM for ETO, ETO-PLGA NP, ETO-PLGA-MPEG NP and ETO-PLGA-PLU NP respectively. The increased cytotoxicities were attributed to increased uptake of the NPs by the cells. Moreover the ETO loaded PLGA-MPEG NP and PLGA-Pluronic NP showed a sustained cytotoxic effect till 5 days on both the cell lines. Results of the long term cytotoxicity study concluded that the drug loaded PLGA nanoparticulate formulations were efficient in decreasing the viability of the L1210 cells over a period of three days, whereas the pure drug exerted its maximum efficiency on the day one itself. Z-stack confocal images of NPs showed fluorescence activity in each section of DU 145 and L1210 cells indicating that the nanoparticles were internalized by the cells. The study concluded that ETO loaded PLGA NPs had higher cytotoxicity compared with that of the free drug and ETO-PLGA-MPEG NP and ETO-PLGA-PLU NP had higher cell uptake efficiency compared with that of ETO-PLGA NP. The developed PLGA based NPs shows promise to be used for cancer therapy.

Biotransformation of a potent anabolic steroid, mibolerone, with Cunninghamella blakesleeana, C. echinulata, and Macrophomina phaseolina, and biological activity evaluation of its metabolites.

PubMed

Siddiqui, Mahwish; Ahmad, Malik Shoaib; Wahab, Atia-Tul-; Yousuf, Sammer; Fatima, Narjis; Naveed Shaikh, Nimra; Rahman, Atta-Ur-; Choudhary, M Iqbal

2017-01-01

Seven metabolites were obtained from the microbial transformation of anabolic-androgenic steroid mibolerone (1) with Cunninghamella blakesleeana, C. echinulata, and Macrophomina phaseolina. Their structures were determined as 10β,17β-dihydroxy-7α,17α-dimethylestr-4-en-3-one (2), 6β,17β-dihydroxy-7α,17α-dimethylestr-4-en-3-one (3), 6β,10β,17β-trihydroxy-7α,17α-dimethylestr-4-en-3-one (4), 11β,17β-dihydroxy-(20-hydroxymethyl)-7α,17α-dimethylestr-4-en-3-one (5), 1α,17β-dihydroxy-7α,17α-dimethylestr-4-en-3-one (6), 1α,11β,17β-trihydroxy-7α,17α-dimethylestr-4-en-3-one (7), and 11β,17β-dihydroxy-7α,17α-dimethylestr-4-en-3-one (8), on the basis of spectroscopic studies. All metabolites, except 8, were identified as new compounds. This study indicates that C. blakesleeana, and C. echinulata are able to catalyze hydroxylation at allylic positions, while M. phaseolina can catalyze hydroxylation of CH2 and CH3 groups of substrate 1. Mibolerone (1) was found to be a moderate inhibitor of β-glucuronidase enzyme (IC50 = 42.98 ± 1.24 μM) during random biological screening, while its metabolites 2-4, and 8 were found to be inactive. Mibolerone (1) was also found to be significantly active against Leishmania major promastigotes (IC50 = 29.64 ± 0.88 μM). Its transformed products 3 (IC50 = 79.09 ± 0.06 μM), and 8 (IC50 = 70.09 ± 0.05 μM) showed a weak leishmanicidal activity, while 2 and 4 were found to be inactive. In addition, substrate 1 (IC50 = 35.7 ± 4.46 μM), and its metabolite 8 (IC50 = 34.16 ± 5.3 μM) exhibited potent cytotoxicity against HeLa cancer cell line (human cervical carcinoma). Metabolite 2 (IC50 = 46.5 ± 5.4 μM) also showed a significant cytotoxicity, while 3 (IC50 = 107.8 ± 4.0 μM) and 4 (IC50 = 152.5 ± 2.15 μM) showed weak cytotoxicity against HeLa cancer cell line. Compound 1 (IC50 = 46.3 ± 11.7 μM), and its transformed products 2 (IC50 = 43.3 ± 7.7 μM), 3 (IC50 = 65.6 ± 2.5 μM), and 4 (IC50 = 89.4 ± 2.7 μM) were also found to be moderately toxic to 3T3 cell line (mouse fibroblast). Interestingly, metabolite 8 showed no cytotoxicity against 3T3 cell line. Compounds 1-4, and 8 were also evaluated for inhibition of tyrosinase, carbonic anhydrase, and α-glucosidase enzymes, and all were found to be inactive.

Evaluation of Phenolic Content Variability along with Antioxidant, Antimicrobial, and Cytotoxic Potential of Selected Traditional Medicinal Plants from India.

PubMed

Singh, Garima; Passsari, Ajit K; Leo, Vincent V; Mishra, Vineet K; Subbarayan, Sarathbabu; Singh, Bhim P; Kumar, Brijesh; Kumar, Sunil; Gupta, Vijai K; Lalhlenmawia, Hauzel; Nachimuthu, Senthil K

2016-01-01

Plants have been used since ancient times as an important source of biologically active substances. The aim of the present study was to investigate the phytochemical constituents (flavonoids and phenolics), antioxidant potential, cytotoxicity against HepG2 (human hepato carcinoma) cancer cell lines, and the antimicrobial activity of the methanol extract of selected traditional medicinal plants collected from Mizoram, India. A number of phenolic compounds were detected using HPLC-DAD-ESI-TOF-MS, mainly Luteolin, Kaempferol, Myricetin, Gallic Acid, Quercetin and Rutin, some of which have been described for the first time in the selected plants. The total phenolic and flavonoid contents showed high variation ranging from 4.44 to 181.91 μg of Gallic Acid equivalent per milligram DW (GAE/mg DW) and 3.17 to 102.2 μg of Quercetin/mg, respectively. The antioxidant capacity was determined by DPPH (IC50 values ranges from 34.22 to 131.4 μg/mL), ABTS (IC50 values ranges from 24.08 to 513.4 μg/mL), and reducing power assays. Antimicrobial activity was assayed against gram positive (Staphylococcus aureus), gram negative (Escherichia coli, Pseudomonas aeruginosa), and yeast (Candida albicans) demonstrating that the methanol extracts of some plants were efficacious antimicrobial agents. Additionally, cytotoxicity was assessed on human hepato carcinoma (HepG2) cancer cell lines and found that the extracts of Albizia lebbeck, Dillenia indica, and Bombax ceiba significantly decreased the cell viability at low concentrations with IC50 values of 24.03, 25.09, and 29.66 μg/mL, respectively. This is the first report of detection of phenolic compounds along with antimicrobial, antioxidant and cytotoxic potential of selected medicinal plants from India, which indicates that these plants might be valuable source for human and animal health.

Design, synthesis and biological evaluation of diaziridinyl quinone isoxazole hybrids.

PubMed

Swapnaja, K Jones M; Yennam, Satyanarayana; Chavali, Murthy; Poornachandra, Y; Kumar, C Ganesh; Muthusamy, Krubakaran; Jayaraman, Venkatesh Babu; Arumugam, Premkumar; Balasubramanian, Sridhar; Sriram, Kiran Kumar

2016-07-19

A series of novel diaziridinyl quinone isoxazole hybrids (9a-9j) were synthesized starting from 2, 5-dimethoxy acetophenone 1 via Claisen reaction, cyclisation, alkoxy carbonylation, hydrolysis, oxidation and aziridine insertion. All the compounds were screened for antimicrobial, anti-biofilm and cytotoxic activities. Among the screened compounds, the compound 9h showed good antibacterial and anti-biofilm activities with MIC value of 3.9, 3.9, 3.9 and 7.8 μg/mL, respectively, and IC50 values of 1.9, 2.5, 2.8 and 5.1 μM, respectively, against Staphylococcus aureus MTCC 96, S. aureus MLS-16 MTCC 2940, Bacillus subtilis MTCC 121 and Klebsiella planticola MTCC 530, and also exhibited potent antifungal activity against Candida albicans MTCC 227, C. albicans MTCC 854 and Candida krusei MTCC 3020 equipotent to standard miconazole (MIC value 7.8 μg/mL). All the synthesized compounds exhibited promising cytotoxicity against A549 and PC3 cell lines (IC50 values between 1 and 4 μM). Compounds 9b and 9j exhibited IC50 value of 0.5 μM which was similar to that of Mitomycin C against PC3 cell line. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Doxorubicin-anti-carcinoembryonic antigen immunoconjugate activity in vitro.

PubMed

Richardson, V J; Ford, C H; Tsaltas, G; Gallant, M E

1989-04-01

An in vitro model consisting of a series of 11 human cancer cell lines with varying density of expression of membrane carcinoembryonic antigen (CEA) has been used to evaluate conjugates of doxorubicin (Adriamycin) covalently linked by a carbodiimide method to goat polyclonal antibodies and mouse monoclonal antibodies to CEA. Conjugates were produced which retained both antigen binding and drug cytotoxicity. IC50 values were determined for free drug, free drug mixed with unconjugated antibodies and for the immunoconjugates. Cell lines that were very sensitive to free drug (IC50 less than 100 ng/ml) were also found to be highly sensitive to conjugated drug and similarly cell lines resistant to drug (IC50 greater than 1,000 ng/ml) were also resistant to conjugated drug. Although there was no correlation between CEA expression and conjugates efficacy, competitive inhibition studies using autologous antibody to block conjugate binding to cells indicated immunoconjugates specificity for the CEA target.

Novel Cholinesterase Inhibitors Based on O-Aromatic N,N-Disubstituted Carbamates and Thiocarbamates.

PubMed

Krátký, Martin; Štěpánková, Šárka; Vorčáková, Katarína; Švarcová, Markéta; Vinšová, Jarmila

2016-02-11

Based on the presence of carbamoyl moiety, twenty salicylanilide N,N-disubstituted (thio)carbamates were investigated using Ellman's method for their ability to inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). O-Aromatic (thio)carbamates exhibited weak to moderate inhibition of both cholinesterases with IC50 values within the range of 1.60 to 311.0 µM. IC50 values for BChE were mostly lower than those obtained for AChE; four derivatives showed distinct selectivity for BChE. All of the (thio)carbamates produced a stronger inhibition of AChE than rivastigmine, and five of them inhibited BChE more effectively than both established drugs rivastigmine and galantamine. In general, 5-chloro-2-hydroxy-N-[4-(trifluoromethyl)-phenyl]benzamide, 2-hydroxy-N-phenylbenzamide as well as N-methyl-N-phenyl carbamate derivatives led to the more potent inhibition. O-{4-Chloro-2-[(4-chlorophenyl)carbamoyl]phenyl} dimethylcarbamothioate was identified as the most effective AChE inhibitor (IC50 = 38.98 µM), while 2-(phenylcarbamoyl)phenyl diphenylcarbamate produced the lowest IC50 value for BChE (1.60 µM). Results from molecular docking studies suggest that carbamate compounds, especially N,N-diphenyl substituted representatives with considerable portion of aromatic moieties may work as non-covalent inhibitors displaying many interactions at peripheral anionic sites of both enzymes. Mild cytotoxicity for HepG2 cells and consequent satisfactory calculated selectivity indexes qualify several derivatives for further optimization.

A Green Synthesis of Chalcones As an Antioxidant and Anticancer

NASA Astrophysics Data System (ADS)

Susanti VH, Elfi; Agustina Eko Setyowati, Widiastuti

2018-01-01

Three chalcones (4’-amino-4-methoxy chalcone, 4’-amino-3,4-dimethoxy chalcone and 4’-amino-3,4,5-trimethoxy chalcone) has been synthesized by a green chemistry approach using grinding technique. Antioxidant activity of the chalcones were assessed using 1,1-biphenyl-2-picrylhydrazyl (DPPH) radical scavenging method. Cytotoxicity of chalcones sythesized was evaluated using a tetrazolium (MTT) colorimetric assay against cervical cancer cell line, HeLa. The antioxidant activity test showed that 4’-amino-4-methoxy chalcone had a stronger activity than the 4’-amino-3,4-dimethoxy chalcone and 4’-amino-3,4,5-trimethoxy chalcone, respectively with IC50 58.85, 64.79 and 210.3 μg/mL. These results indicate that there is a relationship between the structure of chalcone with antioxidant activity, the more methoxy groups in the ring B of the chalcone, antioxidant activity is getting smaller. The chalcone synthesized showed cytotoxicity against HeLa cell line with IC50 value of 31.75, 36.65, 49.04 μg/mL, respectively. It was observed that the highest cytotoxic activity was found at 4’-amino-4-methoxy chalcone (IC50 31.75 μg/mL). Lower activity was showed by 4’-amino-3,4,5-trimethoxy chalcone with IC50 value of 49,04 μg/mL. There is a relationship cytotoxicity with chalcone structure, the more the number of methoxy groups in ring B chalcone, will decrease the activity of cytotoxicity.

Two new triterpenoid saponins from the aerial parts of Anemone taipaiensis.

PubMed

Li, Hui; Wang, Xiao-Yang; Wang, Xia-Yin; Hua, Dong; Liu, Yang; Tang, Hai-Feng

2015-05-01

Phytochemical study on the aerial parts of Anemone taipaiensis for the first time led to the isolation of two new oleanane-type triterpenoid saponins 1 and 2, together with four known saponins (3-6). Their structures were elucidated by extensive spectroscopic analysis and chemical evidences. Saponins 2-4 exhibited cytotoxicity against human glioblastoma U251MG cell line with IC50 values ranging from 1.56 to 80.62 μM.

Antifungal, Antileishmanial, and Cytotoxicity Activities of Various Extracts of Berberis vulgaris (Berberidaceae) and Its Active Principle Berberine

PubMed Central

Mahmoudvand, Hossein; Ayatollahi Mousavi, Seyyed Amin; Sepahvand, Asghar; Sharififar, Fariba; Ezatpour, Behrouz; Gorohi, Fatemeh; Saedi Dezaki, Ebrahim; Jahanbakhsh, Sareh

2014-01-01

In this study, in vitro antidermatophytic activity against Trichophyton mentagrophytes, Trichophyton rubrum, Microsporum canis, and Microsporum gypseum was studied by disk diffusion test and assessment of minimum inhibitory concentration (MIC) using CLSI broth macrodilution method (M38-A2). Moreover, antileishmanial and cytotoxicity activity of B. vulgaris and berberine against promastigotes of Leishmania major and Leishmania tropica were evaluated by colorimetric MTT assay. The findings indicated that the various extracts of B. vulgaris particularly berberine showed high potential antidermatophytic against pathogenic dermatophytes tested with MIC values varying from 0.125 to >4 mg/mL. The results revealed that B. vulgaris extracts as well as berberine were effective in inhibiting L. major and L. tropica promastigotes growth in a dose-dependent manner with IC50 (50% inhibitory concentration) values varying from 2.1 to 26.6 μg/mL. Moreover, it could be observed that berberine as compared with B. vulgaris exhibited more cytotoxicity against murine macrophages with CC50 (cytotoxicity concentration for 50% of cells) values varying from 27.3 to 362.6 μg/mL. Results of this investigation were the first step in the search for new antidermatophytic and antileishmanial drugs. However, further works are required to evaluate exact effect of these extracts in animal models as well as volunteer human subjects. PMID:24977052

National Cancer Institute Pediatric Preclinical Testing Program: Model Description for In Vitro Cytotoxicity Testing

PubMed Central

Kang, Min H.; Smith, Malcolm A.; Morton, Christopher L.; Keshelava, Nino; Houghton, Peter J.; Reynolds, C. Patrick

2010-01-01

Background The National Cancer Institute (NCI) has established the Pediatric Preclinical Testing Program (PPTP) for testing drugs against in vitro and in vivo childhood cancer models to aid in the prioritization of drugs considered for early phase pediatric clinical trials. Procedures In vitro cytotoxicity testing employs a semi-automated fluorescence-based digital imaging cytotoxicity assay (DIMSCAN) that has a 4-log dynamic range of detection. Curve fitting of the fractional survival data of the cell lines in response to various concentrations of the agents was used to calculate relative IC50, absolute IC50, and Ymin values The panel of 23 pediatric cancer cell lines included leukemia (n=6), lymphoma (n=2), rhabdomyosarcoma (n=4), brain tumors (n=3), Ewing family of tumors (EFT, n=4), and neuroblastoma (n=4). The doubling times obtained using DIMSCAN were incorporated into data analyses to estimate the relationship between input cell numbers and final cell number. Results We report in vitro activity data for three drugs (vincristine, melphalan, and etoposide) that are commonly used for pediatric cancer and for the mTOR inhibitor rapamycin, an agent that is currently under preclinical investigation for cancer. To date, the PPTP has completed in vitro testing of 39 investigational and approved agents for single drug activity and two investigational agents in combination with various “standard” chemotherapy drugs. Conclusions This robust in vitro cytotoxicity testing system for pediatric cancers will enable comparisons to response data for novel agents obtained from xenograft studies and from clinical trials. PMID:20922763

Antifungal, Antileishmanial, and Cytotoxicity Activities of Various Extracts of Berberis vulgaris (Berberidaceae) and Its Active Principle Berberine.

PubMed

Mahmoudvand, Hossein; Ayatollahi Mousavi, Seyyed Amin; Sepahvand, Asghar; Sharififar, Fariba; Ezatpour, Behrouz; Gorohi, Fatemeh; Saedi Dezaki, Ebrahim; Jahanbakhsh, Sareh

2014-01-01

In this study, in vitro antidermatophytic activity against Trichophyton mentagrophytes, Trichophyton rubrum, Microsporum canis, and Microsporum gypseum was studied by disk diffusion test and assessment of minimum inhibitory concentration (MIC) using CLSI broth macrodilution method (M38-A2). Moreover, antileishmanial and cytotoxicity activity of B. vulgaris and berberine against promastigotes of Leishmania major and Leishmania tropica were evaluated by colorimetric MTT assay. The findings indicated that the various extracts of B. vulgaris particularly berberine showed high potential antidermatophytic against pathogenic dermatophytes tested with MIC values varying from 0.125 to >4 mg/mL. The results revealed that B. vulgaris extracts as well as berberine were effective in inhibiting L. major and L. tropica promastigotes growth in a dose-dependent manner with IC50 (50% inhibitory concentration) values varying from 2.1 to 26.6  μ g/mL. Moreover, it could be observed that berberine as compared with B. vulgaris exhibited more cytotoxicity against murine macrophages with CC50 (cytotoxicity concentration for 50% of cells) values varying from 27.3 to 362.6  μ g/mL. Results of this investigation were the first step in the search for new antidermatophytic and antileishmanial drugs. However, further works are required to evaluate exact effect of these extracts in animal models as well as volunteer human subjects.

Phytochemical constituents, nutritional values, phenolics, flavonols, flavonoids, antioxidant and cytotoxicity studies on Phaleria macrocarpa (Scheff.) Boerl fruits

PubMed Central

2014-01-01

Background The edible fruits of Phaleria macrocarpa (Scheff.) Boerl are widely used in traditional medicine in Indonesia. It is used to treat a variety of medical conditions such as - cancer, diabetes mellitus, allergies, liver and heart diseases, kidney failure, blood diseases, high blood pressure, stroke, various skin diseases, itching, aches, and flu. Therefore, it is of great interest to determine the biochemical and cytotoxic properties of the fruit extracts. Methods The methanol, hexane, chloroform, ethyl acetate, and water extracts of P. macrocarpa fruits were examined for phytochemicals, physicochemicals, flavonols, flavonoids and phenol content. Its nutritional value (A.O.A.C method), antioxidant properties (DPPH assay) and cytotoxicity (MTT cell proliferation assay) were also determined. Results A preliminary phyotochemical screening of the different crude extracts from the fruits of P. macrocarpa showed the presence secondary metabolites such as of flavonoids, phenols, saponin glycosides and tannins. The ethyl acetate and methanol extracts displayed high antioxidant acitivity (IC50 value of 8.15±0.02 ug/mL) in the DPPH assay comparable to that of the standard gallic acid (IC50 value of 10.8±0.02 ug/mL). Evaluation of cytotoxic activity showed that the crude methanol extract possessed excellent anti-proliferative activity against SKOV-3 (IC50 7.75±2.56 μg/mL) after 72 hours of treatment whilst the hexane and ethyl acetate extracts displayed good cytotoxic effect against both SKOV-3 and MDA-MB231 cell lines. The chloroform extract however, showed selective inhibitory activity in the breast cancer cell line MDA-MB231 (IC50 7.80±1.57 μg/mL) after 48 hours of treatment. There was no cytotoxic effect observed in the Ca Ski cell line and the two normal cell lines (MRC-5 and WRL-68). Conclusion The methanol extract and the ethyl acetate fraction of P. macrocarpa fruits exhibited good nutritional values, good antioxidant and cytotoxic activities, and merits further investigation to identify the specific compound(s) responsible for these activities. PMID:24885709

Synergism of Curcumin and Cytarabine in the Down Regulation of Multi-Drug Resistance Genes in Acute Myeloid Leukemia.

PubMed

Shah, Krupa; Mirza, Sheefa; Desai, Urja; Jain, Nayan; Rawal, Rakesh

2016-01-01

The aim of the study was to find a role of Curcumin from natural source to overcome drug resistance as well as to reduce cytotoxicity profile of the drug in Acute Myeloid Leukemia patients. Primary leukemic cells were obtained from AML patient's bone marrow. These cells were then exposed to different concentration of cytarabine and curcumin to find out IC50 values and also its effect on MDR genes like MDR1, BCRP, LRP and FLT3 by RT-PCR method. Our results suggested that curcumin down regulates MDR genes. Gene expression was decreased by 35.75, 31.30, 27.97 % for MDR1, LRP, BCRP respectively. In FLT3, it was 65.86 % for wild type and 31.79 % for FLT3-ITD. In addition to this, curcumin has also shown anti-proliferative effect as well as synergistic effect in combination with Cytarabine on primary leukemic cells. Thus, we can conclude that curcumin can be used as MDR modulator as well as chemosensitizer in combination with cytarabine, standard chemotherapeutic drug, to reduce the cytotoxicity profile as IC50 value decreases when treated in combination.

Cytotoxic and antibacterial angucycline- and prodigiosin-analogues from the deep-sea derived Streptomyces sp. SCSIO 11594.

PubMed

Song, Yongxiang; Liu, Guangfu; Li, Jie; Huang, Hongbo; Zhang, Xing; Zhang, Hua; Ju, Jianhua

2015-03-16

Two new C-glycoside angucyclines, marangucycline A (1) and marangucycline B (2), along with three known compounds, dehydroxyaquayamycin (3), undecylprodigiosin (4) and metacycloprodigiosin (5), have been identified as products of the deep-sea sediment strain Streptomyces sp. SCSIO 11594. New structures were elucidated on the basis of HRESIMS, 1D and 2D NMR analyses and comparisons to previously reported datasets. Compounds 2 and 4 displayed in vitro cytotoxicity against four cancer cell lines A594, CNE2, HepG2, MCF-7 superior to those obtained with cisplatin, the positive control. Notably, compound 2 bearing a keto-sugar displayed significant cytotoxicity against cancer cell lines with IC50 values ranging from 0.24 to 0.56 μM; An IC50 value of 3.67 μM was found when using non-cancerous hepatic cell line HL7702, demonstrating the cancer cell selectivity of 2. Compounds 1-3 were proved to have weak antibacterial activities against Enterococcus faecalis ATCC29212 with an MIC value of 64.0 μg/mL. Moreover, 3 displayed selective antibacterial activity against methicillin-resistant Staphylococcus epidermidis shhs-E1 with an MIC value of 16.0 μg/mL.

Cytotoxic and Antibacterial Angucycline- and Prodigiosin- Analogues from the Deep-Sea Derived Streptomyces sp. SCSIO 11594

PubMed Central

Song, Yongxiang; Liu, Guangfu; Li, Jie; Huang, Hongbo; Zhang, Xing; Zhang, Hua; Ju, Jianhua

2015-01-01

Two new C-glycoside angucyclines, marangucycline A (1) and marangucycline B (2), along with three known compounds, dehydroxyaquayamycin (3), undecylprodigiosin (4) and metacycloprodigiosin (5), have been identified as products of the deep-sea sediment strain Streptomyces sp. SCSIO 11594. New structures were elucidated on the basis of HRESIMS, 1D and 2D NMR analyses and comparisons to previously reported datasets. Compounds 2 and 4 displayed in vitro cytotoxicity against four cancer cell lines A594, CNE2, HepG2, MCF-7 superior to those obtained with cisplatin, the positive control. Notably, compound 2 bearing a keto-sugar displayed significant cytotoxicity against cancer cell lines with IC50 values ranging from 0.24 to 0.56 μM; An IC50 value of 3.67 μM was found when using non-cancerous hepatic cell line HL7702, demonstrating the cancer cell selectivity of 2. Compounds 1–3 were proved to have weak antibacterial activities against Enterococcus faecalis ATCC29212 with an MIC value of 64.0 μg/mL. Moreover, 3 displayed selective antibacterial activity against methicillin-resistant Staphylococcus epidermidis shhs-E1 with an MIC value of 16.0 μg/mL. PMID:25786061

[Cytotoxicity of chemicals used in household products: 1997- 2004].

PubMed

Ikarashi, Yoshiaki; Kaniwa, Masa-aki; Tsuchiya, Toshie

2005-01-01

The cytotoxicities of chemicals used in household products were evaluated using a neutral red (NR) uptake assay. The chemicals tested during 1997-2004 were rubber additives (accelerators, antioxidants and retarders), solvents, plasticizers and biocides, such as antimicrobials, fungicides, preservatives used in paints, paper, wood and plastic products. The cytotoxicity potential of each chemical was classified by determining the concentrations inducing 50% reduction of NR uptake into Chinese hamster fibroblast V79 cells compared to control (IC50). In vivo eye irritancy of each chemical was estimated by the IC50 value. Most biocides tested showed strong cytotoxicity and had a high probability of inducing strong eye irritation.

Antileishmanial, antimalarial and antimicrobial activities of the extract and isolated compounds from Austroplenckia populnea (Celastraceae).

PubMed

Andrade, Sérgio F; da Silva Filho, Ademar A; de O Resende, Dimas; Silva, Márcio L A; Cunha, Wilson R; Nanayakkara, N P Dhammika; Bastos, Jairo Kenupp

2008-01-01

Austroplenckia populnea (Celastraceae), known as "marmelinho do campo", is used in Brazilian folk medicine as antimicrobial, anti-inflammatory, and antitumoural agent. The aim of the present work was to evaluate the antimicrobial, antileishmanial and antimalarial activities of the crude hydroalcoholic extract of A. populnea (CHE) and some of its isolated compounds. The phytochemical study of the CHE was carried out affording the isolation of methyl populnoate (1), populnoic acid (2), and stigmast-5-en-3-O-beta-(D-glucopyranoside) (3). This is the first time that the presence of compound 3 in A. populnea is reported. The results showed that the CHE presents antifungal and antibacterial activities, especially against Candida glabrata and Candida albicans, for which the CHE showed IC50 values of 0.7 microg mL(-1) and 5.5 microg mL(-1), respectively, while amphotericin B showed an IC50 value of 0.1 microg mL(-1) against both microorganisms. Compounds 1-3 were inactive against all tested microorganisms. In the antileishmanial activity test against Leishmania donovani, the CHE showed an IC50 value of 52 microg mL(-1), while compounds 2 and 3 displayed an IC50 value of 18 microg mL(-1) In the antimalarial assay against Plasmodium falciparum (D6 and W2 clones), it was observed that all evaluated samples were inactive. In order to compare the effect on the parasites with the toxicity to mammalian cells, the cytotoxicity activity of the isolated compounds was evaluated against Vero cells, showing that all evaluated samples exhibited no cytotoxicity at the maximum dose tested.

Propolis from the Stingless Bee Trigona incisa from East Kalimantan, Indonesia, Induces In Vitro Cytotoxicity and Apoptosis in Cancer Cell lines.

PubMed

Kustiawan, Paula M; Phuwapraisirisan, Preecha; Puthong, Songchan; Palaga, Tanapat; Arung, Enos T; Chanchao, Chanpen

2015-01-01

Previously, stingless bee (Trigona spp.) products from East Kalimantan, Indonesia, were successfully screened for in vitro antiproliferative activity against human cancer derived cell lines. It was established that propolis from T. incisa presented the highest in vitro cytotoxicity against the SW620 colon cancer cell line (6% cell survival in 20 μg/mL). Propolis from T. incisa was extracted with methanol and further partitioned with n-hexane, ethyl acetate and methanol. The in vitro cytotoxicity of the extracts was assessed by the MTT assay against human colon (SW620), liver (Hep-G2), gastric (KATO-III), lung (Chago) and breast (BT474) cancer derived cell lines. The active fractions were further enriched by silica gel quick column, absorption and size exclusion chromatography. The purity of each fraction was checked by thin layer chromatography. Cytotoxicity in BT-474 cells induced by cardanol compared to doxorubicin were evaluated by MTT assay, induction of cell cycle arrest and cell death by flow cytometric analysis of propidium iodide and annexin-V stained cells. A cardol isomer was found to be the major compound in one active fraction (F45) of T. incisa propolis, with a cytotoxicity against the SW620 (IC50 of 4.51±0.76 μg/mL), KATO-III (IC50 of 6.06±0.39 μg/mL), Hep-G2 (IC50 of 0.71±0.22 μg/mL), Chago I (IC50 of 0.81±0.18 μg/mL) and BT474 (IC50 of 4.28±0.14 μg/mL) cell lines. Early apoptosis (programmed cell death) of SW620 cells was induced by the cardol containing F45 fraction at the IC50 and IC80 concentrations, respectively, within 2-6 h of incubation. In addition, the F45 fraction induced cell cycle arrest at the G1 subphase. Indonesian stingless bee (T. incisa) propolis had moderately potent in vitro anticancer activity on human cancer derived cell lines. Cardol or 5-pentadecyl resorcinol was identified as a major active compound and induced apoptosis in SW620 cells in an early period (≤6 h) and cell cycle arrest at the G1 subphase. Thus, cardol is a potential candidate for cancer chemotherapy.

Cytotoxic activity of quassinoids from Eurycoma longifolia.

PubMed

Miyake, Katsunori; Li, Feng; Tezuka, Yasuhiro; Awale, Suresh; Kadota, Shigetoshi

2010-07-01

Twenty-four quassinoids isolated from Eurycoma longifolia Jack were investigated for their cytotoxicity against a panel of four different cancer cell lines, which includes three murine cell lines [colon 26-L5 carcinoma (colon 26-L5), B16-BL6 melanoma (B16-BL6), Lewis lung carcinoma (LLC)] and a human lung A549 adenocarcinoma (A549) cell line. Among the tested compounds, eurycomalactone (9) displayed the most potent activity against all the tested cell lines; colon 26-L5 (IC50 = 0.70 microM), B16-BL6 (IC50 = 0.59 microM), LLC (IC50 = 0.78 microM), and A549 (IC50 = 0.73 microM). These activities were comparable to clinically used anticancer agent doxorubicin (colon 26-L5, IC50 = 0.76 microM; B16-BL6, IC50 = 0.86 microM; LLC, IC50 = 0.80 microM; A549, IC50 = 0.66 microM).

2-Hexadecynoic Acid Inhibits Plasmodial FAS-II Enzymes and Arrest Erythrocytic and Liver Stage Plasmodium Infections

PubMed Central

Tasdemir, Deniz; Sanabria, David; Lauinger, Ina L.; Tarun, Alice; Herman, Rob; Perozzo, Remo; Zloh, Mire; Kappe, Stefan H.; Brun, Reto; Carballeira, Néstor M.

2010-01-01

Acetylenic fatty acids are known to display several biological activities, but their antimalarial activity has remained unexplored. In this study, we synthesized the 2-, 5-, 6-, and 9-hexadecynoic acids (HDAs) and evaluated their in vitro activity against erythrocytic (blood) stages of Plasmodium falciparum and liver stages of P. yoelii infections. Since the type II fatty acid biosynthesis pathway (PfFAS-II) has recently been shown to be indispensable for liver stage malaria parasites, the inhibitory potential of the HDAs against multiple P. falciparum FAS-II (PfFAS-II) elongation enzymes was also evaluated. The highest antiplasmodial activity against blood stages of P. falciparum was displayed by 5-HDA (IC50 value 6.6. μg/ml), whereas the 2-HDA was the only acid arresting the growth of liver stage P. yoelii infection, in both flow cytometric assay (IC50 value 2-HDA 15.3 μg/ml, control drug atovaquone 2.5 ng/ml) and immunofluorescense analysis (IC50 2-HDA 4.88 μg/ml, control drug atovaquone 0.37 ng/ml). 2-HDA showed the best inhibitory against the PfFAS-II enzymes PfFabI and PfFabZ with IC50 values of 0.38 and 0.58 μg/ml (IC50 control drugs 14 and 30 ng/ml) respectively. Enzyme kinetics and molecular modeling studies revealed valuable insights into the binding mechanism of 2-HDA on the target enzymes. All HDAs showed in vitro activity against Trypanosoma brucei rhodesiense (IC50 values 3.7–31.7 μg/ml), Trypanosoma cruzi (only 2-HDA, IC50 20.2 μg/ml), and Leishmania donovani (IC50 values 4.1–13.4 μg/ml) with generally low or no significant toxicity on mammalian cells. This is the first study to indicate therapeutic potential of HDAs against various parasitic protozoa. It also points out that the malarial liver stage growth inhibitory effect of the 2-HDA may be promoted via PfFAS-II enzymes. The lack of cytotoxicity, lipophilic nature and calculated pharmacokinetic properties suggest that 2-HDA could be a useful compound to study the interaction of fatty acids with these key P. falciparum enzymes. PMID:20855214

Essential oil of the leaves of Ricinus communis L.: in vitro cytotoxicity and antimicrobial properties.

PubMed

Zarai, Zied; Ben Chobba, Ines; Ben Mansour, Riadh; Békir, Ahmed; Gharsallah, Néji; Kadri, Adel

2012-08-13

The aim of the present study was to appraise the antimicrobial activity of Ricinus communis L. essential oil against different pathogenic microorganisms and the cytotoxic activity against HeLa cell lines. The agar disk diffusion method was used to study the antibacterial activity of Ricinus communis L. essential oil against 12 bacterial and 4 fungi strains. The disc diameters of zone of inhibition (DD), the minimum inhibitory concentrations (MIC) and the concentration inhibiting 50% (IC50) were investigated to characterize the antimicrobial activities of this essential oil. The in vitro cytotoxicity of Ricinus communis L. essential oil was examined using a modified MTT assay; the viability and the IC50 were used to evaluate this test. The essential oil from the leaves of Ricinus communis L. was analyzed by GC-MS and bioassays were carried out. Five constituents of the oil were identified by GC-MS. The antimicrobial activity of the oil was investigated in order to evaluate its efficacy against twelve bacteria and four fungi species, using disc diffusion and minimum inhibitory concentration methods. The essential oil showed strong antimicrobial activity against all microorganisms tested with higher sensitivity for Bacillus subtilis, Staphylococcus aureus and Enterobacter cloacae. The cytotoxic and apoptotic effects of the essential oil on HeLa cell lines were examined by MTT assay. The cytotoxicity of the oil was quite strong with IC50 values less than 2.63 mg/ml for both cell lines. The present study showed the potential antimicrobial and anticarcinogenic properties of the essential oil of Ricinus communis L., indicating the possibilities of its potential use in the formula of natural remedies for the topical treatment of infections.

Enhancement of cytotoxicity of antimicrobial peptide magainin II in tumor cells by bombesin-targeted delivery

PubMed Central

Liu, Shan; Yang, Hao; Wan, Lin; Cai, Hua-wei; Li, Sheng-fu; Li, You-ping; Cheng, Jing-qiu; Lu, Xiao-feng

2011-01-01

Aim: To investigate whether the conjugation of magainin II (MG2), an antimicrobial peptides (AMPs), to the tumor-homing peptide bombesin could enhance its cytotoxicity in tumor cells. Methods: A magainin II-bombesin conjugate (MG2B) was constructed by attaching magainin II (MG2) to bombesin at its N-terminus. The peptides were synthesized using Fmoc-chemistry. The in vitro cytotoxicity of the peptide in cancer cells was quantitatively determined using the CCK-8 cell counting kit. Moreover, the in vivo antitumor effect of the peptide was determined in tumor xenograft models. Results: The IC50 of MG2B for cancer cells (10–15 μmol/L) was at least 10 times lower than the IC50 of unconjugated MG2 (125 μmol/L). Moreover, the binding affinity of MG2B for cancer cells was higher than that of unconjugated MG2. In contrast, conjugation to a bombesin analog lacking the receptor-binding domain failed to increase the cytotoxicity of MG2, suggesting that bombesin conjugation enhances the cytotoxicity of MG2 in cancer cells through improved binding. Indeed, MG2B selectively induced cell death in cancer cells in vitro with the IC50 ranging from 10 to 15 μmol/L, which was about 6–10 times lower than the IC50 for normal cells. MG2B (20 mg/kg per day, intratumorally injected for 5 d) also exhibited antitumor effects in mice bearing MCF-7 tumor grafts. The mean weights of tumor grafts in MG2B- and PBS-treated mice were 0.21±0.05 g and 0.59±0.12 g, respectively. Conclusion: The results suggest that conjugation of AMPs to bombesin might be an alternative approach for targeted cancer therapy. PMID:21131998

Anticancer potential and mechanism of action of mango ginger (Curcuma amada Roxb.) supercritical CO₂ extract in human glioblastoma cells.

PubMed

Ramachandran, Cheppail; Lollett, Ivonne V; Escalon, Enrique; Quirin, Karl-Werner; Melnick, Steven J

2015-04-01

Mango ginger (Curcuma amada Roxb.) is among the less-investigated species of Curcuma for anticancer properties. We have investigated the anticancer potential and the mechanism of action of a supercritical CO2 extract of mango ginger (CA) in the U-87MG human glioblastoma cell line. CA demonstrated higher cytotoxicity than temozolomide, etoposide, curcumin, and turmeric force with IC50, IC75, and IC90 values of 4.92 μg/mL, 12.87 μg/mL, and 21.30 μg/mL, respectively. Inhibitory concentration values of CA for normal embryonic mouse hypothalamus cell line (mHypoE-N1) is significantly higher than glioblastoma cell line, indicating the specificity of CA against brain tumor cells. CompuSyn analysis indicates that CA acts synergistically with temozolomide and etoposide for the cytotoxicity with combination index values of <1. CA treatment also induces apoptosis in glioblastoma cells in a dose-dependent manner and downregulates genes associated with apoptosis, cell proliferation, telomerase activity, oncogenesis, and drug resistance in glioblastoma cells. © The Author(s) 2014.

Chemical composition and in vitro evaluation of antioxidant, antimicrobial, cytotoxicity and anti-acetylcholinesterase properties of Tunisian Origanum majorana L. essential oil.

PubMed

Hajlaoui, Hafedh; Mighri, Hedi; Aouni, Mahjoub; Gharsallah, Néji; Kadri, Adel

2016-06-01

This study investigated the chemical composition and evaluated the antioxidant, antimicrobial, cytotoxic and anti-acetylcholinesterase properties of Tunisian Origanum majorana essential oil. The findings showed that the oil exhibited high activity, particularly in terms of reducing power and β-Carotene bleaching, inducing higher IC50 values than BHT. The oil showed an important antimicrobial activity against 25 bacterial and fungal strains. In fact, the IZ, MIC and MBC values recorded for the bacterial strains were in the range of 8 ± 0-18.33 ± 0.57 mm, 0.097-3.125 and 0.39-6.25 mg/mL, respectively. The IZ, MIC and MFC values of the fungal strains varied between 11±0-28 ± 0 mm, 0.058-0.468 mg/mL and 0.234-1.875 mg/mL, respectively. A low cytotoxic effect was observed against cancer (Hep-2 and HT29) and continuous cell lineage (Vero), with CC50 values ranging from 13.73 to 85.63 mg/mL. The oil was also evaluated for anti-acetylcholinesterase effects, which showed that it exhibited significant activity with IC50 values reaching 150.33 ± 2.02 μg/mL. Copyright © 2016 Elsevier Ltd. All rights reserved.

Mutagenic and Cytotoxicity LQB 123 Profile: Safety and Tripanocidal Effect of a Phenyl-t-Butylnitrone Derivative

PubMed Central

Cupello, Mauricio Peixoto; Saraiva, Francis Monique; Ippolito, Pedro; Fernandes, Andréia da Silva; Costa, Debora de Sousa dos Santos; Paula, Jessica Isis Oliveira; Costa, Paulo Roberto Ribeiro; Dias, Ayres Guimarães

2017-01-01

The therapeutic options for Chagas disease are limited and its treatment presents a number of drawbacks including toxicity, drug resistance, and insufficient effectiveness against the chronic stage of the disease. Therefore, new therapeutical options are mandatory. In the present work, we evaluated the effect of a phenyl-tert-butylnitrone (PBN) derivate, LQB 123, against Trypanosoma cruzi forms. LQB 123 presented a trypanocidal effect against bloodstream trypomastigotes (IC50 = 259.4 ± 6.1 μM) and intracellular amastigotes infecting peritoneal macrophages (IC50 = 188.2 ± 47.5 μM), with no harmful effects upon the mammalian cells (CC50 values greater than 4 mM), resulting in a high selectivity index (CC50/IC50 > 20). Additionally, metacyclic trypomastigotes submitted to LQB 123 presented an IC50 of about 191.8 ± 10.5 μM and epimastigotes forms incubated with different concentrations of LQB 123 presented an inhibition of parasite growth with an IC50 of 255.1 ± 3.6 μM. Finally, we investigated the mutagenic potential of the nitrone by the Salmonella/microsome assay and observed no induction of mutagenicity even in concentrations as high as 33000 μM. Taken together, these results present a nonmutagenic compound, with trypanocidal activity against all relevant forms of T. cruzi, offering new insights into CD treatment suggesting additional in vivo tests. PMID:28316976

A Novel Two-Step Hierarchical Quantitative Structure–Activity Relationship Modeling Work Flow for Predicting Acute Toxicity of Chemicals in Rodents

PubMed Central

Zhu, Hao; Ye, Lin; Richard, Ann; Golbraikh, Alexander; Wright, Fred A.; Rusyn, Ivan; Tropsha, Alexander

2009-01-01

Background Accurate prediction of in vivo toxicity from in vitro testing is a challenging problem. Large public–private consortia have been formed with the goal of improving chemical safety assessment by the means of high-throughput screening. Objective A wealth of available biological data requires new computational approaches to link chemical structure, in vitro data, and potential adverse health effects. Methods and results A database containing experimental cytotoxicity values for in vitro half-maximal inhibitory concentration (IC50) and in vivo rodent median lethal dose (LD50) for more than 300 chemicals was compiled by Zentralstelle zur Erfassung und Bewertung von Ersatz- und Ergaenzungsmethoden zum Tierversuch (ZEBET; National Center for Documentation and Evaluation of Alternative Methods to Animal Experiments). The application of conventional quantitative structure–activity relationship (QSAR) modeling approaches to predict mouse or rat acute LD50 values from chemical descriptors of ZEBET compounds yielded no statistically significant models. The analysis of these data showed no significant correlation between IC50 and LD50. However, a linear IC50 versus LD50 correlation could be established for a fraction of compounds. To capitalize on this observation, we developed a novel two-step modeling approach as follows. First, all chemicals are partitioned into two groups based on the relationship between IC50 and LD50 values: One group comprises compounds with linear IC50 versus LD50 relationships, and another group comprises the remaining compounds. Second, we built conventional binary classification QSAR models to predict the group affiliation based on chemical descriptors only. Third, we developed k-nearest neighbor continuous QSAR models for each subclass to predict LD50 values from chemical descriptors. All models were extensively validated using special protocols. Conclusions The novelty of this modeling approach is that it uses the relationships between in vivo and in vitro data only to inform the initial construction of the hierarchical two-step QSAR models. Models resulting from this approach employ chemical descriptors only for external prediction of acute rodent toxicity. PMID:19672406

SPF32629A and SPF32629B: enantioselective synthesis, determination of absolute configuration, cytotoxicity and antibacterial evaluation.

PubMed

Vegi, Srinivasa Rao; Boovanahalli, Shanthaveerappa K; Patro, Balaram; Mukkanti, K

2011-05-01

We report herein an efficient enantioselective synthesis of SPF32629A and SPF32629B through one-pot enantioselective reduction and protecting-group-free regioselective O-acylation strategy. The absolute configuration of the enantiomerically pure isomers was established by Mosher ester analysis. The inhibitory potencies of the synthesized compounds were assayed in vitro against a panel of microorganisms and against A549 human lung adenocarcinoma cell line. Compounds 2, 11 and 12 displayed moderate to potent antibacterial activity against all the tested strains and compounds 7, 8, 2, 11 and 12 exhibited significant cytotoxicity in a dose-dependent manner with an IC50 values ranging from 2.92 to 4.14 μg/ml and 8-11 μM. Copyright © 2011 Elsevier Masson SAS. All rights reserved.

Growth Inhibition of Human Gynecologic and Colon Cancer Cells by Phyllanthus watsonii through Apoptosis Induction

PubMed Central

Ramasamy, Sujatha; Abdul Wahab, Norhanom; Zainal Abidin, Nurhayati; Manickam, Sugumaran; Zakaria, Zubaidah

2012-01-01

Phyllanthus watsonii Airy Shaw is an endemic plant found in Peninsular Malaysia. Although there are numerous reports on the anti cancer properties of other Phyllanthus species, published information on the cytotoxicity of P. watsonii are very limited. The present study was carried out with bioassay-guided fractionation approach to evaluate the cytotoxicity and apoptosis induction capability of the P. watsonii extracts and fractions on human gynecologic (SKOV-3 and Ca Ski) and colon (HT-29) cancer cells. P. watsonii extracts exhibited strong cytotoxicity on all the cancer cells studied with IC50 values of ≤ 20.0 µg/mL. Hexane extract of P. watsonii was further subjected to bioassay-guided fractionation and yielded 10 fractions (PW-1→PW-10). PW-4→PW-8 portrayed stronger cytotoxic activity and was further subjected to bioassay-guided fractionation and resulted with 8 sub-fractions (PPWH-1→PPWH-8). PPWH-7 possessed greatest cytotoxicity (IC50 values ranged from 0.66 – 0.83 µg/mL) and was selective on the cancer cells studied. LC-MS/MS analysis of PPWH-7 revealed the presence of ellagic acid, geranic acid, glochidone, betulin, phyllanthin and sterol glucoside. Marked morphological changes, ladder-like appearance of DNA and increment in caspase-3 activity indicating apoptosis were clearly observed in both human gynecologic and colon cancer cells treated with P. watsonii especially with PPWH-7. The study also indicated that P. watsonii extracts arrested cell cycle at different growth phases in SKOV-3, Ca Ski and HT-29 cells. Cytotoxic and apoptotic potential of the endemic P. watsonii was investigated for the first time by bioassay-guided approach. These results demonstrated that P. watsonii selectively inhibits the growth of SKOV-3, Ca Ski and HT-29 cells through apoptosis induction and cell cycle modulation. Hence, P. watsonii has the potential to be further exploited for the discovery and development of new anti cancer drugs. PMID:22536331

Investigation of local anesthetic and antimycobacterial activity of Ottonia martiana Miq. (Piperaceae).

PubMed

Cunico, Miriam M; Trebien, Herbert A; Galetti, Fábio C; Miguel, Obdulio G; Miguel, Marilis D; Auer, Celso G; Silva, Célio L; de Souza, Ana Olívia

2015-01-01

Ottonia martiana is a plant popularly known in Brazil by the use for toothache. Ethanolic extract (EE), hexane fraction (HF), dichloromethane fraction (DF) and piperovatine obtained from O. martiana were assayed in vitro and in vivo. The acute toxicity of EE was determined, and LD50 values of 164.5 and 65.0 mg/kg by the oral and intraperitoneal routes, respectively, indicated a high toxicity for EE in vivo, explaining its popular use by topical administration only. A local anesthetic-like effect of EE and its fractions was observed in experimental models using pain induction, and such effect involved an analgesic action. The antimycobacterial activity of EE, HF, DF and piperovatine was evaluated against Mycobacterium tuberculosis H37Rv ATCC 27924. EE, HF, DF, and piperovatine showed a potential antimycobacterial effect with MICs of 16.0, 62.0, 62.0 and 8.0 μg/mL, respectively. Piperovatine was more effective than the EE or the other fractions. The selectivity index (SI=IC50/MIC) values calculated for EE, HF, DF and piperovatine based on the MICs and the cytotoxicity against J774 macrophages (IC50 by MTT assay) revealed values of 6.43, 2.34, 1.5 and 9.66, respectively.

Chemical composition and cytotoxicity evaluation of essential oil from leaves of Casearia sylvestris, its main compound α-zingiberene and derivatives.

PubMed

Bou, Diego Dinis; Lago, João Henrique G; Figueiredo, Carlos R; Matsuo, Alisson L; Guadagnin, Rafael C; Soares, Marisi G; Sartorelli, Patricia

2013-08-08

Casearia sylvestris (Salicaceae), popularly known as "guaçatonga", is a plant widely used in folk medicine to treat various diseases, including cancer. The present work deals with the chemical composition as well as the cytotoxic evaluation of its essential oil, its main constituent and derivatives. Thus, the crude essential oil from leaves of C. sylvestris was obtained using a Clevenger type apparatus and analyzed by GC/MS. This analysis afforded the identification of 23 substances, 13 of which corresponded to 98.73% of the total oil composition, with sesquiterpene a-zingiberene accounting for 50% of the oil. The essential oil was evaluated for cytotoxic activity against several tumor cell lines, giving IC50 values ranging from 12 to 153 mg/mL. Pure a-zingiberene, isolated from essential oil, was also evaluated against the tumor cell lines showing activity for HeLa, U-87, Siha and HL60 cell lines, but with IC50 values higher than those determined for the crude essential oil. Aiming to evaluate the effect of the double bonds of a-zingiberene on the cytotoxic activity, partially hydrogenated a-zingiberene (PHZ) and fully hydrogenated a-zingiberene (THZ) derivatives were obtained. For the partially hydrogenated derivative only cytotoxic activity to the B16F10-Nex2 cell line (IC50 65 mg/mL) was detected, while totally hydrogenated derivative showed cytotoxic activity for almost all cell lines, with B16F10-Nex2 and MCF-7 as exceptions and with IC50 values ranging from 34 to 65 mg/mL. These results indicate that cytotoxic activity is related with the state of oxidation of compound.

Effect of Her-2/neu Signaling on Sensitivity to TRAIL in Prostate Cancer

DTIC Science & Technology

2005-06-01

cytokines (18), and matrix metalloprotease inhibitors (19) are able to render TRAIL-resistant tumor cells sensitive to TRAIL apoptosis. In recent...TRAIL-induced cytotoxicity. As DU-145 cells were treated with acetyl salicylic acid (ASA: aspirin), an inhibitor of IKK , we observed that TRAIL...sulfide (IC50 = 1.02 M for COX-1 and IC50 = 10.43 M for COX-2), NS-398 (a selective COX-2 inhibitor ; IC50 = 4.81 M for COX-1 and IC50 = 0.47 M for COX-2

Synthesis, β-haematin inhibition, and in vitro antimalarial testing of isocryptolepine analogues: SAR study of indolo[3,2-c]quinolines with various substituents at C2, C6, and N11.

PubMed

Wang, Ning; Wicht, Kathryn J; Imai, Kento; Wang, Ming-Qi; Anh Ngoc, Tran; Kiguchi, Ryo; Kaiser, Marcel; Egan, Timothy J; Inokuchi, Tsutomu

2014-05-01

A series of indolo[3,2-c]quinolines were synthesized by modifying the side chains of the ω-aminoalkylamines at the C6 position and introducing substituents at the C2 position, such as F, Cl, Br, Me, MeO and NO2, and a methyl group at the N11 position for an SAR study. The in vitro antiplasmodial activities of the derivative agents against two different strains (CQS: NF54 and CQR: K1) and the cytotoxic activity against normal L6 cells were evaluated. The test results showed that compounds 6k and 6l containing the branched methyl groups of 3-aminopropylamino at C6 with a Cl atom at C2 exhibited a very low cytotoxicity with IC50 values above 4000 nM, high antimalarial activities with IC50 values of about 11 nM for CQS (NF54), IC50 values of about 17 nM for CQR (K1), and RI resistance indices of 1.6. Furthermore, the compounds were tested for β-haematic inhibition, and QSAR revealed an interesting linear correlation between the biological activity of CQS (NF54) and three contributing factors, namely solubility, hydrophilic surface area, and β-haematin inhibition for this series. In vivo testing of 6l showed a reduction in parasitaemia on day 4 with an activity of 38%. Copyright © 2014 Elsevier Ltd. All rights reserved.

Two new triterpenoid saponins from rhizome of Anemone amurensis.

PubMed

Lv, Chong-Ning; Fan, Li; Wang, Jing; Qin, Ru-Lan; Xu, Tan-Ye; Lei, Tian-Li; Lu, Jin-Cai

2015-01-01

Two new triterpenoid saponins were isolated from the 70% ethanol extract of the rhizome of Anemone amurensis, they are oleanolic acid 28-O-β-d-glucopyranosyl-(1 → 3)-α-l-rhamnopyranosyl-(1 → 4)-β-d-glucopyranosyl-(1 → 6)-β-d-glucopyranosyl ester (1) and 23,27-dihydroxy oleanolic acid 3-O-α-l-arabinopyranoside (2). The structures of 1 and 2 were elucidated on the basis of chemical and spectral analysis, including 1D and 2D NMR data and HR-ESI-MS. Compounds 1 and 2 were tested for cytotoxicities against three human cancer cell lines (A549, Hep-G2, and MCF-7). Compound 1 showed potent cytotoxicity with IC50 values of 34.76, 41.17, and 28.92 μM, respectively, while compound 2 with IC50>100 μM.

Evaluation of African medicinal plants for their in vitro trypanocidal activity.

PubMed

Freiburghaus, F; Kaminsky, R; Nkunya, M H; Brun, R

1996-12-01

Petroleum ether, dichloromethane, methanol and water extracts from 24 plants, belonging to 19 families, which are reported in the literature as traditional remedies for sleeping sickness (human African trypanosomiasis) were screened for in vitro activity against Trypanosoma brucei rhodesiense, as well as fro cytotoxicity for a human fibroblast cell-line (WI-38). The trypanocidal activity of the natural compounds berberine and harmane, both documented as being trypanocidal, was also evaluated. Promising trypanocidal activity with IC50 values below 10 micrograms/ml was found in 32 extracts of 13 plant species. The most active extracts with IC50 below 1 microgram/ml were derived from Annona senegalensis, Bussea occidentalis and Physalis angulata. The plant extracts showed a modest selectivity index, in contrast to commercially available trypanocides which have a more distinct selective toxicity against trypanosomes.

Development of a novel class of B-RafV600E-selective inhibitors through virtual screening and hierarchical hit optimization

PubMed Central

Kong, Xiangqian; Qin, Jie; Li, Zeng; Vultur, Adina; Tong, Linjiang; Feng, Enguang; Rajan, Geena; Liu, Shien; Lu, Junyan; Liang, Zhongjie; Zheng, Mingyue; Zhu, Weiliang; Jiang, Hualiang; Herlyn, Meenhard; Liu, Hong; Marmorstein, Ronen; Luo, Cheng

2012-01-01

Oncogenic mutations in critical nodes of cellular signaling pathways have been associated with tumorigenesis and progression. The B-Raf protein kinase, a key hub in the canonical MAPK signaling cascade, is mutated in a broad range of human cancers and especially in malignant melanoma. The most prevalent B-RafV600E mutant exhibits elevated kinase activity and results in constitutive activation of the MAPK pathway, thus making it a promising drug target for cancer therapy. Herein, we described the development of novel B-RafV600E selective inhibitors via multi-step virtual screening and hierarchical hit optimization. Nine hit compounds with low micromolar IC50 values were identified as B-RafV600E inhibitors through virtual screening. Subsequent scaffold-based analogue searching and medicinal chemistry efforts significantly improved both the inhibitor potency and oncogene selectivity. In particular, compounds 22f and 22q possess nanomolar IC50 values with selectivity for B-RafV600E in vitro and exclusive cytotoxicity against B-RafV600E harboring cancer cells. PMID:22875039

Chemical constituents and antioxidant and biological activities of the essential oil from leaves of Solanum spirale.

PubMed

Keawsa-ard, Sukanya; Liawruangrath, Boonsom; Liawruangrath, Saisunee; Teerawutgulrag, Aphiwat; Pyne, Stephen G

2012-07-01

The essential oil of the leaves Solanium spirale Roxb. was isolated by hydrodistillation and analyzed for the first time using GC and GC-MS. Thirty-nine constituents were identified, constituting 73.36% of the total chromatographical oil components. (E)-Phytol (48.10%), n-hexadecanoic acid (7.34%), beta-selinene (3.67%), alpha-selinene (2.74%), octadecanoic acid (2.12%) and hexahydrofarnesyl acetone (2.00%) were the major components of this oil. The antioxidant activity of the essential oil was evaluated by using the DPPH (1,1-diphenyl-2-picrylhydrazyl) radical scavenging assay. The oil exhibited week antioxidant activity with an IC50 of 41.89 mg/mL. The essential oil showed significant antibacterial activity against both Gram-negative Escherichia coli and Gram-positive Staphylococcus aureus with MIC values of 43.0 microg/mL and 21.5 microg/mL, respectively. It also showed significant cytotoxicity against KB (oral cancer), MCF-7 (breast cancer) and NCI-H187 (small cell lung cancer) with the IC50 values of 26.42, 19.69, and 24.02 microg/mL, respectively.

Antiparasitic activity of natural and semi-synthetic tirucallane triterpenoids from Schinus terebinthifolius (Anacardiaceae): structure/activity relationships.

PubMed

Morais, Thiago R; da Costa-Silva, Thais A; Tempone, Andre G; Borborema, Samanta Etel T; Scotti, Marcus T; de Sousa, Raquel Maria F; Araujo, Ana Carolina C; de Oliveira, Alberto; de Morais, Sérgio Antônio L; Sartorelli, Patricia; Lago, João Henrique G

2014-05-05

Leishmaniasis and Chagas are diseases caused by parasitic protozoans that affect the poorest population in the World, causing a high mortality and morbidity. As a result of highly toxic and long-term treatments, the discovery of novel, safe and more efficacious drugs is essential. In this work, the in vitro antiparasitic activity and mammalian cytotoxicity of three natural tirucallane triterpenoids, isolated from leaves of Schinus terebinthifolius (Anacardiaceae), and nine semi-synthetic derivatives were investigated against Leishmania (L.) infantum and Trypanosoma cruzi. Trypomastigotes of T. cruzi were the most susceptible parasites and seven compounds demonstrated a trypanocidal activity with IC50 values in the range between 15 and 58 µg/mL. Four compounds demonstrated selectivity towards the intracellular amastigotes of Leishmania, with IC50 values in the range between 28 and 97 µg/mL. The complete characterization of triterpenoids was afforded after thorough analysis of nuclear magnetic resonance (NMR) data as well as electrospray ionization mass spectrometry (ESI-MS). Additionally, structure-activity relationships were performed using Decision Trees.

Anti-viral and cytotoxic norbisabolane sesquiterpenoid glycosides from Phyllanthus emblica and their absolute configurations.

PubMed

Lv, Jun-Jiang; Yu, Shan; Xin, Ying; Cheng, Rong-Rong; Zhu, Hong-Tao; Wang, Dong; Yang, Chong-Ren; Xu, Min; Zhang, Ying-Jun

2015-09-01

In an effort to identify anti-viral and cytotoxic compounds from Phyllanthus spp., 14 highly oxygenated norbisabolane sesquiterpenoids, phyllaemblicins H1-H14, were isolated from the roots of Phyllanthus emblica Linn, along with phyllaemblicins B and C and glochicoccinoside D. Their structures were determined on the basis of detailed spectroscopic analysis and chemical methods. Determination of absolute configurations of these compounds was facilitated by theoretical calculations of electronic circular dichroism (ECD) spectra using time-dependent density functional theory (TDDFT) for the aglycone components, and pre-column derivative/chiral HPLC analysis for the monosaccharides. The known glochicoccinoside D displayed potent activity against influenza A virus strain H3N2 and hand, foot and mouth virus EV71, with IC50 values of 4.5±0.6 and 2.6±0.7 μg/ml, respectively. Phyllaemblicin H1 showed moderate cytotoxicity against human cancer cell lines A-549 and SMMC-7721, with IC50 values of 4.7±0.7 and 9.9±1.3 μM, respectively. Copyright © 2015 Elsevier Ltd. All rights reserved.

Synthesis of novel amides based on acridone scaffold with interesting antineoplastic activity.

PubMed

Mahajan, Anand A; Rane, Rajesh A; Amritkar, Anish A; Naphade, Shital S; Miniyar, Pankaj B; Bangalore, Pavan Kumar; Karpoormath, Rajshekhar

2015-01-01

In search of novel cytotoxic agents based on acridone scaffold, twenty five derivatives of acridone-2- carboxamide were synthesized and evaluated against a panel of eleven cancer cell lines by using MTT assay. Amides, A5 and A8 (IC50 = 0.3 µM) exhibited good cytotoxicity against MCF7. Compound A22 (IC50 = 4.3 µM) was found to be selectively cytotoxic against cancer cell line MCF7 and KB403. Particularly, promising cytotoxic activities were shown by amides A6 (IC50 = 0.7 µM), A16 (IC50 = 6.3 µM), A8 (IC50 = 0.9 µM ), A21 (IC50 = 1.3 µM), A5 (IC50 = 2.9 µM), A8 (IC50 = 2.8 µM), A14 (IC50 = 0.8 µM), A9 (IC50 = 0.8 µM) and A8 (IC50 = 0.4 µM) against cell lines; PA1, WRL68, CaCO2, TK-10, K-562, PC-3, HOP-92, ECV-304 and UACC-257, respectively. The favorable cytotoxic profile and non-toxicity towards normal human cells displayed by the derivative revealed their potential for further anticancer drug developments.

Virucidal activity of Colombian Lippia essential oils on dengue virus replication in vitro.

PubMed

Ocazionez, Raquel Elvira; Meneses, Rocio; Torres, Flor Angela; Stashenko, Elena

2010-05-01

The inhibitory effect of Lippia alba and Lippia citriodora essential oils on dengue virus serotypes replication in vitro was investigated. The cytotoxicity (CC50) was evaluated by the MTT assay and the mode of viral inhibitory effect was investigated with a plaque reduction assay. The virus was treated with the essential oil for 2 h at 37 masculineC before cell adsorption and experiments were conducted to evaluate inhibition of untreated-virus replication in the presence of oil. Antiviral activity was defined as the concentration of essential oil that caused 50% reduction of the virus plaque number (IC50). L. alba oil resulted in less cytotoxicity than L. citriodora oil (CC50: 139.5 vs. 57.6 microg/mL). Virus plaque reduction for all four dengue serotypes was observed by treatment of the virus before adsorption on cell. The IC50 values for L. alba oil were between 0.4-32.6 microg/mL and between 1.9-33.7 microg/mL for L. citriodora oil. No viral inhibitory effect was observed by addition of the essential oil after virus adsorption. The inhibitory effect of the essential oil seems to cause direct virus inactivation before adsorption on host cell.

Anti-inflammatory and cytotoxic neoflavonoids and benzofurans from Pterocarpus santalinus.

PubMed

Wu, Shou-Fang; Chang, Fang-Rong; Wang, Sheng-Yang; Hwang, Tsong-Long; Lee, Chia-Lin; Chen, Shu-Li; Wu, Chin-Chung; Wu, Yang-Chang

2011-05-27

Five new benzofurans, pterolinuses A-E (1-5), six new neoflavonoids, pterolinuses F-J (8-13), and five known compounds (6, 7, 14-16) were isolated from an extract of Pterocarpus santalinus heartwood. All new structures were elucidated by spectroscopic methods, and configurations were confirmed by CD spectral data and optical rotation values. The isolates were evaluated for anti-inflammatory and cytotoxic activities. Six compounds (1, 2, 4, 6, 7, and 15) showed significant inhibition in at least one anti-inflammatory assay. Compound 2 showed the best selective effect against superoxide anion generation in human neutrophils with, an IC50 value of 0.19 μg/mL, and was 6.2-fold more potent than the positive control LY294002. Compound 14 showed the highest cytotoxicity against Ca9-22 cancer cells, with an IC50 value of 0.46 μg/mL.

Chaetoglobosins from Chaetomium globosum, an endophytic fungus in Ginkgo biloba, and their phytotoxic and cytotoxic activities.

PubMed

Li, He; Xiao, Jian; Gao, Yu-Qi; Tang, Jiang Jiang; Zhang, An-Ling; Gao, Jin-Ming

2014-04-30

In preceding studies, cultivation of Chaetomium globosum, an endophytic fungus in Ginkgo biloba, produced five cytochalasan mycotoxins, chaetoglobosins A, G, V, Vb, and C (1-5), in three media. In the present work, five known chaetoglobosins, C, E, F, Fex, and 20-dihydrochaetoglobosin A (5-9), together with the four known compounds (11-14), were isolated from the MeOH extracts of the solid culture of the same endophyte. The structures of these metabolites were elucidated on the basis of spectroscopic analysis. Treatment of chaetoglobosin F (7) with (diethylamino)sulfur trifluoride (DAST) in dichloromethane afforded an unexpected fluorinated chaetoglobosin, named chaetoglobosin Fa (10), containing an oxolane ring between C-20 and C-23. The phytotoxic effects of compounds 1, 3-8, and 10 were assayed on radish seedlings; some of these compounds (1, 3, and 6-8) significantly inhibited the growth of radish (Raphanus sativus) seedlings with inhibitory rates of >60% at a concentration of 50 ppm, which was comparable or superior to the positive control, glyphosate. In addition, the cytotoxic activities against HCT116 human colon cancer cells were also tested, and compounds 1 and 8-10 showed remarkable cytotoxicity with IC50 values ranging from 3.15 to 8.44 μM, in comparison to the positive drug etoposide (IC50 = 2.13 μM). The epoxide ring between C-6 and C-7 or the double bond at C-6(12) led to a drastically increased cytotoxicity, and chaetoglobosin Fa (10) displayed a markedly increased cytotoxicity but decreased phytotoxicity.

[Chemical constituents from endophyte Chaetomium globosum in Imperata cylindrical].

PubMed

Shen, Li; Zhu, Li; Wei, Zhong-qi; Li, Xiao-wen; Li, Ming; Song, Yong-chun

2015-12-01

Isolation and purification of chemical constituents from solid culture of endophyte Chaetomium globosum in Imperata cylindrical was performed through silica gel column chromatography, gel filtration over Sephadex LH-20 and preparative HPLC. Nine compounds were obtained and their structures were determined as chaetoglobosin F(1), chaetoglobosin Fex(2), chaetoglobosin E(3) cytoglobosin A(4), penochalasin C(S), isochaetoglobosin D (6), N-benzoylphenylalaninyl-N-benzoyphenylalaninate(7), uracil(8) and 5-methyluracil(9), respectively, based on HR-MS and NMR data and comparison with literatures. Compound 7 was isolated from Chaeeomium sp. for the first time. In vitro cytotoxicity of compounds was evaluated using MTT mothed and 1,3,4 and 5 showed inhibition activity to the human cervical carcinoma cell HeLa with IC50 values of 99.43, 23.77, 97.92, 86.25 micromol x L(-1), while positive cotolocisnin Ad apno1ch alse IC50 24.33 micromol x L(-1).

Chemical constituents from rhizome of Anemone amurensis.

PubMed

Lv, Chong-Ning; Li, Yan-Jiao; Wang, Jing; Qin, Ru-Lan; Lei, Tian-Li; Lu, Jin-Cai

2016-07-01

Phytochemical investigation of the 70% EtOH extract of the rhizome of Anemone amurensis led to the isolation of two new oleanane-type triterpenoid saponins 1 and 2. Their structures were elucidated on the basis of chemical and spectral analysis, including 1D, 2D NMR data, and HR-ESI-MS. Compounds 1 and 2 were tested for cytotoxicities against two human cancer cell lines (A549 and Hep-G2). Compound 2 showed potent cytotoxicity with IC50 values of 38.53 and 66.17 μM, respectively, while compound 1 with IC50 > 100 μM.

Bond-based bilinear indices for computational discovery of novel trypanosomicidal drug-like compounds through virtual screening.

PubMed

Castillo-Garit, Juan Alberto; del Toro-Cortés, Oremia; Vega, Maria C; Rolón, Miriam; Rojas de Arias, Antonieta; Casañola-Martin, Gerardo M; Escario, José A; Gómez-Barrio, Alicia; Marrero-Ponce, Yovani; Torrens, Francisco; Abad, Concepción

2015-01-01

Two-dimensional bond-based bilinear indices and linear discriminant analysis are used in this report to perform a quantitative structure-activity relationship study to identify new trypanosomicidal compounds. A data set of 440 organic chemicals, 143 with antitrypanosomal activity and 297 having other clinical uses, is used to develop the theoretical models. Two discriminant models, computed using bond-based bilinear indices, are developed and both show accuracies higher than 86% for training and test sets. The stochastic model correctly indentifies nine out of eleven compounds of a set of organic chemicals obtained from our synthetic collaborators. The in vitro antitrypanosomal activity of this set against epimastigote forms of Trypanosoma cruzi is assayed. Both models show a good agreement between theoretical predictions and experimental results. Three compounds showed IC50 values for epimastigote elimination (AE) lower than 50 μM, while for the benznidazole the IC50 = 54.7 μM which was used as reference compound. The value of IC50 for cytotoxicity of these compounds is at least 5 times greater than their value of IC50 for AE. Finally, we can say that, the present algorithm constitutes a step forward in the search for efficient ways of discovering new antitrypanosomal compounds. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Synthesis, molecular properties prediction and cytotoxic screening of 3-(2-aryl-2-oxoethyl)isobenzofuran-1(3H)-ones.

PubMed

da Silva Maia, Angélica Faleiros; Siqueira, Raoni Pais; de Oliveira, Fabrício Marques; Ferreira, Joana Gasperazzo; da Silva, Silma Francielle; Caiuby, Clarice Alves Dale; de Oliveira, Leandro Licursi; de Paula, Sérgio Oliveira; Souza, Rafael Aparecido Carvalho; Guilardi, Silvana; Bressan, Gustavo Costa; Teixeira, Róbson Ricardo

2016-06-15

In the present investigation, a collection of nineteen 3-(2-aryl-2-oxoethyl)isobenzofuran-1(3H)-ones was synthesized and screened for their cytotoxic activity against a panel of three leukemia cancer cell lines. The compounds were prepared via ZrOCl2·8H2O catalyzed condensation reactions between phthalaldehydic acid and different acetophenones. The reactions were carried out free of solvent and the isobenzofuran-1(3H)-ones were obtained in good yields (80-92%). The identities of the synthesized compounds were confirmed upon IR and NMR ((1)H and (13)C) spectroscopy as well as high resolution mass spectrometry analyses. Structures of compounds 1, 4 and 16 were also investigated by X-ray analysis. The synthesized compounds were submitted to in vitro bioassays against HL-60, K562 and NALM6 cancer cell lines using MTT cytotoxicity assay. After 48h of treatment, twelve derivatives were able to reduce cell viability and presented IC50 values equal to or below 20μmolL(-1) against at least one of the evaluated lineages. The most active compound corresponded to 3-(3-methylphenyl-2-oxoethyl)isobenzofuran-1(3H)-one (18) (IC50 values obtained for HL-60, K562 and NALM6 were, respectively, 13.5μmolL(-1), 8.83μmolL(-1), and 5.24μmolL(-1)). In addition, compound 18 was capable of triggering apoptosis on NALM6 cells. All isobenzofuranones herein evaluated did not present cytotoxicity on peripheral blood mononuclear cells (PBMC), suggesting selective cytotoxic effect on leukemic cells. A computational study allowed prediction of pharmacokinetics and drug-likeness properties of the synthesized compounds. DFT calculations were performed to obtain the energy values of HOMO, LUMO, and dipole moments of isobenzofuranones. Copyright © 2016 Elsevier Ltd. All rights reserved.

A new isobenzofuranone from the mangrove endophytic fungus Penicillium sp. (ZH58).

PubMed

Yang, Jianxiang; Huang, Riming; Qiu, Sheng Xiang; She, Zhigang; Lin, Yongcheng

2013-10-01

A new isobenzofuranone, 4-(methoxymethyl)-7-methoxy-6-methyl-1(3H)-isobenzofuranone (1), together with seven known compounds, dilation (2), lumichrome (3), curvulari (4), 5,5'-oxy-dimethylene-bis(2-furaldehyde) (5), chromone (6), harman(1-methyl-β-carboline) (7), N9-methyl-1methyl-β-carboline (8), was isolated from the mangrove endophytic fungus, Penicillium sp. ZH58 obtained from the South China Sea coast. Their structures were determined by analysis of spectroscopic data. Compound 1 exhibited cytotoxicity against KB and KBV200 cells with IC50 values of 6 and 10 μg/mL, respectively.

Corchorus olitorius (jute) extract induced cytotoxicity and genotoxicity on human multiple myeloma cells (ARH-77).

PubMed

İşeri, Özlem Darcansoy; Yurtcu, Erkan; Sahin, Feride Iffet; Haberal, Mehmet

2013-06-01

Corchorus olitorius L. (Malvaceae) has industrial importance in world jute production and is a widely cultivated and consumed crop in Cyprus and in some Arabic countries. The present study investigated cytotoxic and genotoxic effects of leaf extracts (LE) and seed extracts (SE) of the C. olitorius on the multiple myeloma-derived ARH-77 cells. The extracts were also evaluated for their total phenol content (TPC) and free radical scavenging activity (FRSA). C. olitorius was collected from Nicosia, Cyprus. TPC and FRSA were measured by Folin-Ciocalteu and DPPH free radical methods, respectively. Cytotoxicity was evaluated by the MTT assay (4-2048 µg/mL range), and DNA damage (at IC50 and ½IC50) was measured by the comet assay. The LE had significantly higher total phenol (78 mg GAE/g extract) than the SE (2 mg GAE/g extract) with significantly higher FRSA (IC50 LE: 23 µg/mL and IC50 SE: 10 401 µg/mL). Both LE and SE exerted cytotoxic effects on cells after 48 h. The IC50 of SE (17 µg/mL) was lower than LE (151 µg/mL), which demonstrates its higher cytotoxicity on cells. The extracts were applied at 150 and 75 µg/mL for LE and at 17 and 8.5 µg/mL for SE, and the results of the comet assay revealed that the extracts induced genotoxic damage on ARH-77 cells. In both 48 h leaf and seed extract treatments, genotoxic damage significantly increased with increasing concentrations at relevant cytotoxic concentrations. To our knowledge, this is the first report demonstrating the high cytotoxic potential of C. olitorius SE and the genotoxic potential of LE and SE.

In Vitro Synergism of Trifluorothymidine and Ganciclovir against HSV-1

PubMed Central

Hobden, Jeffery A.; Kumar, Manish; Kaufman, Herbert E.; Clement, Christian; Varnell, Emily D.; Bhattacharjee, Partha S.

2011-01-01

Purpose. To determine whether trifluorothymidine (TFT) and ganciclovir (GCV) are synergistic against herpes simplex virus type 1 (HSV-1). Methods. TFT and GCV activity against 12 strains of HSV-1 (including an acyclovir-resistant strain) was measured by plaque-forming unit (PFU) inhibition. Cellular toxicity was assessed with an MTT dye reduction assay. Synergism was determined by calculating fractional inhibitory concentration (FIC indices) based on PFU reduction. Results. Concentrations of TFT resulting in 50% inhibition of PFUs (IC50) of acyclovir-susceptible HSV-1 strains ranged from 3.07 ± 0.36 to 12.52 ± 0.61 μM. GCV IC50 values ranged from 0.40 ± 0.02 to 1.59 ± 0.14 μM. IC50 values of TFT and GCV against the acyclovir-resistant strain were 15.40 ± 3.17 and 93.00 ± 9.64 μM, respectively. Concentrations of TFT or GCV resulting in 50% cell cytotoxicity (CC50) were 0.99 ± 0.01 and 92.91 ± 8.92 μM, respectively. TFT and GCV combined (10:1) were 10 times more potent against all acyclovir-susceptible HSV-1 strains. For 8 of 12 HSV-1 strains, the IC50 of TFT and GCV combined was lower than the CC50 of either drug. For acyclovir-susceptible HSV-1 strains, TFT and GCV combined generated a FIC index of <0.5, suggesting strong synergism between the two drugs. The FIC value for TFT and GCV combined against the acyclovir-resistant HSV-1 strain was 0.84, indicating nonantagonism. Conclusions. TFT and GCV are synergistic against acyclovir-susceptible HSV-1 at concentrations significantly less toxic than if each antiviral were used as a sole agent. PMID:20861476

Design, Synthesis, and Biological Evaluation of 4-Phenoxyquinoline Derivatives Containing Benzo[d]thiazole-2-yl Urea as c-Met Kinase Inhibitors.

PubMed

Lei, Hongrui; Hu, Gang; Wang, Yu; Han, Pei; Liu, Zijian; Zhao, Yanfang; Gong, Ping

2016-08-01

A series of novel 4-phenoxyquinoline derivatives containing the benzo[d]thiazole-2-yl urea moiety were synthesized and evaluated for their cytotoxicity against the HT-29, MKN-45, and H460 cell lines. The structures of the target compounds were confirmed by (1) H NMR and MS spectra. Most of them showed moderate to excellent potency against the three tested cell lines. Especially, compound 23 was identified a promising agent (c-Met IC50  = 17.6 nM), showing the most potent anticancer activities with IC50 values of 0.18, 0.06, and 0.01 µM against the HT-29, MKN-45, and H460 cell lines, respectively. The docking results of 23 with the c-Met kinase model 3LQ8 showed a specific binding mode between the ligand and the target protein. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Discovery and Structure–Activity Relationship of Novel 2,3-Dihydrobenzofuran-7-carboxamide and 2,3-Dihydrobenzofuran-3(2H)-one-7-carboxamide Derivatives as Poly(ADP-ribose)polymerase-1 Inhibitors

PubMed Central

2015-01-01

Novel substituted 2,3-dihydrobenzofuran-7-carboxamide (DHBF-7-carboxamide) and 2,3-dihydrobenzofuran-3(2H)-one-7-carboxamide (DHBF-3-one-7-carboxamide) derivatives were synthesized and evaluated as inhibitors of poly(ADP-ribose)polymerase-1 (PARP-1). A structure-based design strategy resulted in lead compound 3 (DHBF-7-carboxamide; IC50 = 9.45 μM). To facilitate synthetically feasible derivatives, an alternative core was designed, DHBF-3-one-7-carboxamide (36, IC50 = 16.2 μM). The electrophilic 2-position of this scaffold was accessible for extended modifications. Substituted benzylidene derivatives at the 2-position were found to be the most potent, with 3′,4′-dihydroxybenzylidene 58 (IC50 = 0.531 μM) showing a 30-fold improvement in potency. Various heterocycles attached at the 4′-hydroxyl/4′-amino of the benzylidene moiety resulted in significant improvement in inhibition of PARP-1 activity (e.g., compounds 66–68, 70, 72, and 73; IC50 values from 0.718 to 0.079 μM). Compound 66 showed selective cytotoxicity in BRCA2-deficient DT40 cells. Crystal structures of three inhibitors (compounds (−)-13c, 59, and 65) bound to a multidomain PARP-1 structure were obtained, providing insights into further development of these inhibitors. PMID:24922587

Oleanane-type saponins from Anemone taipaiensis and their cytotoxic activities.

PubMed

Wang, Xiaoyang; Zhang, Wei; Gao, Kai; Lu, Yunyang; Tang, Haifeng; Sun, Xiaoli

2013-09-01

Phytochemical investigation of the n-BuOH extract of the rhizomes of Anemone taipaiensis led to the isolation of three new oleanane-type triterpenoid saponins (1-3), together with four known saponins (4-7). Their structures were elucidated on the basis of spectroscopic analysis and chemical derivatization. All the compounds were isolated for the first time from A. taipaiensis. The cytotoxicity of these compounds was evaluated in five human cancer cell lines including A549 (lung carcinoma), HeLa (cervical carcinoma), HepG2 (hepatocellular carcinoma), HL-60 (promyelocytic leukemia), and U87MG (glioblastoma). The monodesmosidic saponin 4 exhibited cytotoxic activity toward all cancer cell lines, with IC50 values ranging from 6.42 to 18.16 μM. In addition, the bisdesmosidic saponins 1 and 7 showed selective cytotoxicity against the U87MG cells. Copyright © 2013 Elsevier B.V. All rights reserved.

Phytotoxic activity of bibenzyl derivatives from the orchid Epidendrum rigidum.

PubMed

Hernández-Romero, Yanet; Acevedo, Laura; Sánchez, María de los Angeles; Shier, W Thomas; Abbas, Hamed K; Mata, Rachel

2005-08-10

A whole plant chloroform-methanol extract of the orchid Epidendrum rigidum inhibited radicle growth of Amaranthus hypochondriacus seedlings (IC50 = 300 microg/mL). Bioassay-guided fractionation furnished four phytotoxins, namely, gigantol (1), batatasin III (2), 2,3-dimethoxy-9,10-dihydrophenathrene-4,7-diol (9), and 3,4,9-trimethoxyphenanthrene-2,5-diol (11), along with the known flavonoids apigenin, vitexin, and isovetin and the triterterpenoids 24,24-dimethyl-9,19-cyclolanostane-25-en-3beta-ol (14) and 24-methyl-9,19-cyclolanostane-25-en-3beta-ol (15). Stilbenoids 1, 2, 9, and 11 inhibited radicle growth of A. hypochondriacus with IC50 values of 0.65, 0.1, 0.12, and 5.9 microM, respectively. Foliar application of gigantol (1) at 1 microM to 4 week old seedlings of A. hypochondriacus reduced shoot elongation by 69% and fresh weight accumulation by 54%. Bibenzyls 1 and 2, as well as synthetic analogues 4'-hydroxy-3,3',5-trimethoxybibenzyl (3), 3,3',4',5-tetramethoxybibenzyl (4), 3,4'-dihydroxy-5-methoxybibenzyl (5), 3'-O-methylbatatasin III (6), 3,3',5-trihydroxybibenzyl (7), and 3,4',5-trihydroxybibenzyl (8), were tested for phytotoxicity in axenic cultures of the small aquatic plant Lemna pausicostata. All bibenzyls derivatives except 7 and 8 inhibited growth and increased cellular leakage with IC50 values of 89.9-180 and 89.9-166 microM, respectively. The natural and synthetic bibenzyls showed marginal cytotoxicity on animal cells. The results suggest that orchid bibenzyls may be good lead compounds for the development of novel herbicidal agents.

Identification of cellular and molecular factors determining the response of cancer cells to six ergot alkaloids.

PubMed

Mrusek, Marco; Seo, Ean-Jeong; Greten, Henry Johannes; Simon, Michael; Efferth, Thomas

2015-02-01

Ergot alkaloids are psychoactive and vasoconstricting agents of the fungus Claviceps purpurea causing poisoning such as ergotism in medieval times (St. Anthony's Fire). This class of substances also inhibits tumor growth in vitro and in vivo, though the underlying mechanisms are unclear as yet. We investigated six ergot alkaloids (agroclavine, ergosterol, ergocornin E, ergotamine, dihydroergocristine, and 1-propylagroclavine tartrate) for their cytotoxicity towards tumor cell lines of the National Cancer Institute, USA. 1-Propylagroclavine tartrate (1-PAT) revealed the strongest cytotoxicity. Out of 76 clinically established anticancer drugs, cross-resistance was found between the ergot alkaloids and 6/7 anti-hormonal drugs (=85.7 %) and 5/15 DNA-alkylating drugs (=33.3 %). The IC50 values for the six alkaloids were not correlated to well-known determinants of drug resistance, such as proliferative activity (as measured by cell doubling times, PCNA expression, and cell cycle distribution), the multidrug resistance-mediating P-glycoprotein/MDR1 and expression or mutations of oncogenes and tumor suppressor genes (EGFR, RAS, TP53). While resistance of control drugs (daunorubicin, cisplatin, erlotinib) correlated with these classical resistance mechanisms, ergot alkaloids did not. Furthermore, COMPARE and hierarchical cluster analyses were performed of mRNA microarray data to identify genes correlating with sensitivity or resistance to 1-PAT. Twenty-three genes were found with different biological functions (signal transducers, RNA metabolism, ribosome constituents, cell cycle and apoptosis regulators etc.). The expression of only 3/66 neuroreceptor genes correlated with the IC50 values for 1-PAT, suggesting that the psychoactive effects of ergot alkaloids may not play a major role for the cytotoxic activity against cancer cells. In conclusion, the cytotoxicity of ergot alkaloids is not involved in classical mechanisms of drug resistance opening the possibility to bypass resistance and to treat otherwise drug-resistant and refractory tumors. The modes of action are multifactorial, which is a typical feature of many natural compounds.

Cytotoxic diterpenoids from Jatropha curcas cv. nigroviensrugosus CY Yang Roots.

PubMed

Liu, JieQing; Yang, YuanFeng; Xia, JianJun; Li, XuYang; Li, ZhongRong; Zhou, Lin; Qiu, MingHua

2015-09-01

An investigation of phytochemicals from the roots of Jatropha curcas cv. nigroviensrugosus resulted in the isolation of twenty diterpenoids, including lathyranlactone, an unusual diterpenoid lactone possessing a 5/13/3 tricyclic skeleton, jatrocurcasenones A-E and jatrophodiones B-E, as well as 10 known analogues. All isolates were evaluated for cytotoxicity against the HL-60, SMMC-772, A-549, MCF-7 and SW480 human tumor cell lines using the MTS viability assay. Four of the known analogues showed cytotoxic activity in these cell lines, with IC50 values ranging from 2.0 to 23.0 μM. Moreover, the assessment of their cytotoxic structure-activity relationships showed the epoxy ring between C-5 and C-6 and the hydroxyl group at C-2 were the key functionalities for cytotoxicity. Copyright © 2015 Elsevier Ltd. All rights reserved.

Discovery and Evaluation of Thiazinoquinones as Anti-Protozoal Agents

PubMed Central

Lam, Cary F. C.; Pearce, A. Norrie; Tan, Shen H.; Kaiser, Marcel; Copp, Brent R.

2013-01-01

Pure compound screening has identified the dioxothiazino-quinoline-quinone ascidian metabolite ascidiathiazone A (2) to be a moderate growth inhibitor of Trypanosoma brucei rhodesiense (IC50 3.1 μM) and Plasmodium falciparum (K1 dual drug resistant strain) (IC50 3.3 μM) while exhibiting low levels of cytotoxicity (L6, IC50 167 μM). A series of C-7 amide and Δ2(3) analogues were prepared that explored the influence of lipophilicity and oxidation state on observed anti-protozoal activity and selectivity. Little variation in anti-malarial potency was observed (IC50 0.62–6.5 μM), and no correlation was apparent between anti-malarial and anti-T. brucei activity. Phenethylamide 7e and Δ2(3)-glycine analogue 8k exhibited similar anti-Pf activity to 2 but with slightly enhanced selectivity (SI 72 and 93, respectively), while Δ2(3)-phenethylamide 8e (IC50 0.67 μM, SI 78) exhibited improved potency and selectivity towards T. brucei rhodesiense compared to the natural product hit. A second series of analogues were prepared that replaced the quinoline ring of 2 with benzofuran or benzothiophene moieties. While esters 10a/10b and 15 were once again found to exhibit cytotoxicity, carboxylic acid analogues exhibited potent anti-Pf activity (IC50 0.34–0.035 μM) combined with excellent selectivity (SI 560–4000). In vivo evaluation of a furan carboxylic acid analogue against P. berghei was undertaken, demonstrating 85.7% and 47% reductions in parasitaemia with ip or oral dosing respectively. PMID:24022732

Cranberry Proanthocyanidins are Cytotoxic to Human Cancer Cells and Sensitize Platinum-Resistant Ovarian Cancer Cells to Paraplatin

PubMed Central

Singh, Ajay P.; Singh, Rakesh K.; Kim, Kyu Kwang; Satyan, K. S.; Nussbaum, Roger; Torres, Monica; Brard, Laurent; Vorsa, Nicholi

2010-01-01

Polyphenolic extracts of the principal flavonoid classes present in cranberry were screened in vitro for cytotoxicity against solid tumor cells lines, identifying two fractions composed principally of proanthocyanidins (PACs) with potential anticancer activity. Matrix-Assisted Laser Desorption/Ionization Time-Of-Flight Mass Spectrometry (MALDI-TOF-MS) analysis of the proanthocyanidins (PACs) fractions indicated the presence of A-type PACs with 1–4 linkages containing between 2–8 epicatechin units with a maximum of 1 epigallocatechin unit. PACs exhibited in vitro cytotoxicity against platinum-resistant human ovarian, neuroblastoma and prostate cancer cell lines (IC50 = 79–479 μg/mL) but were non-cytotoxic to lung fibroblast cells (IC50 > 1000 μg/ml). SKOV-3 ovarian cancer cells treated with PACs exhibited classic apoptotic changes. PACs acted synergistically with paraplatin in SKOV-3 cells. Pretreatment of SKOV-3 cells with PACs (106 μg/ ml) resulted in a significant reduction of the paraplatin IC50 value. Similarly, in a BrdU incorporation assay, co-treatment of SKOV-3 cells with PACs and paraplatin revealed reduced cell proliferation at lower concentrations than with either individually. In SKOV-3 cell cultures co-treated with PAC-1 and paraplatin, an HPLC analysis indicated differential quantitative presence of various PAC oligomers such as DP-8, -9, -11 and -14 indicating either selective binding or uptake. Cranberry proanthocyanidins exhibit cell-line specific cytotoxicity, induce apoptotic markers and augment cytotoxicity of paraplatin in platinum-resistant SKOV-3 ovarian cancer cells. PMID:19172579

Brazilian Cerrado Qualea grandiflora Mart. Leaves Exhibit Antiplasmodial and Trypanocidal Activities In vitro

PubMed Central

Cordeiro, Thuany de Moura; Borghetti, Fabian; Caldas Oliveira, Sarah C.; Bastos, Izabela Marques Dourado; de Santana, Jaime Martins; Grellier, Philippe; Charneau, Sébastien

2017-01-01

Background: The rapid spread of drug-resistant strains of protozoan parasites required the urgent need for new effective drugs. Natural products offer a variety of chemical structures, which make them a valuable source of lead compounds for the development of such new drugs. Cerrado is the second largest biome in Brazil and has the richest flora of all the world savannahs. We selected Qualea grandiflora, a plant species known for its proprieties in folk medicine and its antibacterial activity. Objective: However, its antiprotozoal activity was not yet explored. Materials and Methods: We investigated the activities of fractions from the ethyl acetate extract of Q. grandiflora leaves against human life forms of Plasmodium falciparum, Trypanosoma cruzi, and Trypanosoma brucei gambiense, and for its cytotoxicity upon the rat L6-myoblast cell line. Ten fractions were produced by ethyl acetate:hexane chromatography. Results and Conclusion: The fractions showed no cytotoxicity against L-6 cells (IC50 > 100 μg/mL) and no hemolysis propriety. Three fractions had a moderate activity against P. falciparum, anyone was active against T. cruzi but four fractions demonstrated a high activity against bloodstream forms of T. brucei gambiense (8.0< IC50 <15 μg/mL). Identification and characterization of the active compounds are currently under investigation. SUMMARY Qualea grandiflora is an endemic tree of the Brazilian Cerrado, which presents medicinal propertiesTen fractions of the ethyl acetate extract of Q. grandiflora leaves were assessed against Plasmodium falciparum, Trypanosoma Cruzi, and Trypanosoma brucei gambienseNo fraction showed relevant cytotoxicity and hemolysis activityAll the fractions presented antiplasmodial and trypanocidal activitiesThree fractions with moderate antiplasmodial activity (49< IC50 <56 μg/mL)Four fractions with high activity against bloodstream forms of T. brucei gambiense (8.0< IC50 <15 μg/mL). Abbreviations used: CQ: Chloroquine, DMSO: Dimethyl sulfoxide, HEPES: 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid, HMI: Modified Iscove's medium, IC50: Concentration inhibiting 50% of parasite growth, IC90: Concentration inhibiting 90% of parasite growth, MTT: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, RPMI: Roswell Park Memorial Institute, SD: Standard deviation, SI: Ratio of cytotoxicity to biological activity − TC50/IC50, TC50: Concentration causing 50% of cell growth inhibition, TC90: Concentration causing 90% of cell growth inhibition, TLC: Thin-layer chromatography PMID:29200731

New structure–activity relationships of chalcone inhibitors of breast cancer resistance protein: polyspecificity toward inhibition and critical substitutions against cytotoxicity

PubMed Central

Rangel, Luciana Pereira; Winter, Evelyn; Gauthier, Charlotte; Terreux, Raphaël; Chiaradia-Delatorre, Louise D; Mascarello, Alessandra; Nunes, Ricardo J; Yunes, Rosendo A; Creczynski-Pasa, Tania B; Macalou, Sira; Lorendeau, Doriane; Baubichon-Cortay, Hélène; Ferreira-Pereira, Antonio; Di Pietro, Attilio

2013-01-01

Adenosine triphosphate-binding cassette subfamily G member 2 (ABCG2) plays a major role in cancer cell multidrug resistance, which contributes to low eifficacy of chemotherapy. Chalcones were recently found to be potent and specific inhibitors, but unfortunately display a significant cytotoxicity. A cellular screening against ABCG2-mediated mitoxantrone efflux was performed here by flow cytometry on 54 chalcone derivatives from three different series with a wide panel of substituents. The identified leads, with submicromolar IC50 (half maximal inhibitory concentration) values, showed that the previously identified 2′-OH-4′,6′-dimethoxyphenyl, as A-ring, could be efficiently replaced by a 2′-naphthyl group, or a 3′,4′-methylenedioxyphenyl with lower affinity. Such a structural variability indicates 3polyspecificity of the multidrug transporter for inhibitors. At least two methoxyl groups were necessary on B-ring for optimal inhibition, but substitution at positions 3, 4, and 5 induced cytotoxicity. The presence of a large O-benzyl substituent at position 4 and a 2′-naphthyl as A-ring markedly decreased the cytotoxicity, giving a high therapeutic ratio, which constitutes a critical requirement for future in-vivo assays in animal models. PMID:24109177

Cytotoxic and apoptotic effects of bortezomib and gefitinib compared to alkylating agents on human glioblastoma cells.

PubMed

Pédeboscq, Stéphane; L'Azou, Béatrice; Passagne, Isabelle; De Giorgi, Francesca; Ichas, François; Pometan, Jean-Paul; Cambar, Jean

2008-01-01

Glioblastoma is a malignant astrocytic tumor with a median survival of about 12 months for which new therapeutic strategies are required. We therefore examined the cytotoxicity of anticancer drugs with different mechanisms of action on two human glioblastoma cell lines expressing various levels of EGFR (epidermal growth factor receptor). Apoptosis induced by these anticancer agents was evaluated by flow cytometry. The cytotoxicity of alkylating drugs followed a dose-effect curve and cytotoxicity index values were lower with carboplatin than with BCNU and temozolomide. Anti-EGFR gefitinib (10 microM) cytotoxicity on DBTRG.05-MG expressing high levels of EGFR was significantly higher than on U87-MG expressing low levels of EGFR. Carboplatin and temozolomide cytotoxicity was potentiated with the addition of gefitinib on DBTRG.05-MG. Among the anticancer agents tested, the proteasome inhibitor bortezomib was the most cytotoxic with very low IC50 on the two cell lines. Moreover, all anticancer drugs tested induced apoptosis in a concentration-dependent manner. Bortezomib proved to be a more potent inductor of apoptosis than gefitinib and alkylating agents. These results show the efficacy of bortezomib and of the association between conventional chemotherapy and gefitinib on glioblastoma cells and therefore suggest the interest of these molecules in the treatment of glioblastoma.

Antimicrobial, Cytotoxic and Antioxidant Activities and Determination of the Total Tannin Content of Bark Extracts Endopleura uchi

PubMed Central

Politi, Flávio A. S.; de Mello, João C. P.; Migliato, Ketylin F.; Nepomuceno, Andréa L. A.; Moreira, Raquel R. D.; Pietro, Rosemeire C. L. R.

2011-01-01

Endopleura uchi is a typical Amazonian tree and its bark is popularly employed in the preparation of teas against myomas, arthritis, influenza, diarrhea and cancer. In this study, the antioxidant activity, cytotoxicity and antimicrobial activity of five different extracts of the bark, selected by their total tannin content, were assessed. The potential antioxidant activity of the extracts was determined by 2.2-diphenyl-1-picrylhydrazyl radical scavenging assay and the values found were very similar among the extracts and to the standards antioxidants used in the tests. Cytotoxicity analysis in mammalian cells indicated that all the tested extracts exhibited IC50 values higher than the highest concentration used, showing that they do not present a risk when consumed under these conditions. Extract tested against five bacterial strains and one yeast strain did not show satisfactory growth inhibitory activity, and even the extracts that showed some antimicrobial activity were not effective at any dilution to determine the minimum inhibitory concentration. The results may serve as a reference for subsequent works, since such reference values described in the literature for the bark of E. uchi. PMID:21731469

Enzyme-triggered delivery of chlorambucil from conjugates based on the cell-penetrating peptide BP16.

PubMed

Soler, Marta; González-Bártulos, Marta; Figueras, Eduard; Ribas, Xavi; Costas, Miquel; Massaguer, Anna; Planas, Marta; Feliu, Lidia

2015-02-07

The undecapeptide KKLFKKILKKL-NH2 (BP16) is a non-toxic cell-penetrating peptide (CPP) that is mainly internalized into cancer cells through a clathrin dependent endocytic mechanism and localizes in late endosomes. Moreover, this CPP is able to enhance the cellular uptake of chlorambucil (CLB) improving its cytotoxicity. In this work, we further explored the cell-penetrating properties of BP16 and those of its arginine analogue BP308. We investigated the influence on the cytotoxicity and on the cellular uptake of conjugating CLB at the N- or the C-terminal end of these undecapeptides. The effect of incorporating the cathepsin B-cleavable sequence Gly-Phe-Leu-Gly in CLB-BP16 and CLB-BP308 conjugates was also evaluated. The activity of CLB was significantly improved when conjugated at the N- or the C-terminus of BP16, or at the N-terminus of BP308. While CLB alone was not active (IC50 of 73.7 to >100 μM), the resulting conjugates displayed cytotoxic activity against CAPAN-1, MCF-7, PC-3, 1BR3G and SKMEL-28 cell lines with IC50 values ranging from 8.7 to 25.5 μM. These results were consistent with the internalization properties observed for the corresponding 5(6)-carboxyfluorescein-labeled conjugates. The presence of the tetrapeptide Gly-Phe-Leu-Gly at either the N- or the C-terminus of CLB-BP16 conjugates further increased the efficacy of CLB (IC50 of 3.6 to 16.2 μM), which could be attributed to its selective release in the lysosomal compartment. Enzymatic assays with cathepsin B showed the release of CLB-Gly-OH from these sequences within a short time. Therefore, the combination of BP16 with an enzymatic cleavable sequence can be used as a drug delivery system for the effective uptake and release of drugs in cancer cells.

Linalool, a Piper aduncum essential oil component, has selective activity against Trypanosoma cruzi trypomastigote forms at 4°C.

PubMed

Villamizar, Luz Helena; Cardoso, Maria das Graças; Andrade, Juliana de; Teixeira, Maria Luisa; Soares, Maurilio José

2017-02-01

Recent studies showed that essential oils from different pepper species (Piper spp.) have promising leishmanicidal and trypanocidal activities. In search for natural compounds against Trypanosoma cruzi, different forms of the parasite were incubated for 24 h at 28ºC or 4ºC with Piper aduncum essential oil (PaEO) or its main constituents linalool and nerolidol. PaEO chemical composition was obtained by GC-MS. Drug activity assays were based on cell counting, MTT data or infection index values. The effect of PaEO on the T. cruzi cell cycle and mitochondrial membrane potential was evaluated by flow cytometry. PaEO was effective against cell-derived (IC50/24 h: 2.8 μg/mL) and metacyclic (IC50/24 h: 12.1 μg/mL) trypomastigotes, as well as intracellular amastigotes (IC50/24 h: 9 μg/mL). At 4ºC - the temperature of red blood cells (RBCs) storage in blood banks - cell-derived trypomastigotes were more sensitive to PaEO (IC50/24 h = 3.8 μg/mL) than to gentian violet (IC50/24 h = 24.7 mg/mL). Cytotoxicity assays using Vero cells (37ºC) and RBCs (4ºC) showed that PaEO has increased selectivity for cell-derived trypomastigotes. Flow cytometry analysis showed that PaEO does not affect the cell cycle of T. cruzi epimastigotes, but decreases their mitochondrial membrane potential. GC-MS data identified nerolidol and linalool as major components of PaEO, and linalool had trypanocidal effect (IC50/24 h: 306 ng/mL) at 4ºC. The trypanocidal effect of PaEO is likely due to the presence of linalool, which may represent an interesting candidate for use in the treatment of potentially contaminated RBCs bags at low temperature.

Linalool, a Piper aduncum essential oil component, has selective activity against Trypanosoma cruzi trypomastigote forms at 4°C

PubMed Central

Villamizar, Luz Helena; Cardoso, Maria das Graças; de Andrade, Juliana; Teixeira, Maria Luisa; Soares, Maurilio José

2017-01-01

BACKGROUND Recent studies showed that essential oils from different pepper species (Piper spp.) have promising leishmanicidal and trypanocidal activities. OBJECTIVES In search for natural compounds against Trypanosoma cruzi, different forms of the parasite were incubated for 24 h at 28ºC or 4ºC with Piper aduncum essential oil (PaEO) or its main constituents linalool and nerolidol. METHODS PaEO chemical composition was obtained by GC-MS. Drug activity assays were based on cell counting, MTT data or infection index values. The effect of PaEO on the T. cruzi cell cycle and mitochondrial membrane potential was evaluated by flow cytometry. FINDINGS PaEO was effective against cell-derived (IC50/24 h: 2.8 μg/mL) and metacyclic (IC50/24 h: 12.1 μg/mL) trypomastigotes, as well as intracellular amastigotes (IC50/24 h: 9 μg/mL). At 4ºC - the temperature of red blood cells (RBCs) storage in blood banks - cell-derived trypomastigotes were more sensitive to PaEO (IC50/24 h = 3.8 μg/mL) than to gentian violet (IC50/24 h = 24.7 mg/mL). Cytotoxicity assays using Vero cells (37ºC) and RBCs (4ºC) showed that PaEO has increased selectivity for cell-derived trypomastigotes. Flow cytometry analysis showed that PaEO does not affect the cell cycle of T. cruzi epimastigotes, but decreases their mitochondrial membrane potential. GC-MS data identified nerolidol and linalool as major components of PaEO, and linalool had trypanocidal effect (IC50/24 h: 306 ng/mL) at 4ºC. MAIN CONCLUSION The trypanocidal effect of PaEO is likely due to the presence of linalool, which may represent an interesting candidate for use in the treatment of potentially contaminated RBCs bags at low temperature. PMID:28177047

Poly(amido)amine (PAMAM) dendrimer-cisplatin complexes for chemotherapy of cisplatin-resistant ovarian cancer cells

NASA Astrophysics Data System (ADS)

Yellepeddi, Venkata Kashyap; Vangara, Kiran Kumar; Palakurthi, Srinath

2013-09-01

Dendrimer-cisplatin complexes were prepared using PAMAM dendrimers with terminal -NH2 and -COOH groups as well as biotin-conjugated dendrimers. Preformulation parameters of dendrimer-cisplatin complexes were studied using differential scanning calorimetry (DSC) and inductively coupled plasma-mass spectrometry (ICP-MS). Cytotoxicity and mechanism of cytotoxicity of dendrimer-cisplatin complexes was investigated in OVCAR-3, SKOV, A2780 and cisplatin-resistant CP70 human ovarian cancer cell lines. The loading of cisplatin in dendrimers was 11 % (w/w). PAMAM G4 dendrimers with amine surface groups (biotinylated and native) have shown 2.5- to 3.0-fold reduction in IC50 values in ovarian cancer cells when compared with carboxylate surface dendrimers ( p < 0.05). A correlation was observed among cytotoxicity of the complexes, cellular uptake, and platinum-DNA adduct formation. Treatment with dendrimer-cisplatin complexes resulted in a 7.0-fold increase ( p < 0.05) in expression of apoptotic genes ( Bcl2, Bax, p53) and 13.2- to 27.1-fold increase ( p < 0.05) in the activity of caspases 3, 8, and 9 in vitro. Results suggest that PAMAM dendrimers can be used as potential carrier for cisplatin chemotherapy of ovarian cancer.

One new 19-nor cucurbitane-type triterpenoid from the stems of Momordica charantia.

PubMed

Li, Yong-chao; Xu, Xin-juan; Yang, Jing; Wu, Xing-gang; Fu, Qing-yun

2016-01-01

One new 19-nor cucurbitane-type triterpenoid (3β,9β,25-trihydroxy-7β-methoxy-19-nor-cucurbita-5,23(E)-diene) (1), together with other six known cucurbitane-type triterpenoids (2-7), were isolated from the stems of Momordica charantia L. The chemical structure of 1 was elucidated by extensive 1D NMR and 2D NMR (HSQC, HMBC, COSY and ROESY), MS experiments. Using MTT assay, compound 1 exhibited weak cytotoxicity against HL-60, A-549, and SK-BR-3 cell lines with the IC50 values at 27.3, 32.7 and 26.6 μM, respectively.

Phytoconstituents with Radical Scavenging and Cytotoxic Activities from Diospyros shimbaensis

PubMed Central

Aronsson, Per; Munissi, Joan J. E.; Gruhonjic, Amra; Fitzpatrick, Paul A.; Landberg, Göran; Nyandoro, Stephen S.; Erdelyi, Mate

2016-01-01

As part of our search for natural products having antioxidant and anticancer properties, the phytochemical investigation of Diospyros shimbaensis (Ebenaceae), a plant belonging to a genus widely used in East African traditional medicine, was carried out. From its stem and root barks the new naphthoquinone 8,8′-oxo-biplumbagin (1) was isolated along with the known tetralones trans-isoshinanolone (2) and cis-isoshinanolone (3), and the naphthoquinones plumbagin (4) and 3,3′-biplumbagin (5). Compounds 2, 4, and 5 showed cytotoxicity (IC50 520–82.1 μM) against MDA-MB-231 breast cancer cells. Moderate to low cytotoxicity was observed for the hexane, dichloromethane, and methanol extracts of the root bark (IC50 16.1, 29.7 and > 100 μg/mL, respectively), and for the methanol extract of the stem bark (IC50 59.6 μg/mL). The radical scavenging activity of the isolated constituents (1–5) was evaluated on the 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assay. The applicability of the crude extracts and of the isolated constituents for controlling degenerative diseases is discussed. PMID:28933383

In vitro antiplasmodial activity, cytotoxicity and chemical profiles of sponge species of Cuban coasts.

PubMed

Mendiola, Judith; Regalado, Erik L; Díaz-García, Alexis; Thomas, Olivier P; Fernández-Calienes, Aymé; Rodríguez, Hermis; Laguna, Abilio; Valdés, Olga

2014-01-01

Aqueous and organic fractions from the crude extracts of 17 sponge species collected at Boca de Calderas, Havana, Cuba were analysed. The organic fractions of Mycale laxissima, Clathria echinata and Agelas cerebrum exhibited values of concentrations causing 50% inhibition of in vitro growth of Plasmodium berghei (IC50) of 42.3 ± 5.1, 52 ± 9.7 and 60.3 ± 10.6 μg/mL, respectively, while their selectivity indexes for fibroblast cell lines were 9.45, 4.24 and 8.7, correspondingly. These fractions reduced parasitemia of infected Balb/c mice as well. Selective cytotoxicity indexes against tumour HeLa cells focused an interest on the aqueous fraction of M. laxissima (>7.12) and organic fractions of Polymastia nigra (5.95), A. cerebrum (5.48) and Niphates erecta (>4.2). Triterpenoids/steroids and alkaloids detected in the organic fractions of M. laxissima, C. echinata and A. cerebrum should be isolated for future investigation.

Two new ortho benzoquinones from Uncaria rhynchophylla.

PubMed

Zhang, Qian; Chen, Lei; Hu, Le-Jian; Liu, Wen-Yuan; Feng, Feng; Qu, Wei

2016-03-01

The present study was designed to determine the chemical constituents of the stems and hooks of Uncaria rhynchophylla. The chemical constituents were isolated and purified from CH2Cl2 fraction by chromatography. Their structures were elucidated by spectroscopic analyses. Their cytotoxicity was tested using MTT method. Two new ortho benzoquinones, 3-diethylamino-5-methoxy-1, 2-benzoquinone (1) and 3-ethylamino-5-methoxy-1, 2-benzoquinone (2), together with a known compound isorhynchophyllic acid (3) were isolated from U. rhynchophylla. These compounds were evaluated for their cytotoxicity against cancer cells A549, HepG2 and A2780. Compounds 1 and 2 were new ortho benzoquinones and showed weak antiproliferative activities on A549, HepG2 and A2780 cells. Compound 3 significantly inhibited the proliferation of A549, HepG2 and A2780 cells with IC50 values being 5.8, 12.8 and 11.8 µmol·L(-1), respectively. Copyright © 2016 China Pharmaceutical University. Published by Elsevier B.V. All rights reserved.

Evaluation of the cytotoxic and genotoxic potential of lecithin/chitosan nanoparticles

NASA Astrophysics Data System (ADS)

Taner, Gökçe; Yeşilöz, Recep; Özkan Vardar, Deniz; Şenyiğit, Taner; Özer, Özgen; Degen, Gisela H.; Başaran, Nurşen

2014-02-01

Nanoparticles-based drug targeting delivery systems have been introduced in the treatment for various diseases because of their effective properties, although there have been conflicting results on the toxicity of nanoparticles. In the present study, the aim was to evaluate the cytotoxicity and the genotoxicity of different concentrations of lecithin/chitosan nanoparticles with and without clobetasol-17-propionate (CP) by neutral red uptake (NRU) cytotoxicity assay and single cell gel electrophoresis (Comet) and cytokinesis-blocked micronucleus assays. The IC50 values of lecithin/chitosan nanoparticles with/without CP were found as 1.9 and 1.8 %, respectively, in the NRU cytotoxicity test. High concentrations of lecithin/chitosan nanoparticles induced DNA damage in human lymphocytes as evaluated by comet assay. The micronucleus frequency was increased by the lecithin/chitosan treatment in a dose-dependent manner. Also at the two highest concentrations, a significant increase in micronucleus formation was observed. Lecithin/chitosan nanoparticles with CP did not increase the frequency of micronucleus and also did not induce additional DNA damage when compared with lecithin/chitosan nanoparticles without CP; therefore, CP itself has not found to be genotoxic at the studied concentration.

Effect of Ottoman Viper (Montivipera xanthina (Gray, 1849)) Venom on Various Cancer Cells and on Microorganisms.

PubMed

Yalcın, Husniye Tansel; Ozen, Mehmet Ozgün; Gocmen, Bayram; Nalbantsoy, Ayse

2014-01-01

Cytotoxic and antimicrobial effects of Montivipera xanthina venom against LNCaP, MCF-7, HT-29, Saos-2, Hep3B, Vero cells and antimicrobial activity against selected bacterial and fungal species: Staphylococcus aureus ATCC 25923, Escherichia coli ATCC 25922, E. coli O157H7, Enterococcus faecalis 29212, Enterococcus faecium DSM 13590, Staphylococcus epidermidis ATCC 12228, S. typhimirium CCM 5445, Proteus vulgaris ATCC 6957 and Candida albicans ATCC 10239 were studied for evaluating the potential medical benefit of this snake venom. Cytotoxicity of venom was determined using MTT assay. Snake venom cytotoxicity was expressed as the venom dose that killed 50 % of the cells (IC50). The antimicrobial activity of venom was studied by minimal inhibitory concentration (MIC) and disc diffusion assay. MIC was determined using broth dilution method. The estimated IC50 values of venom varied from 3.8 to 12.7 or from 1.9 to 7.2 μg/ml after treatment with crude venom for 24 or 48 h for LNCaP, MCF-7, HT-29 and Saos-2 cells. There was no observable cytotoxic effect on Hep3B and Vero cells. Venom exhibited the most potent activity against C. albicans (MIC, 7.8 μg/ml and minimal fungicidal concentration, 62.5 μg/ml) and S. aureus (MIC, 31.25 μg/ml). This study is the first report showing the potential of M. xanthina venom as an alternative therapeutic approach due to its cytotoxic and antimicrobial effects.

Cytotoxic and Antifungal Constituents Isolated from the Metabolites of Endophytic Fungus DO14 from Dendrobium officinale.

PubMed

Wu, Ling-Shang; Jia, Min; Chen, Ling; Zhu, Bo; Dong, Hong-Xiu; Si, Jin-Ping; Peng, Wei; Han, Ting

2015-12-22

Two novel cytotoxic and antifungal constituents, (4S,6S)-6-[(1S,2R)-1, 2-dihydroxybutyl]-4-hydroxy-4-methoxytetrahydro-2H-pyran-2-one (1), (6S,2E)-6-hydroxy-3-methoxy-5-oxodec-2-enoic acid (2), together with three known compounds, LL-P880γ (3), LL-P880α (4), and Ergosta-5,7,22-trien-3b-ol (5) were isolated from the metabolites of endophytic fungi from Dendrobium officinale. The chemical structures were determined based on spectroscopic methods. All the isolated compounds 1-5 were evaluated by cytotoxicity and antifungal effects. Our present results indicated that compounds 1-4 showed notable anti-fungal activities (minimal inhibitory concentration (MIC) ≤ 50 μg/mL) for all the tested pathogens including Candida albicans, Cryptococcus neoformans, Trichophyton rubrum, Aspergillus fumigatus. In addition, compounds 1-4 possessed notable cytotoxcities against human cancer cell lines of HL-60 cells with the IC50 values of below 100 μM. Besides, compounds 1, 2, 4 and 5 showed strong cytotoxities on the LOVO cell line with the IC50 values were lower than 100 μM. In conclusion, our study suggested that endophytic fungi of D. officinale are great potential resources to discover novel agents for preventing or treating pathogens and tumors.

Genotoxic potential of selected cytostatic drugs in human and zebrafish cells.

PubMed

Gajski, Goran; Gerić, Marko; Žegura, Bojana; Novak, Matjaž; Nunić, Jana; Bajrektarević, Džejla; Garaj-Vrhovac, Vera; Filipič, Metka

2016-08-01

Due to their increasing use, the residues of anti-neoplastic drugs have become emerging pollutants in aquatic environments. Most of them directly or indirectly interfere with the cell's genome, which classifies them into a group of particularly dangerous compounds. The aim of the present study was to conduct a comparative in vitro toxicological characterisation of three commonly used cytostatics with different mechanisms of action (5-fluorouracil [5-FU], cisplatin [CDDP] and etoposide [ET]) towards zebrafish liver (ZFL) cell line, human hepatoma (HepG2) cells and human peripheral blood lymphocytes (HPBLs). Cytotoxicity was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and acridine orange/ethidium bromide staining. All three drugs induced time- and dose-dependent decreases in cell viability. The sensitivity of ZFL and HepG2 cells towards the cytotoxicity of 5-FU was comparable (half maximal inhibitory concentration (IC50) 5.3 to 10.4 μg/mL). ZFL cells were more sensitive towards ET- (IC50 0.4 μg/mL) and HepG2 towards CDDP- (IC50 1.4 μg/mL) induced cytotoxicity. Genotoxicity was determined by comet assay and cytokinesis block micronucleus (CBMN) assay. ZFL cells were the most sensitive, and HPBLs were the least sensitive. In ZFL cells, induction of DNA strand breaks was a more sensitive genotoxicity endpoint than micronuclei (MNi) induction; the lowest effective concentration (LOEC) for DNA strand break induction was 0.001 μg/mL for ET, 0.01 μg/mL for 5-FU and 0.1 μg/mL for CDDP. In HepG2 cells, MNi induction was a more sensitive genotoxicity endpoint. The LOEC values were 0.01 μg/mL for ET, 0.1 μg/mL for 5-FU and 1 μg/mL for CDDP. The higher sensitivity of ZFL cells to cytostatic drugs raises the question of the impact of such compounds in aquatic ecosystem. Since little is known on the effect of such drugs on aquatic organisms, our results demonstrate that ZFL cells provide a relevant and sensitive tool to screen genotoxic potential of environmental pollutant in the frame of hazard assessment.

Biological Activities and Composition of Ferulago carduchorum Essential Oil

PubMed Central

Golfakhrabadi, Fereshteh; Khanavi, Mahnaz; Ostad, Seyed Nasser; Saeidnia, Soodabeh; Vatandoost, Hassan; Abai, Mohammad Reza; Hafizi, Mitra; Yousefbeyk, Fatemeh; Rad, Yaghoob Razzaghi; Baghenegadian, Ameneh; Ardekani, Mohammad Reza Shams

2015-01-01

Background: Ferulago carduchorum Boiss and Hausskn belongs to the Apiaceae family. This plant grows in west part of Iran that local people added it to dairy and oil ghee to delay expiration date and give them a pleasant taste. The aim of this study was to investigate the antioxidant, antimicrobial, acetyl cholinesterase inhibition, cytotoxic, larvicidal activities and composition of essential oil of F. carduchorum. Methods: Acetyl cholinesterase (AChE) inhibitory, larvicidal activities and chemical composition of essential oil of F. carduchorum were investigated. Besides, antioxidant, antimicrobial and cytotoxic activities of essential oil were tested using DPPH, microdilution method and MTT assay, respectively. Results: The major components of essential oil were (z)-β-ocimene (43.3%), α-pinene (18.23%) and bornyl acetate (3.98%). Among 43 identified components, monoterpenes were the most compounds (84.63%). The essential oil had noticeable efficiency against Candida albicans (MIC= 2340 μg ml−1) and it was effective against Anopheles stephensi with LC50 and LC90 values of 12.78 and 47.43 ppm, respectively. The essential oil could inhibit AChE (IC50= 23.6 μl ml−1). The essential oil showed high cytotoxicity on T47D, HEP-G2 and HT-29 cell lines (IC50< 2 μg ml−1). Conclusion: The essential oil of F. carduchorum collected from west of Iran had anti-Candida, larvicidal and cytotoxicity effects and should be further investigated in others in vitro and in vivo experimental models. PMID:26114148

Lipophilicity-dependent ruthenium N-heterocyclic carbene complexes as potential anticancer agents.

PubMed

Lv, Gaochao; Guo, Liubin; Qiu, Ling; Yang, Hui; Wang, Tengfei; Liu, Hong; Lin, Jianguo

2015-04-28

Five Ru(II)-N-heterocyclic carbenes (NHC) (1-5) were synthesized by reacting the appropriately substituted imidazolium chlorides with Ag2O, forming the NHC-silver chloride in situ followed by transmetalation with dimeric p-cymene ruthenium(II) dichloride. All the complexes were characterized by NMR and ESI-MS, and complex 1 was also characterized by single-crystal X-ray diffraction. The IC50 values of these five complexes were determined by the MTT-based assay on four human cancer cell lines, SKOV-3 (ovarian), PC-3 (prostate), MDA-MB-231 (breast) and EC109 (esophagus). The cytotoxicities of these complexes changed from a moderate effect to a fine one, corresponding to the increasing lipophilicity order of the complex of 2 < 1 < 3 < 4 < 5 (0.91, 0.88, 1.36, 1.85 and 2.62 for 1–5 respectively). Complex 5 showed the most cytotoxicity with the IC50 values 10.3 ± 0.3 μM for SKOV-3, 2.9 ± 0.1 μM for PC-3, 8.2 ± 0.6 μM for MDA-MB-231, 6.4 ± 0.2 μM for EC109 cell lines. Due to the superior cytotoxicity of complex 5 against the PC-3 cell lines, further biological evaluations were carried out to elucidate its action mechanism. The morphologic changes and cell cycle analysis showed that complex 5 can inhibit PC-3 cell lines by inducing cell cycle arrest at the G2/M phase. The DNA binding experiments further demonstrate that complex 5 has a better binding ability for DNA (Kb = 2.2 × 10(6) M(-1)) than complexes 1-4 (3.8 × 10(5), 7.0 × 10(5), 5.7 × 10(5), and 1.9 × 10(5) respectively).

Fluopsin C induces oncosis of human breast adenocarcinoma cells.

PubMed

Ma, Li-sha; Jiang, Chang-you; Cui, Min; Lu, Rong; Liu, Shan-shan; Zheng, Bei-bei; Li, Lin; Li, Xia

2013-08-01

Fluopsin C, an antibiotic isolated from Pseudomonas jinanesis, has shown antitumor effects on several cancer cell lines. In the current study, the oncotic cell death induced by fluopsin C was investigated in human breast adenocarcinoma cells in vitro. Human breast adenocarcinoma cell lines MCF-7 and MD-MBA-231 were used. The cytotoxicity was evaluated using MTT assay. Time-lapse microscopy and transmission electron microscopy were used to observe the morphological changes. Cell membrane integrity was assessed with propidium iodide (PI) uptake and lactate dehydrogenase (LDH) assay. Flow cytometry was used to measure reactive oxygen species (ROS) level and mitochondrial membrane potential (Δψm). A multimode microplate reader was used to analyze the intracellular ATP level. The changes in cytoskeletal system were investigated with Western blotting and immunostaining. Fluopsin C (0.5-8 μmol/L) reduced the cell viability in dose- and time-dependent manners. Its IC50 values in MCF-7 and MD-MBA-231 cells at 24 h were 0.9 and 1.03 μmol/L, respectively. Fluopsin C (2 μmol/L) induced oncosis in both the breast adenocarcinoma cells characterized by membrane blebbing and swelling, which was blocked by pretreatment with the pan-caspase inhibitor Z-VAD-fmk. In MCF-7 cells, fluopsin C caused PI uptake into the cells, significantly increased LDH release, induced cytoskeletal system degradation and ROS accumulation, decreased the intracellular ATP level and Δψm. Noticeably, fluopsin C exerted comparable cytotoxicity against the normal human hepatocytes (HL7702) and human mammary epithelial cells with the IC50 values at 24 h of 2.7 and 2.4 μmol/L, respectively. Oncotic cell death was involved in the anticancer effects of fluopsin C on human breast adenocarcinoma cells in vitro. The hepatoxicity of fluopsin C should not be ignored.

Synthesis and Cytotoxic Evaluation of Steroidal Copper (Cu (II)) Complexes

PubMed Central

Huang, Yanmin; Kong, Erbin; Zhan, Junyan; Chen, Shuang; Gan, Chunfang; Liu, Zhiping; Pang, Liping

2017-01-01

Using estrone and pregnenolone as starting materials, some steroidal copper complexes were synthesized by the condensation of steroidal ketones with thiosemicarbazide or diazanyl pyridine and then complexation of steroidal thiosemicarbazones or steroidal diazanyl pyridines with Cu (II). The complexes were characterized by IR, NMR, and HRMS. The synthesized compounds were screened for their cytotoxicity against HeLa, Bel-7404, and 293T cell lines in vitro. The results show that all steroidal copper (II) complexes display obvious antiproliferative activity against the tested cancer cells. The IC50 values of complexes 5 and 12 against Bel-7404 (human liver carcinoma) are 5.0 and 7.0 μM. PMID:29180937

Marine-Derived Penicillium Species as Producers of Cytotoxic Metabolites

PubMed Central

Su, Mingzhi; Song, Shao-Jiang; Jung, Jee H.

2017-01-01

Since the discovery of penicillin, Penicillium has become one of the most attractive fungal genera for the production of bioactive molecules. Marine-derived Penicillium has provided numerous excellent pharmaceutical leads over the past decades. In this review, we focused on the cytotoxic metabolites * (* Cytotoxic potency was referred to five different levels in this review, extraordinary (IC50/LD50: <1 μM or 0.5 μg/mL); significant (IC50/LD50: 1~10 μM or 0.5~5 μg/mL); moderate (IC50/LD50: 10~30 μM or 5~15 μg/mL); mild (IC50/LD50: 30~50 μM or 15~25 μg/mL); weak (IC50/LD50: 50~100 μM or 25~50 μg/mL). The comparative potencies of positive controls were referred when they were available). produced by marine-derived Penicillium species, and on their cytotoxicity mechanisms, biosyntheses, and chemical syntheses. PMID:29064452

Real-Time Cytotoxicity Assay for Rapid and Sensitive Detection of Ricin from Complex Matrices

PubMed Central

Pauly, Diana; Worbs, Sylvia; Kirchner, Sebastian; Shatohina, Olena; Dorner, Martin B.; Dorner, Brigitte G.

2012-01-01

Background In the context of a potential bioterrorist attack sensitive and fast detection of functionally active toxins such as ricin from complex matrices is necessary to be able to start timely countermeasures. One of the functional detection methods currently available for ricin is the endpoint cytotoxicity assay, which suffers from a number of technical deficits. Methodology/Findings This work describes a novel online cytotoxicity assay for the detection of active ricin and Ricinus communis agglutinin, that is based on a real-time cell electronic sensing system and impedance measurement. Characteristic growth parameters of Vero cells were monitored online and used as standardized viability control. Upon incubation with toxin the cell status and the cytotoxic effect were visualized using a characteristic cell index–time profile. For ricin, tested in concentrations of 0.06 ng/mL or above, a concentration-dependent decrease of cell index correlating with cytotoxicity was recorded between 3.5 h and 60 h. For ricin, sensitive detection was determined after 24 h, with an IC50 of 0.4 ng/mL (for agglutinin, an IC50 of 30 ng/mL was observed). Using functionally blocking antibodies, the specificity for ricin and agglutinin was shown. For detection from complex matrices, ricin was spiked into several food matrices, and an IC50 ranging from 5.6 to 200 ng/mL was observed. Additionally, the assay proved to be useful in detecting active ricin in environmental sample materials, as shown for organic fertilizer containing R. communis material. Conclusions/Significance The cell-electrode impedance measurement provides a sensitive online detection method for biologically active cytotoxins such as ricin. As the cell status is monitored online, the assay can be standardized more efficiently than previous approaches based on endpoint measurement. More importantly, the real-time cytotoxicity assay provides a fast and easy tool to detect active ricin in complex sample matrices. PMID:22532852

Synthesis, biological activity and molecular modeling study of new Schiff bases incorporated with indole moiety.

PubMed

Halawa, Ahmed H; El-Gilil, Shimaa Mohamed Abd; Bedair, Ahmed H; Shaaban, Mohamed; Frese, Marcel; Sewald, Norbert; Eliwa, Essam M; El-Agrody, Ahmed M

2017-10-26

A new series of heterocyclic Schiff bases 2-9 containing indole moiety were synthesized by facile and efficient condensation of indole-3/2/5-carboxaldehyde (1a/1b/1c) with different aromatic and heterocyclic primary amines using conventional and/or microwave irradiation methods. The structures of the obtained compounds were assigned by sophisticated spectroscopic and spectrometric techniques (1D-NMR, 2D-NMR and MS). The synthesized compounds were screened for their cytotoxicity and antibacterial activities. In vitro cytotoxicity screening revealed that compound 5 exhibited moderate activity against KB-3-1 cell line (IC50=57.7 μM) while 5-indolylimino derivative 7 indicated close to the activity (IC50=19.6 μM) in comparison with the positive control (+)-Griseofulvin (IC50=19.2 μM), while the tested compounds 5, 6b, 7 and 9 revealed good or moderate antibacterial activity. In addition, molecular docking study of Schiff bases 2-9 was performed by Molecular Operating Environment (MOE 2014.09) program on the matrix metalloproteinase-8 (MMP-8) (Protein Data Bank (PDB) ID: 1MNC) in an attempt to explore their mode of action as anticancer drugs.

Anti-proliferative effects, cell cycle G2/M phase arrest and blocking of chromosome segregation by probimane and MST-16 in human tumor cell lines

PubMed Central

Lu, Da Yong; Huang, Min; Xu, Cheng Hui; Yang, Wei Yi; Hu, Chao Xin; Lin, Li Ping; Tong, Lin Jiang; Li, Mei Hong; Lu, Wei; Zhang, Xiong Wen; Ding, Jian

2005-01-01

Background Anticancer bisdioxopiperazines, including ICRF-154, razoxane (Raz, ICRF-159) and ICRF-193, are a family of anticancer agents developed in the UK, especially targeting metastases of neoplasms. Two other bisdioxopiperazine derivatives, probimane (Pro) and MST-16, were synthesized at the Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. Cytotoxic activities and mechanisms of Raz (+)-steroisomer (ICRF-187, dexrazoxane), Pro and MST-16 against tumor cells were evaluated by MTT colorimetry, flow cytometry and karyotyping. Results Pro was cytotoxic to human tumor cell lines in vitro (IC50<50 μM for 48 h). Four human tumor cell lines (SCG-7901, K562, A549 and HL60) were susceptible to Pro at low inhibitory concentrations (IC50 values < 10 μM for 48 h). Although the IC50 against HeLa cell line of vincristine (VCR, 4.56 μM), doxorubicin (Dox, 1.12 μM) and 5-fluoruouracil (5-Fu, 0.232 μM) are lower than Pro (5.12 μM), ICRF-187 (129 μM) and MST-16 (26.4 μM), VCR, Dox and 5-Fu shows a low dose-related – high cytotoxic activity. Time-response studies showed that the cytotoxic effects of Pro are increased for 3 days in human tumor cells, whereas VCR, Dox and 5-Fu showed decreased cytotoxic action after 24 h. Cell cycle G2/M phase arrest and chromosome segregation blocking by Pro and MST-16 were noted. Although there was similar effects of Pro and MST-16 on chromosome segregation blocking action and cell cycle G2/M phase arrest at 1- 4 μM, cytotoxicity of Pro against tumor cells was higher than that of MST-16 in vitro by a factor of 3- 10 folds. Our data show that Pro may be more effective against lung cancer and leukemia while ICRF-187 and MST-16 shows similar IC50 values only against leukemia. Conclusion It suggests that Pro has a wider spectrum of cytotoxic effects against human tumor cells than other bisdioxopiperazines, especially against solid tumors, and with a single cytotoxic pathway of Pro and MST-16 affecting chromosome segregation and leading also to cell G2/ M phase arrests, which finally reduces cell division rates. Pro may be more potent than MST-16 in cytotoxicity. High dose- and time- responses of Pro, when compared with VCR, 5-Fu and Dox, were seen that suggest a selectivity of Pro against tumor growth. Compounds of bisdioxopiperazines family may keep up their cytotoxic effects longer than many other anticancer drugs. PMID:15963241

Cytotoxicity Evaluation of Essential Oil and its Component from Zingiber officinale Roscoe.

PubMed

Lee, Yongkyu

2016-07-01

Zingiber officinale Roscoe has been widely used as a folk medicine to treat various diseases, including cancer. This study aims to re-examine the therapeutic potential of co-administration of natural products and cancer chemotherapeutics. Candidate material for this project, α-zingiberene, was extracted from Zingiber officinale Roscoe, and α-zingiberene makes up 35.02 ± 0.30% of its total essential oil. α-Zingiberene showed low IC50 values, 60.6 ± 3.6, 46.2 ± 0.6, 172.0 ± 6.6, 80.3 ± 6.6 (μg/mL) in HeLa, SiHa, MCF-7 and HL-60 cells each. These values are a little bit higher than IC50 values of general essential oil in those cells. The treatment of α-zingiberene produced nucleosomal DNA fragmentation in SiHa cells, and the percentage of sub-diploid cells increased in a concentration-dependent manner in SiHa cells, hallmark features of apoptosis. Mitochondrial cytochrome c activation and an in vitro caspase-3 activity assay demonstrated that the activation of caspases accompanies the apoptotic effect of α-zingiberene, which mediates cell death. These results suggest that the apoptotic effect of α-zingiberene on SiHa cells may converge caspase-3 activation through the release of mitochondrial cytochrome c into cytoplasm. It is considered that anti-proliferative effect of α-zingiberene is a result of apoptotic effects, and α-zingiberene is worth furthermore study to develop it as cancer chemotherapeutics.

Biological Activities of the Essential Oil from Erigeron floribundus.

PubMed

Petrelli, Riccardo; Orsomando, Giuseppe; Sorci, Leonardo; Maggi, Filippo; Ranjbarian, Farahnaz; Biapa Nya, Prosper C; Petrelli, Dezemona; Vitali, Luca A; Lupidi, Giulio; Quassinti, Luana; Bramucci, Massimo; Hofer, Anders; Cappellacci, Loredana

2016-08-13

Erigeron floribundus (Asteraceae) is an herbaceous plant widely used in Cameroonian traditional medicine to treat various diseases of microbial and non-microbial origin. In the present study, we evaluated the in vitro biological activities displayed by the essential oil obtained from the aerial parts of E. floribundus, namely the antioxidant, antimicrobial and antiproliferative activities. Moreover, we investigated the inhibitory effects of E. floribundus essential oil on nicotinate mononucleotide adenylyltransferase (NadD), a promising new target for developing novel antibiotics, and Trypanosoma brucei, the protozoan parasite responsible for Human African trypanosomiasis. The essential oil composition was dominated by spathulenol (12.2%), caryophyllene oxide (12.4%) and limonene (8.8%). The E. floribundus oil showed a good activity against Staphylococcus aureus (inhibition zone diameter, IZD of 14 mm, minimum inhibitory concentration, MIC of 512 µg/mL). Interestingly, it inhibited the NadD enzyme from S. aureus (IC50 of 98 µg/mL), with no effects on mammalian orthologue enzymes. In addition, T. brucei proliferation was inhibited with IC50 values of 33.5 µg/mL with the essential oil and 5.6 µg/mL with the active component limonene. The essential oil exhibited strong cytotoxicity on HCT 116 colon carcinoma cells with an IC50 value of 14.89 µg/mL, and remarkable ferric reducing antioxidant power (tocopherol-equivalent antioxidant capacity, TEAC = 411.9 μmol·TE/g).

Cytotoxicity Evaluation of Essential Oil and its Component from Zingiber officinale Roscoe

PubMed Central

Lee, Yongkyu

2016-01-01

Zingiber officinale Roscoe has been widely used as a folk medicine to treat various diseases, including cancer. This study aims to re-examine the therapeutic potential of co-administration of natural products and cancer chemotherapeutics. Candidate material for this project, α-zingiberene, was extracted from Zingiber officinale Roscoe, and α-zingiberene makes up 35.02 ± 0.30% of its total essential oil. α-Zingiberene showed low IC50 values, 60.6 ± 3.6, 46.2 ± 0.6, 172.0 ± 6.6, 80.3 ± 6.6 (μg/mL) in HeLa, SiHa, MCF-7 and HL-60 cells each. These values are a little bit higher than IC50 values of general essential oil in those cells. The treatment of α-zingiberene produced nucleosomal DNA fragmentation in SiHa cells, and the percentage of sub-diploid cells increased in a concentration-dependent manner in SiHa cells, hallmark features of apoptosis. Mitochondrial cytochrome c activation and an in vitro caspase-3 activity assay demonstrated that the activation of caspases accompanies the apoptotic effect of α-zingiberene, which mediates cell death. These results suggest that the apoptotic effect of α-zingiberene on SiHa cells may converge caspase-3 activation through the release of mitochondrial cytochrome c into cytoplasm. It is considered that anti-proliferative effect of α-zingiberene is a result of apoptotic effects, and α-zingiberene is worth furthermore study to develop it as cancer chemotherapeutics. PMID:27437089

Cadmium-coordinated supramolecule suppresses tumor growth of T-cell leukemia in mice

PubMed Central

Zhou, Xiaoping; Koizumi, Yukio; Zhang, Muxin; Natsui, Miyuki; Koyota, Souichi; Yamada, Manabu; Kondo, Yoshihiko; Hamada, Fumio; Sugiyama, Toshihiro

2015-01-01

Cadmium is a toxic pollutant with occupational and environmental significance, due to its diverse toxic effects. Supramolecules that conjugate and decontaminate toxic metals have potential for use in treatment of cadmium intoxication. In addition, metal-coordinating ability has been postulated to contribute to the cytotoxic effects of anti-tumor agents such as cisplatin or bleomycin. Thiacalixarenes, cyclic oligomers of p-alkylphenol bridged by sulfur atoms, are supramolecules known to have potent coordinating ability to metal ions. In this study, we show that cadmium-coordinated thiacalix[4]arene tetrasulfate (TC4ATS-Cd) exhibits an anti-proliferative effect against T-cell leukemia cells. Cadmium exhibited cytotoxicity with IC50 values ranging from 36 to 129 μM against epithelia-derived cancer cell lines, while TC4ATS-Cd elicited no significant cytotoxicity (IC50 > 947 μM). However, a number of T-cell leukemia cell lines exhibited marked sensitivity to TC4ATS-Cd. In Jurkat cells, toxicity of TC4ATS-Cd occurred with an IC50 of 6.9 μM, which is comparable to that of 6.5 μM observed for cadmium alone. TC4ATS-Cd induced apoptotic cell death through activation of caspase-3 in Jurkat cells. In a xenograft model, TC4ATS-Cd (13 mg/kg) treatment significantly suppressed the tumor growth of Jurkat cells in mice. In addition, TC4ATS-Cd-treated mice exhibited significantly less cadmium accumulation in liver and kidney compared to equimolar cadmium-treated mice. These results suggest that cadmium-coordinated supramolecules may have therapeutic potential for treatment of T-cell leukemia. PMID:25735932

Synthesis, characterization and biological evaluation of ruthenium flavanol complexes against breast cancer

NASA Astrophysics Data System (ADS)

Singh, Ashok Kumar; Saxena, Gunjan; Sahabjada; Arshad, M.

2017-06-01

Four Ru(II) DMSO complexes (M1R-M4R) having substituted flavones viz. 3-Hydroxy-2-(4-methoxyphenyl)-4H-chromen-4-one (HL1), 3-Hydroxy-2-(4-nitrophenyl)-4H-chromen-4-one (HL2), 3-Hydroxy-2-(4-dimethylaminophenyl)-4H-chromen-4-one (HL3) and 3-Hydroxy-2-(4-chlorophenyl)-4H-chromen-4-one (HL4) were synthesized and characterized by elemental analysis, IR, UV-Vis, 1H NMR spectroscopies and ESI-MS. The molecular structures of the complexes were investigated by integrated spectroscopic and computational techniques (DFT). Both ligands as well as their complexes were screened for anticancer activities against breast cancer cell lines MCF-7. Cytotoxicity was assayed by MTT [3-(4, 5-dimethyl thiazol-2-yl)-2, 5-diphenyl tetrazolium bromide] assay. All ligands and their complexes exhibited significant cytotoxic potential of 5-40 μM concentration at incubation period of 24 h. The cell cytotoxicity increased significantly in a concentration-dependent manner. In this series of compounds, HL2 (IC50 17.2 μM) and its complex M2R (IC50 16 μM) induced the highest cytotoxicity.

[Cytotoxicity of the secondary metabolites of Marine Mangrove Fungus Paecilomyces sp. tree 1-7 on human hepatoma cell line HepG2].

PubMed

Cai, Xiao-Ling; Gao, Jun-Ping; Li, Qing; Wen, Lu; She, Zhi-Gang; Lin, Yong-Cheng

2008-06-01

To study the cytotoxicity of the secondary metabolites of Marine Mangrove Fungus Paecilomyces sp. Tree 1-7 on human hepatoma cell line HepG2 cultured in vitro. Three groups were divided: compounds group, 5-Fu group and control group. The cytotoxicity was measured by MTT method when HepG2 cells were treated by different concentration of the secondary metabolites of Paecilomyces sp. Tree 1-7. Secalonic acid A, tenellic acid A and alternin inhibited the growth of human hepatoma cell line HepG2, the IC50 separately were 2.0, 62.1 and 7.0 microg/ml. Secalonic acid A and alternin have strong cytotoxicity on HepG2 cultured in vitro.

Gold catalyzed double condensation reaction: Synthesis, antimicrobial and cytotoxicity of spirooxindole derivatives.

PubMed

Parthasarathy, K; Praveen, Chandrasekar; Jeyaveeran, J C; Prince, A A M

2016-09-01

Microwave assisted synthesis of spirooxindoles via tandem double condensation between isatins and 4-hydroxycoumarin under gold catalysis is reported. The reaction is practical to perform, since the products can be isolated by simple filtration without requiring tedious column chromatography. The scope of this chemistry is exemplified by preparing structurally diverse spirooxindoles (22 examples) in excellent yields. Antimicrobial evaluation of the synthesized compounds revealed that three compounds (3a, 3f and 3s) exhibited significant MIC values in comparison to the standard drugs. Molecular docking studies of these compounds with AmpC-β-lactamase receptor revealed that 3a exhibited minimum binding energy (-117.819kcal/mol) indicating its strong affinity towards amino acid residues via strong hydrogen bond interaction. All compounds were also evaluated for their in vitro cytotoxicity against COLO320 cancer cells. Biological assay and molecular docking studies demonstrated that 3g is the most active compound in terms of its low IC50 value (50.0μM) and least free energy of binding (-8.99kcal/mol) towards CHK1 receptor, respectively. Copyright © 2016 Elsevier Ltd. All rights reserved.

Studies on the cytotoxicity of miscellaneous compounds from Eupatorium betonicaeforme (D.C.) Baker (Asteraceae).

PubMed

Rocha, Danilo D; Dantas, Ivana N F; Albuquerque, Maria Rose Jane R; Montenegro, Raquel C; Pessoa, Cláudia; de Moraes, Manoel Odorico; Pessoa, Otília Deusdênia L; Silveira, Edilberto R; Costa-Lotufo, Letícia V

2007-12-01

A detailed study on the cytotoxic effects of five known constituents isolated from the flowers and roots of Eupatorium betonicaeforme is reported, including 2,2-dimethyl-6-vinylchroman-4-one (1), 2-senecioyl-4-vinylphenol (2), 6-acetyl-2,2-dimethylchroman-4-one (3), (4E)-8beta-angeloyloxy-9beta,10beta-dihydroxy-1-oxogermacra-4,11(13)-dien-12,6alpha-olide (4), and 3beta-hydroxyicosan-1,5beta-olide (5). The sesquiterpene lactone 4 exhibited the highest cytotoxicity, with IC50 values ranging from 3.9 to 9.9 microM, showing some degree of cell selectivity. The antiproliferative activity of 4 was examined towards HL-60 cells, and found to diminish cell viability in a dose-dependent manner. Moreover, at all concentrations tested, there was a decrease in the number of cells capable of incorporating 5-bromo-2'-deoxyuridine (BrdU), indicating disruption of DNA synthesis. The morphological changes induced by 4 were compatible with apoptotic cell death. This work, thus, corroborates the anticancer potential of Eupatorium secondary metabolites.

Histamine H1-receptor antagonists against Leishmania (L.) infantum: an in vitro and in vivo evaluation using phosphatidylserine-liposomes.

PubMed

Pinto, Erika G; da Costa-Silva, Thais A; Tempone, Andre Gustavo

2014-09-01

Considering the limited and toxic therapeutic arsenal available for visceral leishmaniasis (VL), the drug repositioning approach could represent a promising tool to the introduction of alternative therapies. Histamine H1-receptor antagonists are drugs belonging to different therapeutic classes, including antiallergics and anxyolitics. In this work, we described for the first time the activity of H1-antagonists against L. (L.) infantum and their potential effectiveness in an experimental hamster model. The evaluation against promastigotes demonstrated that chlorpheniramine, cinnarizine, hydroxyzine, ketotifen, loratadine, quetiapine and risperidone exerted a leishmanicidal effect against promastigotes, with IC50 values in the range of 13-84μM. The antihistaminic drug cinnarizine demonstrated effectiveness against the intracellular amastigotes, with an IC50 value of 21μM. The mammalian cytotoxicity was investigated in NCTC cells, resulting in IC50 values in the range of 57-229μM. Cinnarizine was in vivo studied as a free formulation and entrapped into phosphatidylserine-liposomes. The free drug was administered for eight consecutive days at 50mg/kg by intraperitoneal route (i.p.) and at 100mg/kg by oral route to L. infantum-infected hamsters, but showed lack of effectiveness in both regimens, as detected by real time PCR. The liposomal formulation was administered by i.p. route at 3mg/kg for eight days and reduced the parasite burden to 54% in liver when compared to untreated group; no improvement was observed in the spleen of infected hamsters. Cinnarizine is the first antihistaminic drug with antileishmanial activity and could be used as scaffold for drug design studies for VL. Copyright © 2014 Elsevier B.V. All rights reserved.

Application of Receiver Operating Characteristic Analysis to Refine the Prediction of Potential Digoxin Drug Interactions

PubMed Central

Ellens, Harma; Deng, Shibing; Coleman, JoAnn; Bentz, Joe; Taub, Mitchell E.; Ragueneau-Majlessi, Isabelle; Chung, Sophie P.; Herédi-Szabó, Krisztina; Neuhoff, Sibylle; Palm, Johan; Balimane, Praveen; Zhang, Lei; Jamei, Masoud; Hanna, Imad; O’Connor, Michael; Bednarczyk, Dallas; Forsgard, Malin; Chu, Xiaoyan; Funk, Christoph; Guo, Ailan; Hillgren, Kathleen M.; Li, LiBin; Pak, Anne Y.; Perloff, Elke S.; Rajaraman, Ganesh; Salphati, Laurent; Taur, Jan-Shiang; Weitz, Dietmar; Wortelboer, Heleen M.; Xia, Cindy Q.; Xiao, Guangqing; Yamagata, Tetsuo

2013-01-01

In the 2012 Food and Drug Administration (FDA) draft guidance on drug-drug interactions (DDIs), a new molecular entity that inhibits P-glycoprotein (P-gp) may need a clinical DDI study with a P-gp substrate such as digoxin when the maximum concentration of inhibitor at steady state divided by IC50 ([I1]/IC50) is ≥0.1 or concentration of inhibitor based on highest approved dose dissolved in 250 ml divide by IC50 ([I2]/IC50) is ≥10. In this article, refined criteria are presented, determined by receiver operating characteristic analysis, using IC50 values generated by 23 laboratories. P-gp probe substrates were digoxin for polarized cell-lines and N-methyl quinidine or vinblastine for P-gp overexpressed vesicles. Inhibition of probe substrate transport was evaluated using 15 known P-gp inhibitors. Importantly, the criteria derived in this article take into account variability in IC50 values. Moreover, they are statistically derived based on the highest degree of accuracy in predicting true positive and true negative digoxin DDI results. The refined criteria of [I1]/IC50 ≥ 0.03 and [I2]/IC50 ≥ 45 and FDA criteria were applied to a test set of 101 in vitro-in vivo digoxin DDI pairs collated from the literature. The number of false negatives (none predicted but DDI observed) were similar, 10 and 12%, whereas the number of false positives (DDI predicted but not observed) substantially decreased from 51 to 40%, relative to the FDA criteria. On the basis of estimated overall variability in IC50 values, a theoretical 95% confidence interval calculation was developed for single laboratory IC50 values, translating into a range of [I1]/IC50 and [I2]/IC50 values. The extent by which this range falls above the criteria is a measure of risk associated with the decision, attributable to variability in IC50 values. PMID:23620486

Alkylphosphocholines and curcumin induce programmed cell death in cutaneous T-cell lymphoma cell lines.

PubMed

Yosifov, Deyan Y; Kaloyanov, Kaloyan A; Guenova, Margarita L; Prisadashka, Kamelia; Balabanova, Maria B; Berger, Martin R; Konstantinov, Spiro M

2014-01-01

While most patients with early-stage cutaneous T-cell lymphomas (CTCL) have a very good prognosis, the survival of patients with extensive tumour stage and visceral involvement remains extremely poor and necessitates the development of more effective treatment modalities. In this study, we evaluated the in vitro effects of two alkylphosphocholines (APCs, miltefosine and erufosine) and the polyphenolic compound curcumin on 5 human CTCL cell lines (Hut-78, HH, MJ, My-La CD4+ and My-La CD8+). All tested drugs showed considerable cytotoxic activity, as determined by the MTT dye reduction assay. The IC50 values of both APCs ranged from the low micromolar level (Hut-78 cells) to 60-80μM (HH cells). The IC50 values of curcumin ranged from 12 to 24μM. All tested drugs induced apoptosis, as ascertained by morphological changes, DNA fragmentation and activation of caspase cascades. Miltefosine and erufosine induced dephosphorylation of Akt in My-La CD8+ cells and phosphorylation of JNK in Hut-78 and My-La CD8+ cells. APCs increased the level of the autophagic marker LC3B in Hut-78 and MJ cells. Results from co-treatment with autophagy modulators suggested that the cytotoxicity of APCs in CTCL cells is mediated, at least in part, by induction of autophagy. Copyright © 2013 Elsevier Ltd. All rights reserved.

Cytotoxic Effects of Sarcophyton sp. Soft Corals—Is There a Correlation to Their NMR Fingerprints?

PubMed Central

Farag, Mohamed A.; Fekry, Mostafa I.; Al-Hammady, Montasser A.; Khalil, Mohamed N.; El-Seedi, Hesham R.; Meyer, Achim; Westphal, Hildegard; Wessjohann, Ludger A.

2017-01-01

Sarcophyton sp. soft corals are rich in cembranoid diterpenes, which represent the main chemical defense of corals against their natural predators in addition to their myriad biological effects in humans. Quantitative NMR (qNMR) was applied for assessing the diterpene variation in 16 soft coral specimens in the context of their genotype, origin, and growing habitat. qNMR revealed high diterpene levels in Sarcophyton sp. compared to Sinularia and Lobophyton, with (ent)sarcophines as major components (17–100 µg/mg) of the coral tissues. Multivariate data analysis was employed to classify samples based on the quantified level of diterpenes, and compared to the untargeted NMR approach. Results revealed that qNMR provided a stronger classification model of Sarcophyton sp. than untargeted NMR fingerprinting. Additionally, cytotoxicity of soft coral crude extracts was assessed against androgen-dependent prostate cancer cell lines (PC3) and androgen-independent colon cancer cell lines (HT-29), with IC50 values ranging from 10–60 µg/mL. No obvious correlation between the extracts’ IC50 values and their diterpene levels was found using either Spearman or Pearson correlations. This suggests that this type of bioactivity may not be easily predicted by NMR metabolomics in soft corals, or is not strongly correlated to measured diterpene levels. PMID:28677625

Novel 1, 3-N, O-Spiroheterocyclic compounds inhibit heparanase activity and enhance nedaplatin-induced cytotoxicity in cervical cancer cells.

PubMed

Song, Yanan; Hu, Bin; Qu, Hongjie; Wang, Lu; Zhang, Yunxiao; Tao, Jinchao; Cui, Jinquan

2016-06-14

Heparanase (HPA) is an enzyme that plays an important role in cancer metastasis and angiogenesis and is a potential target for molecular treatment of tumors. We previously found that abnormally high HPA expression in cervical cancer tissues is associated with poor survival and increased lymph node metastasis. The present study was conducted to assess the utility of inhibiting HPA enzyme activity in cervical cancer treatment. Two series of 13 novel HPA inhibitors were synthesized and optimized. All tested inhibitors reduced HPA enzyme activity (IC50 values ranged from 4.47 μM to 47.19 μM) and inhibited the growth of HeLa cells (IC50 values ranged from 48.16 μM to 96.64 μM). The No. 16 inhibitor inhibited the migration and growth of HeLa and Siha cells in a dose- and time-dependent manner, and increased cell apoptosis and cell cycle G0/G1 and G2/M phase arrest, while decreasing the S phase cell population. More importantly, No. 16 sensitized cervical cancer cells to low concentrations of nedaplatin, decreased HPA, c-Myc and h-TERT levels, and increased p53 levels in HeLa and Siha cells. These results suggest that this HPA inhibitor reduced proliferation and HPA expression in cervical cancer cells by restoring p53 activity and downregulating h-TERT and c-Myc expression.

PRE-CLINICAL EVALUATION OF EXTRACTS AND ESSENTIAL OILS FROM BETEL-LIKE SCENT PIPER SPECIES IDENTIFIED POTENTIAL CANCER TREATMENT

PubMed Central

Sanubol, Arisa; Chaveerach, Arunrat; Tanee, Tawatchai; Sudmoon, Runglawan

2017-01-01

Background: Nine Piper species with betel-like scents are sources of industrial and medicinal aromatic chemicals, but there is lack of information on cytotoxicity and genotoxicity for human safety, including how these plants impact human cervical cancer cell line. Methods: Plant leaves were extracted with hexane and hydro-distilled for essential oils. The extracts and oils were pre-clinically studied based on cyto - and genotoxicity using microculture tetrazolium (MTT) and comet assays. Results: The crude extracts showed an IC50 in leukocytes and HeLa cells of 58.59-97.31 mg/ml and 34.91-101.79 mg/ml, the LD50 is higher than 5000 mg/kg. With lower values than the crude extracts, the essential oils showed an IC50 in leukocytes and HeLa cells of 0.023-0.059 μg/ml and 0.025-0.043 μg/ml the LD50 is less than 50 mg/kg. IC50 values showed that the essential oils were highly toxic than the crude extracts. At the level of human genetic materials, the crude extracts of two species, including P. betloides and P. crocatum, showed a significant toxicity (p < 0.05) in leukocytes. The other samples were non-toxic. The crude extracts of all samples showed significant genotoxicity in HeLa cells. The essential oils of all studied Piper species showed insignificant toxicity in leukocytes. For HeLa cells, the eight-studied species showed significant toxicity in HeLa cells, whereas only P. submultinerve showed insignificant toxicity. Conclusion: The crude extracts and essential oils should be tested as putative cervical cancer treatments due to less toxicity in human normal cells. PMID:28480386

Characterization of antiproliferative activity constituents from Artocarpus heterophyllus.

PubMed

Zheng, Zong-Ping; Xu, Yang; Qin, Chuan; Zhang, Shuang; Gu, Xiaohong; Lin, Yingying; Xie, Guobin; Wang, Mingfu; Chen, Jie

2014-06-18

Artocarpus heterophyllus is an evergreen fruit tree cultivated in many tropical regions. Previous studies have shown that some of its compositions exhibited potential tyrosinase inhibition activities. This study indentified 8 new phenolic compounds, artoheterophyllins E-J (1-6), 4-geranyl-2',3,4',5-tetrahydroxy-cis-stilbene (7), and 5-methoxymorican M (8) and 2 new natural compounds (9 and 10), 2,3-dihydro-5,7-dihydroxy-2-(2-hydroxy-4-methoxyphenyl)-4H-benzopyran-4-one and 6-[(1S,2S)-1,2-dihydroxy-3-methylbutyl]-2-(2,4-dihydroxyphenyl)-5-hydroxy-7-methoxy-3-(3-methyl-2-buten-1-yl)-4H-1-benzopyran-4-one, together with 23 known compounds (11-33), from the ethanol extract of the wood of A. heterophyllus. The structures of the eight new compounds (1-8) and two new natural compounds were established by extensive 1D- and 2D-NMR experiments. The anticancer effects of the isolated compounds were examined in MCF-7, H460, and SMMC-7721 human cancer cell lines by MTT assay. Compounds 5, 11, 12, and 30 significantly reduced the cell viabilities of these cell lines. Especially, compounds 11 and 30 resulted in more potent cytotoxicity than the positive control, 5-fluorouracil (5-Fu), in SMMC-7721 cell line, with IC50 values of 15.85 and 12.06 μM, whereas compound 30 exhibited more potent cytotoxicity than 5-Fu in NCI-H460 cell line, with an IC50 value of 5.19 μM. In addition, this study suggests that compounds 11 and 30 from the wood of A. heterophyllus have anticancer potential via MAPK pathways.

Investigation of imatinib loaded surface decorated biodegradable nanocarriers against glioblastoma cell lines: Intracellular uptake and cytotoxicity studies.

PubMed

Khan, Abrar M; Ahmad, Farhan Jalees; Panda, Amulya K; Talegaonkar, Sushama

2016-06-30

Overexpression of P-glycoprotein (P-gp) efflux transporter in glioma cells thwarts the build-up of therapeutic concentration of drugs usually resulting into poor therapeutic outcome. To surmount aforesaid challenge, Imatinib (IMM) loaded Poly-lactide-co-glycolic acid nanoparticles (IMM-PLGA-NPs) were developed and optimized by Box Behnken Design as a new treatment stratagem in malignant glioma. Optimized NPs were functionalized with Pluronic(®) P84, P-gp inhibitor (IMM-PLGA-P84-NPs) which showed size, PDI, zeta potential, drug loading, 182.63±13.56nm, 0.196±0.021, -15.2±1.49mV, 40.63±2.04μg/mg, respectively. Intracellular uptake study conducted on A172, U251MG and C6 glioma cells demonstrated significantly high uptake of IMM through NPs when compared with IMM solution (IMM-S), p<0.001. IMM-PLGA-P84-NPs showed better uptake in P-gp expressing cell line (U251MG and C6) while uncoated NPs showed higher uptake in non-P-gp expressing cell line (A-172). Cytotoxicity studies demonstrated significantly low IC50 for both IMM-PLGA-NPs and IMM-PLGA-P84-NPs when compared with IC50 of IMM-S. IMM-PLGA-P84-NPs showed a significantly low IC50 against P-gp overexpressing cell lines when compared with IC50 of IMM-PLGA-NPs. In contrary, IMM-PLGA-NPs showed lower IC50 against non P-gp expressing cell line. This study demonstrated the feasibility of targeting surface decorated NPs to multidrug resistant gliomas. However, to address its clinical utility extensive in vivo studies are required. Copyright © 2016 Elsevier B.V. All rights reserved.

2,4,6-Trichlorophenylhydrazine Schiff bases as DPPH radical and super oxide anion scavengers.

PubMed

Khan, Khalid Mohammed; Shah, Zarbad; Ahmad, Viqar Uddin; Khan, Momin; Taha, Muhammad; Rahim, Fazal; Ali, Sajjad; Ambreen, Nida; Perveen, Shahnaz; Choudhary, M Iqbal; Voelter, Wolfgang

2012-05-01

Syntheses of thirty 2,4,6-trichlorophenylhydrazine Schiff bases 1-30 were carried out and evaluated for their in vitro DPPH radical and super oxide anion scavenging activities. Compounds 1-30 have shown a varying degree of DPPH radical scavenging activity and their IC50 values range between 4.05-369.30 µM. The compounds 17, 28, 18, 14, 8, 15, 12, 2, 29, and 7 exhibited IC50 values ranging between 4.05±0.06-24.42±0.86 µM which are superior to standard n-propylgallate (IC50=30.12±0.27 µM). Selected compounds have shown a varying degree of superoxide anion radical scavenger activity and their IC50 values range between 91.23-406.90 µM. The compounds 28, 8, 17, 15, and 14, showed IC50 values between 91.23±1.2-105.31±2.29 µM which are superior to standard n-propylgallate (IC50=106.34±1.6 µM).

Cytotoxic diterpenes from roots of Crossopetalum gaumeri, a Celastraceae species from Yucatan Peninsula.

PubMed

Miron-Lopez, Gumersindo; Bazzocchi, Isabel L; Jimenez-Diaz, Ignacio A; Moujir, Laila M; Quijano-Quiñones, Ramiro; Quijano, Leovigildo; Mena-Rejon, Gonzalo J

2014-05-01

Four new diterpenes, crossogumerins A-D (1-4) along with six known ones (5-10) were isolated from the root bark of Crossopetalum gaumeri, an endemic medicinal plant from the Yucatan Peninsula. Their structures were elucidated on the basis of 1D and 2D NMR techniques, including HMQC, HMBC, and ROESY experiments. Compounds 1-5, 8-10 were evaluated for cytotoxicity against HeLa (carcinoma of the cervix) and Hep-2 (lung carcinoma) human tumor cells lines and against normal Vero cells (African green monkey kidney) in lag and log phase of growth. Podocarpane diterpenes, crossogumerin B (2) and nimbiol (10), exhibited the highest activity against HeLa cells (IC50 values of 3.1 and 8.1 μM, respectively), but also selectivity on Vero cells (SI 22.6 and 7.5, respectively). The preliminary SAR studies suggest that an epoxy moiety in ring B and a hydrogen bond-donor group strategically positioned in the diterpene core are important requirements for cytotoxicity and selectivity. Copyright © 2014. Published by Elsevier Ltd.

In vitro antiplasmodial activity of benzophenones and xanthones from edible fruits of Garcinia species.

PubMed

Lyles, James T; Negrin, Adam; Khan, Shabana I; He, Kan; Kennelly, Edward J

2014-06-01

Species of Garcinia have been used to combat malaria in traditional African and Asian medicines, including Ayurveda. In the current study, we have identified antiplasmodial benzophenone and xanthone compounds from edible Garcinia species by testing for in vitro inhibitory activity against Plasmodium falciparum. Whole fruits of Garcinia xanthochymus, G. mangostana, G. spicata, and G. livingstonei were extracted and tested for antiplasmodial activity. Garcinia xanthochymus was subjected to bioactivity-guided fractionation to identify active partitions. Purified benzophenones (1-9) and xanthones (10-18) were then screened in the plasmodial lactate dehydrogenase assay and tested for cytotoxicity against mammalian (Vero) cells. The benzophenones guttiferone E (4), isoxanthochymol (5), and guttiferone H (6), isolated from G. xanthochymus, and the xanthones α-mangostin (15), β-mangostin (16), and 3-isomangostin (17), known from G. mangostana, showed antiplasmodial activity with IC50 values in the range of 4.71-11.40 µM. Artemisinin and chloroquine were used as positive controls and exhibited IC50 values in the range of 0.01-0.24 µM. The identification of antiplasmodial benzophenone and xanthone compounds from G. xanthochymus and G. mangostana provides evidence for the antiplasmodial activity of Garcinia species and warrants further investigation of these fruits as dietary sources of chemopreventive compounds. Georg Thieme Verlag KG Stuttgart · New York.

Chemical composition, leishmanicidal and cytotoxic activities of the essential oils from Mangifera indica L. var. Rosa and Espada.

PubMed

Ramos, Eduardo H S; Moraes, Marcílio M; Nerys, Laís L de A; Nascimento, Silene C; Militão, Gardênia C G; de Figueiredo, Regina C B Q; da Câmara, Cláudio A G; Silva, Teresinha Gonçalves

2014-01-01

The essential oils from Mangifera indica var. Rosa and Espada latex were obtained by hydrodistillation and analyzed using GC-FID and GC-MS. Twenty-seven components were identified. The main compound in the essential oil from M. indica var. Espada (EOMiE) was terpinolene (73.6%). The essential oil of M. indica var. Rosa (EOMiR) was characterized by high amounts of β-pinene (40.7%) and terpinolene (28.3%). In the test for leishmanicidal activity against promastigotes forms of L. amazonensis, EOMiR and EOMiE showed IC50 (72 h) of 39.1 and 23.0 μg/mL, respectively. In macrophages, EOMiR and EOMiE showed CC50 of 142.84 and 158.65 μg/mL, respectively. However, both were more specific to the parasite than macrophages, with values of selectivity index of 6.91 for EOMiE and 3.66 for EOMiR. The essential oils were evaluated for their cytotoxicity against the human tumor cells HEp-2, HT-29, NCI-H292, and HL-60. The EOMiR and EOMiE were most effective against the HL-60, with IC50 values of 12.3 and 3.6 μg/mL, respectively. The results demonstrated that the essential oils of M. indica can destroy L. amazonensis and inhibit tumor cell growth. These findings contribute to the knowledge of the Brazilian biodiversity as a source of potential therapeutic agents.

Chemical Composition, Leishmanicidal and Cytotoxic Activities of the Essential Oils from Mangifera indica L. var. Rosa and Espada

PubMed Central

Ramos, Eduardo H. S.; Moraes, Marcílio M.; Nerys, Laís L. de A.; Nascimento, Silene C.; Militão, Gardênia C. G.; de Figueiredo, Regina C. B. Q.; da Câmara, Cláudio A. G.; Silva, Teresinha Gonçalves

2014-01-01

The essential oils from Mangifera indica var. Rosa and Espada latex were obtained by hydrodistillation and analyzed using GC-FID and GC-MS. Twenty-seven components were identified. The main compound in the essential oil from M. indica var. Espada (EOMiE) was terpinolene (73.6%). The essential oil of M. indica var. Rosa (EOMiR) was characterized by high amounts of β-pinene (40.7%) and terpinolene (28.3%). In the test for leishmanicidal activity against promastigotes forms of L. amazonensis, EOMiR and EOMiE showed IC50 (72 h) of 39.1 and 23.0 μg/mL, respectively. In macrophages, EOMiR and EOMiE showed CC50 of 142.84 and 158.65 μg/mL, respectively. However, both were more specific to the parasite than macrophages, with values of selectivity index of 6.91 for EOMiE and 3.66 for EOMiR. The essential oils were evaluated for their cytotoxicity against the human tumor cells HEp-2, HT-29, NCI-H292, and HL-60. The EOMiR and EOMiE were most effective against the HL-60, with IC50 values of 12.3 and 3.6 μg/mL, respectively. The results demonstrated that the essential oils of M. indica can destroy L. amazonensis and inhibit tumor cell growth. These findings contribute to the knowledge of the Brazilian biodiversity as a source of potential therapeutic agents. PMID:25136617

Cytotoxic 14-Membered Macrolides from a Mangrove-Derived Endophytic Fungus, Pestalotiopsis microspora.

PubMed

Liu, Shuai; Dai, Haofu; Makhloufi, Gamall; Heering, Christian; Janiak, Christoph; Hartmann, Rudolf; Mándi, Attila; Kurtán, Tibor; Müller, Werner E G; Kassack, Matthias U; Lin, Wenhan; Liu, Zhen; Proksch, Peter

2016-09-23

Seven new 14-membered macrolides, pestalotioprolides C (2), D-H (4-8), and 7-O-methylnigrosporolide (3), together with four known analogues, pestalotioprolide B (1), seiricuprolide (9), nigrosporolide (10), and 4,7-dihydroxy-13-tetradeca-2,5,8-trienolide (11), were isolated from the mangrove-derived endophytic fungus Pestalotiopsis microspora. Their structures were elucidated by analysis of NMR and MS data and by comparison with literature data. Single-crystal X-ray diffraction analysis was used to confirm the absolute configurations of 1, 2, and 10, while Mosher's method and the TDDFT-ECD approach were applied to determine the absolute configurations of 5 and 6. Compounds 3-6 showed significant cytotoxicity against the murine lymphoma cell line L5178Y with IC50 values of 0.7, 5.6, 3.4, and 3.9 μM, respectively, while compound 5 showed potent activity against the human ovarian cancer cell line A2780 with an IC50 value of 1.2 μM. Structure-activity relationships are discussed. Coculture of P. microspora with Streptomyces lividans caused a roughly 10-fold enhanced accumulation of compounds 5 and 6 compared to axenic fungal control.

NITRIC OXIDE INHIBITORY ACTIVITY OF STRYCHNOS SPINOSA (LOGANIACEAE) LEAF EXTRACTS AND FRACTIONS

PubMed Central

AI, Isa; JP, Dzoyem; SA, Adebayo; MM, Suleiman; JN, Eloff

2016-01-01

Background: The study was aimed at determining the anti-inflammatory activity of fractions and extracts obtained from Strychnos spinosa leaves on a mediator of inflammation nitric oxide (NO). Materials and Methods: Leaves were extracted with acetone and separated into fractions with different polarities by solvent-solvent fractionation. The Griess assay was used to determine the nitric oxide (NO) inhibitory activity. Cellular toxicity was determined by “using the MTT reduction assay”. Results: With the exception of the ethyl acetate fraction which had an IC50 >750 μg/mL, all extracts and fractions had significant nitric oxide-inhibitory activity. The most active being the water fraction, chloroform fraction and the dichloromethane/methanol extracts with IC50 values of 88.43 μg/mL, 96.72 μg/mL and 115.62 μg/mL, respectively. The extracts and fractions had low cytotoxicity on macrophage U937 cell lines. Conclusion: Extracts and fractions of Strychnos spinosa leaves may be promising sources of natural anti-inflammatory agents. Findings obtained from this study showed that Strychnos spinosa leaves possess promising anti-inflammatory action and could be used in the treatment of inflammation-related conditions. PMID:28480356

Annatto Constituent Cis-Bixin Has Selective Antimyeloma Effects Mediated by Oxidative Stress and Associated with Inhibition of Thioredoxin and Thioredoxin Reductase

PubMed Central

Tibodeau, Jennifer D.; Isham, Crescent R.

2010-01-01

Abstract In pursuit of the anticancer effects of seeds of the rain forest plant Bixa orellana (annatto), we found that its constituent cis-bixin induced cytotoxicity in a wide variety of tumor cell lines (IC50 values from 10 to 50 μM, 24-h exposures) and, importantly, also selectively killed freshly collected patient multiple myeloma cells and highly drug-resistant multiple myeloma cell lines. Mechanistic studies indicated that cis-bixin–induced cytotoxicity was greatly attenuated by co-treatment with glutathione or N-acetylcysteine (NAC); whereas fluorescence-activated cell sorting (FACS) assays using the cell-permeable dyes 5-(and-6) chloromethyl-2′,7′-dichlorodihydrofluorescein diacetate, acetyl ester (CM-H2DCFDA), or dihydroethidium demonstrated that cis-bixin rapidly induced cellular reactive oxygen species (ROS) in dose- and time-dependent fashions, collectively implicating ROS as contributory to cis-bixin–induced cytotoxicity. In pursuit of potential contributors to ROS imposition by cis-bixin, we found that cis-bixin inhibited both thioredoxin (Trx) and thioredoxin reductase (TrxR1) activities at concentrations comparable to those required for cytotoxicity, implicating the inhibition of these redox enzymes as potentially contributing to its ability to impose cellular ROS and to kill cancer cells. Collectively, our studies indicate that the annatto constituent cis-bixin has intriguing selective antimyeloma activity that appears to be mediated through effects on redox signaling. Antioxid. Redox Signal. 13, 987–997. PMID:20170403

ICM0301s, new angiogenesis inhibitors from Aspergillus sp. F-1491. I. Taxonomy, fermentation, isolation and biological activities.

PubMed

Kumagai, Hiroyuki; Someno, Tetsuya; Dobashi, Kazuyuki; Isshiki, Kunio; Ishizuka, Masaaki; Ikeda, Daishiro

2004-02-01

In the course of screening program for inhibitors of angiogenesis, novel substances designated as ICM0301A approximately H (1 approximately 8) were isolated from the culture broth of Aspergillus sp. F-1491. ICM0301s inhibited the growth of human umbilical vein endothelial cells (HUVECs) induced by basic fibroblast growth factor (bFGF) with IC50 values of 2.2 approximately 9.3 microg/ml. ICM0301A (1) showed significant anti-angiogenic activity at lower than 10 microg/ml in the angiogenesis model using rat aorta cultured in fibrin gel. ICM0301s showed very low cytotoxicity against various tumor cells. Furthermore, 1CM0301A did not show any toxic symptom in mice by intraperitoneal injection at 100 mg/kg.

Antiparasitic activity of diallyl trisulfide (Dasuansu) on human and animal pathogenic protozoa (Trypanosoma sp., Entamoeba histolytica and Giardia lamblia) in vitro.

PubMed

Lun, Z R; Burri, C; Menzinger, M; Kaminsky, R

1994-03-01

Garlic (Allium sativum L.) and one of its major components, allicin, have been known to have antibacterial and antifungal activity for a long time. Diallyl trisulfide is a chemically stable final transformation product of allicin which was synthesized in 1981 in China and used for treatment of bacterial, fungal and parasitic infections in man. The activity of diallyl trisulfide was investigated in several important protozoan parasites in vitro. The IC50 (concentration which inhibits metabolism or growth of parasites by 50%) for Trypanosoma brucei brucei, T.b. rhodesiense, T.b. gambiense, T. evansi, T. congolense and T. equiperdum was in the range of 0.8-5.5 micrograms/ml. IC50 values were 59 micrograms/ml for Entamoeba histolytica and 14 micrograms/ml for Giardia lamblia. The cytotoxicity of the compound was evaluated on two fibroblast cell lines (MASEF, Mastomys natalensis embryo fibroblast and HEFL-12, human embryo fibroblast) in vitro. The maximum tolerated concentration for both cell lines was 25 micrograms/ml. The results indicate that the compound has potential to be used for treatment of several human and animal parasitic diseases.

Cytotoxic and HIV-1 enzyme inhibitory activities of Red Sea marine organisms.

PubMed

Ellithey, Mona S; Lall, Namrita; Hussein, Ahmed A; Meyer, Debra

2014-02-25

Cancer and HIV/AIDS are two of the greatest public health and humanitarian challenges facing the world today. Infection with HIV not only weakens the immune system leading to AIDS and increasing the risk of opportunistic infections, but also increases the risk of several types of cancer. The enormous biodiversity of marine habitats is mirrored by the molecular diversity of secondary metabolites found in marine animals, plants and microbes which is why this work was designed to assess the anti-HIV and cytotoxic activities of some marine organisms of the Red Sea. The lipophilic fractions of methanolic extracts of thirteen marine organisms collected from the Red Sea (Egypt) were screened for cytotoxicity against two human cancer cell lines; leukaemia (U937) and cervical cancer (HeLa) cells. African green monkey kidney cells (Vero) were used as normal non-malignant control cells. The extracts were also tested for their inhibitory activity against HIV-1 enzymes, reverse transcriptase (RT) and protease (PR). Cytotoxicity results showed strong activity of the Cnidarian Litophyton arboreum against U-937 (IC50; 6.5 μg/ml ±2.3) with a selectivity index (SI) of 6.45, while the Cnidarian Sarcophyton trochliophorum showed strong activity against HeLa cells (IC50; 5.2 μg/ml ±1.2) with an SI of 2.09. Other species showed moderate to weak cytotoxicity against both cell lines. Two extracts showed potent inhibitory activity against HIV-1 protease; these were the Cnidarian jelly fish Cassiopia andromeda (IC50; 0.84 μg/ml ±0.05) and the red algae Galaxura filamentosa (2.6 μg/ml ±1.29). It is interesting to note that the most active extracts against HIV-1 PR, C. andromeda and G. filamentosa showed no cytotoxicity in the three cell lines at the highest concentration tested (100 μg/ml). The strong cytotoxicity of the soft corals L. arboreum and S. trochliophorum as well as the anti-PR activity of the jelly fish C. andromeda and the red algae G. filamentosa suggests the medicinal potential of crude extracts of these marine organisms.

Cytotoxic acyl amides from the soil fungus Gymnascella dankaliensis.

PubMed

Hammerschmidt, Lena; Aly, Amal H; Abdel-Aziz, Mohammed; Müller, Werner E G; Lin, Wenhan; Daletos, Georgios; Proksch, Peter

2015-02-15

The soil fungus Gymnascella dankaliensis was collected in the vicinity of the Giza pyramids, Egypt. When grown on solid rice medium the fungus yielded four new compounds including 11'-carboxygymnastatin N (1), gymnastatin S (2), dankamide (3), and aranorosin-2-methylether (4), the latter having been reported previously only as a semisynthetic compound. In addition, six known metabolites (5-10) were isolated. Addition of NaCl or KBr to the rice medium resulted in the accumulation of chlorinated or brominated compounds as indicated by LC-MS analysis due to the characteristic isotope patterns observed. From the rice medium spiked with 3.5% NaCl the known chlorinated compounds gymnastatin A (11) and gymnastatin B (12) were obtained. All isolated compounds were unambiguously structurally elucidated on the basis of comprehensive spectral analysis (1D and 2D NMR, and mass spectrometry), as well as by comparison with the literature. Compounds 4, 7 and 11 showed potent cytotoxicity against the murine lymphoma cell line L5178Y (IC50 values 0.44, 0.58 and 0.64μM, respectively), whereas 12 exhibited moderate activity with an IC50 value of 5.80μM. Copyright © 2015 Elsevier Ltd. All rights reserved.

Cytotoxic and HIV-1 enzyme inhibitory activities of Red Sea marine organisms

PubMed Central

2014-01-01

Background Cancer and HIV/AIDS are two of the greatest public health and humanitarian challenges facing the world today. Infection with HIV not only weakens the immune system leading to AIDS and increasing the risk of opportunistic infections, but also increases the risk of several types of cancer. The enormous biodiversity of marine habitats is mirrored by the molecular diversity of secondary metabolites found in marine animals, plants and microbes which is why this work was designed to assess the anti-HIV and cytotoxic activities of some marine organisms of the Red Sea. Methods The lipophilic fractions of methanolic extracts of thirteen marine organisms collected from the Red Sea (Egypt) were screened for cytotoxicity against two human cancer cell lines; leukaemia (U937) and cervical cancer (HeLa) cells. African green monkey kidney cells (Vero) were used as normal non-malignant control cells. The extracts were also tested for their inhibitory activity against HIV-1 enzymes, reverse transcriptase (RT) and protease (PR). Results Cytotoxicity results showed strong activity of the Cnidarian Litophyton arboreum against U-937 (IC50; 6.5 μg/ml ±2.3) with a selectivity index (SI) of 6.45, while the Cnidarian Sarcophyton trochliophorum showed strong activity against HeLa cells (IC50; 5.2 μg/ml ±1.2) with an SI of 2.09. Other species showed moderate to weak cytotoxicity against both cell lines. Two extracts showed potent inhibitory activity against HIV-1 protease; these were the Cnidarian jelly fish Cassiopia andromeda (IC50; 0.84 μg/ml ±0.05) and the red algae Galaxura filamentosa (2.6 μg/ml ±1.29). It is interesting to note that the most active extracts against HIV-1 PR, C. andromeda and G. filamentosa showed no cytotoxicity in the three cell lines at the highest concentration tested (100 μg/ml). Conclusion The strong cytotoxicity of the soft corals L. arboreum and S. trochliophorum as well as the anti-PR activity of the jelly fish C. andromeda and the red algae G. filamentosa suggests the medicinal potential of crude extracts of these marine organisms. PMID:24568567

Synthesis, molecular structure, spectral analysis, and biological activity of new malonamide derivatives as α-glucosidase inhibitors

NASA Astrophysics Data System (ADS)

Barakat, Assem; Islam, Mohammad Shahidul; Al-Majid, Abdullah Mohammed; Soliman, Saied M.; Ghabbour, Hazem A.; Yousuf, Sammer; Choudhary, M. Iqbal; Ul-Haq, Zaheer

2017-04-01

Two new malonamide derivatives were synthesized via the Michael addition of N1,N3-di(pyridin-2-yl)malonamide to α,β-unsaturated ketones using a 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) catalyst at room temperature. All reactions efficiently furnished the desired malonamide derivatives, which differed only in their substitution on one phenyl group, with one derivative bearing a bromine substituent and the other bearing a methyl group. The structures of newly synthesized compounds were then elucidated by single-crystal X-ray diffraction, infrared spectroscopy, NMR spectroscopy, mass spectrometry, and elemental analysis. In addition, the synthesized compounds were evaluated for their in vitro cytotoxicity against cancer cell lines and for α-glucosidase inhibition. The target compounds exhibited enhanced α-glucosidase inhibition activity (i.e., IC50 = 12.8 ± 0.1 and 28.4 ± 0.2 μM) compared to the common drug acarbose (IC50 = 840 ± 1.73 μM). Both compounds were found to be non-cytotoxic against H460 (lung carcinoma) and T3T (normal fibroblast) cell lines. In addition, the bromo-substituted derivative exhibited weak cytotoxic against cervical cancer HeLa (IC50 = 13.8 ± 0.4 μM) and breast cancer MCF-7 (IC50 = 21.11 ± 0.88 μM) cell lines, while the methyl-substituted derivative showed weak cytotoxicity against the MCF-7 cell line (IC50 = 47.9 ± 0.7 μM). Density functional theory (DFT) B3LYP/6-311G(d,p) calculations were employed to examine the molecular structures and electronic properties of the prepared compounds. As expected, the bromo-derivative (2.2377 D) exhibited a higher polarity than the methyl-derivative (1.9160 D). Furthermore, the HOMO and LUMO diagrams were constructed and the electronic spectra of both compounds were assigned using time-dependent (TD)-DFT calculations. Finally, the calculated NMR chemical shifts correlated well with the experimental data.

Bioactivity-guided isolation of anti-hepatitis B virus active sesquiterpenoids from the traditional Chinese medicine: Rhizomes of Cyperus rotundus.

PubMed

Xu, Hong-Bo; Ma, Yun-Bao; Huang, Xiao-Yan; Geng, Chang-An; Wang, Hao; Zhao, Yong; Yang, Tong-Hua; Chen, Xing-Long; Yang, Cai-Yan; Zhang, Xue-Mei; Chen, Ji-Jun

2015-08-02

The rhizome of Cyperus rotundus (C. rotundus) is a well-known traditional Chinese medicine to cure hepatitis in many formulae, but the active components responsible for hepatitis have not been elucidated. According to our bioassay on HepG2.2.15 cell line in vitro, the ethanol extract of C. rotundus demonstrated potent anti-HBV activity. This current study was designed to isolate and identify the anti-HBV active constituents from the rhizomes of C. rotundus. Bioactivity and LC-MS guided fractionation on the extract of C. rotundus using various chromatographic techniques including open-column, Sephadex LH-20 and semi-preparative high performance liquid chromatography led to the isolation and identification of thirty-seven sesquiterpenoids. Structural elucidation of the isolates was carried out by extensive spectroscopic analyses (UV, IR, HRMS, 1D- and 2D -NMR). The anti-HBV activity and cytotoxicity were evaluated on the HBV-transfected HepG2.2.15 cell line in vitro. The cytotoxicity effects of the isolates were assessed by a MTT assay. The secretions of HBsAg and HBeAg in the culture medium were detected by ELISA method, and the load of HBV DNA was quantified by real-time fluorescent PCR technique. Five new patchoulane-type sesquiterpenoids, namely cyperene-3, 8-dione (1), 14-hydroxy cyperotundone (2), 14-acetoxy cyperotundone (3), 3β-hydroxycyperenoic acid (4) and sugetriol-3, 9-diacetate (5), along with 32 known sesquiterpenoids were isolated from the active fractions of C. rotundus. Compounds 2 and 3 were the first cyperotundone-type sesquiterpenoids with a hydroxyl group at C-14 position. Nine eudesmane-type sesquiterpenoids (15-21 and 23-24) significantly inhibited the HBV DNA replication with IC50 values of 42.7±5.9, 22.5±1.9, 13.2±1.2, 10.1±0.7, 14.1±1.1, 15.3±2.7, 13.8±0.9, 19.7±2.1 and 11.9±0.6 μM, respectively, of which, compounds 17, 21, 23 and 24 possessed high SI values of 250.4, 125.5,>259.6 and 127.5, respectively. Two patchoulane-type sesquiterpenoids (4 and 7) effectively suppressed the secretion of HBsAg in a dose-dependent manner with IC50 values of 46.6±14.3 (SI=31.0) and 77.2±13.0 (SI=1.7) μM, respectively. Compounds 2, 8, 12, 15, 17 and 25 possessed moderate activities against HBeAg secretion with IC50 values of 162.5±18.9 (SI=13.3), 399.2±90.0 (SI=10.6), 274.7±70.8 (SI=5.2), 313.9±87.5 (SI=7.2), 334.0±70.4 (SI=9.9) and 285.3±20.9 (SI=15.5) μM, respectively. This is the first study to reveal the anti-HBV constituents of C. rotundus, demonstrating that the eudesmane-type sesquiterpenoids might contribute to the anti-HBV activity of the rhizomes of C. rotundus. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Environmental Toxin Screening Using Human-Derived 3D Bioengineered Liver and Cardiac Organoids.

PubMed

Forsythe, Steven D; Devarasetty, Mahesh; Shupe, Thomas; Bishop, Colin; Atala, Anthony; Soker, Shay; Skardal, Aleksander

2018-01-01

Environmental toxins, such as lead and other heavy metals, pesticides, and other compounds, represent a significant health concern within the USA and around the world. Even in the twenty-first century, a plethora of cities and towns in the U.S. have suffered from exposures to lead in drinking water or other heavy metals in food or the earth, while there is a high possibility of further places to suffer such exposures in the near future. We employed bioengineered 3D human liver and cardiac organoids to screen a panel of environmental toxins (lead, mercury, thallium, and glyphosate), and charted the response of the organoids to these compounds. Liver and cardiac organoids were exposed to lead (10 µM-10 mM), mercury (200 nM-200 µM), thallium (10 nM-10 µM), or glyphosate (25 µM-25 mM) for a duration of 48 h. The impacts of toxin exposure were then assessed by LIVE/DEAD viability and cytotoxicity staining, measuring ATP activity and determining IC50 values, and determining changes in cardiac organoid beating activity. As expected, all of the toxins induced toxicity in the organoids. Both ATP and LIVE/DEAD assays showed toxicity in both liver and cardiac organoids. In particular, thallium was the most toxic, with IC50 values of 13.5 and 1.35 µM in liver and cardiac organoids, respectively. Conversely, glyphosate was the least toxic of the four compounds, with IC50 values of 10.53 and 10.85 mM in liver and cardiac organoids, respectively. Additionally, toxins had a negative influence on cardiac organoid beating activity as well. Thallium resulting in the most significant decreases in beating rate, followed by mercury, then glyphosate, and finally, lead. These results suggest that the 3D organoids have significant utility to be deployed in additional toxicity screening applications, and future development of treatments to mitigate exposures. 3D organoids have significant utility to be deployed in additional toxicity screening applications, such as future development of treatments to mitigate exposures, drug screening, and environmental toxin detection.

Potentiation of luteolin cytotoxicity by flavonols fisetin and quercetin in human chronic lymphocytic leukemia cell lines.

PubMed

Sak, Katrin; Kasemaa, Kristi; Everaus, Hele

2016-09-14

Despite numerous studies chronic lymphocytic leukemia (CLL) still remains an incurable disease. Therefore, all new compounds and novel strategies which are able to eradicate CLL cells should be considered as valuable clues for a potential future remedy against this malignancy. In the present study, the cytotoxic profiles of natural flavonoids were described in two human CLL cell lines, HG-3 and EHEB, indicating the flavone luteolin as the most potent flavonoid with half-maximal inhibitory constants (IC50) of 37 μM and 26 μM, respectively. Luteolin significantly increased the apoptotic cell population in both cell lines by increasing the activities of caspases-3 and -9 and triggering the intrinsic apoptotic pathway. Two flavonols, fisetin and quercetin, were somewhat less efficient in suppressing cellular viability, whereas baicalein, chrysin, (+)-catechin and hesperetin exerted only a small or no response at doses as high as 100 μM. Both fisetin and quercetin were able to augment the cytotoxic activity of luteolin in both cell lines by reducing the IC50 values up to four fold. As a result of this, luteolin displayed cytotoxicity activity already at low micromolar concentrations that could potentially be physiologically achievable through oral ingestion. No other tested flavonoids were capable of sensitizing CLL cells to luteolin pointing to a specific binding of fisetin and quercetin to the cellular targets which interfere with the signaling pathways induced by luteolin. Although further molecular studies to unravel this potentiating mechanism are certainly needed, this phenomenon could contribute to future remedies for prevention and treatment of chronic lymphocytic leukemia.

Chemical composition and biological activity of Abies alba and A. koreana seed and cone essential oils and characterization of their seed hydrolates.

PubMed

Wajs-Bonikowska, Anna; Sienkiewicz, Monika; Stobiecka, Agnieszka; Maciąg, Agnieszka; Szoka, Łukasz; Karna, Ewa

2015-03-01

The chemical composition, including the enantiomeric excess of the main terpenes, the antimicrobial and antiradical activities, as well as the cytotoxicity of Abies alba and A. koreana seed and cone essential oils were investigated. Additionally, their seed hydrolates were characterized. In the examined oils and hydrolates, a total of 174 compounds were identified, which comprised 95.6-99.9% of the volatiles. The essential oils were mainly composed of monoterpene hydrocarbons, whereas the composition of the hydrolates, differing from the seed oils of the corresponding fir species, consisted mainly of oxygenated derivatives of sesquiterpenes. The seed and cone essential oils of both firs exhibited DPPH-radical-scavenging properties and low antibacterial activity against the bacterial strains tested. Moreover, they evoked only low cytotoxicity towards normal fibroblasts and the two cancer cell lines MCF-7 and MDA-MBA-231. At concentrations up to 50 μg/ml, all essential oils were safe in relation to normal fibroblasts. Although they induced cytotoxicity towards the cancer cells at concentrations slightly lower than those required for the inhibition of fibroblast proliferation, their influence on cancer cells was weak, with IC50 values similar to those observed towards normal fibroblasts. Copyright © 2015 Verlag Helvetica Chimica Acta AG, Zürich.

In vitro and in vivo activity of melflufen (J1)in lymphoma.

PubMed

Delforoush, Maryam; Strese, Sara; Wickström, Malin; Larsson, Rolf; Enblad, Gunilla; Gullbo, Joachim

2016-04-04

Melphalan has been used in the treatment of various hematologic malignancies for almost 60 years. Today it is part of standard therapy for multiple myeloma and also as part of myeloablative regimens in association with autologous allogenic stem cell transplantation. Melflufen (melphalan flufenamide ethyl ester, previously called J1) is an optimized derivative of melphalan providing targeted delivery of active metabolites to cells expressing aminopeptidases. The activity of melflufen has compared favorably with that of melphalan in a series of in vitro and in vivo experiments performed preferentially on different solid tumor models and multiple myeloma. Melflufen is currently being evaluated in a clinical phase I/II trial in relapsed or relapsed and refractory multiple myeloma. Cytotoxicity of melflufen was assayed in lymphoma cell lines and in primary tumor cells with the Fluorometric Microculture Cytotoxicity Assay and cell cycle analyses was performed in two of the cell lines. Melflufen was also investigated in a xenograft model with subcutaneous lymphoma cells inoculated in mice. Melflufen showed activity with cytotoxic IC50-values in the submicromolar range (0.011-0.92 μM) in the cell lines, corresponding to a mean of 49-fold superiority (p < 0.001) in potency vs. melphalan. In the primary cultures melflufen yielded slightly lower IC50-values (2.7 nM to 0.55 μM) and an increased ratio vs. melphalan (range 13-455, average 108, p < 0.001). Treated cell lines exhibited a clear accumulation in the G2/M-phase of the cell cycle. Melflufen also showed significant activity and no, or minimal side effects in the xenografted animals. This study confirms previous reports of a targeting related potency superiority of melflufen compared to that of melphalan. Melflufen was active in cell lines and primary cultures of lymphoma cells, as well as in a xenograft model in mice and appears to be a candidate for further evaluation in the treatment of this group of malignant diseases.

In vitro antiproliferative/cytotoxic activity on cancer cell lines of a cardanol and a cardol enriched from Thai Apis mellifera propolis

PubMed Central

2012-01-01

Background Propolis is a complex resinous honeybee product. It is reported to display diverse bioactivities, such as antimicrobial, anti-inflammatory and anti-tumor properties, which are mainly due to phenolic compounds, and especially flavonoids. The diversity of bioactive compounds depends on the geography and climate, since these factors affect the floral diversity. Here, Apis mellifera propolis from Nan province, Thailand, was evaluated for potential anti-cancer activity. Methods Propolis was sequentially extracted with methanol, dichloromethane and hexane and the cytotoxic activity of each crude extract was assayed for antiproliferative/cytotoxic activity in vitro against five human cell lines derived from duet carcinoma (BT474), undifferentiated lung (Chaco), liver hepatoblastoma (Hep-G2), gastric carcinoma (KATO-III) and colon adenocarcinoma (SW620) cancers. The human foreskin fibroblast cell line (Hs27) was used as a non-transformed control. Those crude extracts that displayed antiproliferative/cytotoxic activity were then further fractionated by column chromatography using TLC-pattern and MTT-cytotoxicity bioassay guided selection of the fractions. The chemical structure of each enriched bioactive compound was analyzed by nuclear magnetic resonance and mass spectroscopy. Results The crude hexane and dichloromethane extracts of propolis displayed antiproliferative/cytotoxic activities with IC50 values across the five cancer cell lines ranging from 41.3 to 52.4 μg/ml and from 43.8 to 53.5 μg/ml, respectively. Two main bioactive components were isolated, one cardanol and one cardol, with broadly similar in vitro antiproliferation/cytotoxicity IC50 values across the five cancer cell lines and the control Hs27 cell line, ranging from 10.8 to 29.3 μg/ml for the cardanol and < 3.13 to 5.97 μg/ml (6.82 - 13.0 μM) for the cardol. Moreover, both compounds induced cytotoxicity and cell death without DNA fragmentation in the cancer cells, but only an antiproliferation response in the control Hs27 cells However, these two compounds did not account for the net antiproliferation/cytotoxic activity of the crude extracts suggesting the existence of other potent compounds or synergistic interactions in the propolis extracts. Conclusion This is the first report that Thai A. mellifera propolis contains at least two potentially new compounds (a cardanol and a cardol) with potential anti-cancer bioactivity. Both could be alternative antiproliferative agents for future development as anti-cancer drugs. PMID:22458642

HPLC analysis of phenolic acids, antioxidant activity and in vitro effectiveness of green and roasted Caffea arabica bean extracts: a comparative study.

PubMed

El-Nabi, Sobhy El-Sayed Hassab; Dawoud, Gouda T M; El-Garawani, Islam Mohamed; El Shafey, Samraa Samy

2018-01-24

Coffee is a popular drink; it is one of the most commercialized food products and a rich source of biologically active compounds that are important for human health. This study aimed to prove the anticancer activity of green coffee (GC) and roasted coffee (RC) bean aqueous extracts (Coffea arabica) on breast cancer adenocarcinoma cell line (MCF-7) and the safety of both extracts on normal human peripheral blood lymphocytes culture (HPBL). Total phenolic content for GC and RC extracts was measured and result of both extracts were (0.308±0.016 & 0.233±0.013mg/g) respectively. The phenolic acids were screened by HPLC at the wavelength of 254& 278 and 300 nm and 5-caffeoylquinic acids (Chlorogenic acid), the predominant form of phenolic acids, was identified in GC and RC samples. Ferric reducing antioxidant power (FRAP) as well as the free radical scavenging activity (DPPH) proved the antioxidant properties of both extracts. The DPPH IC50 mean values of GC and RC extracts were (2.4±0.08, 2.3±0.16 μg/ml) respectively. Cytotoxicity of both extracts on MCF-7 cells were evaluated by neutral red uptake assay which showed the IC50 mean values (377±5.7,500±8.1 μg/ml) for GC and RC extracts respectively. The safety of both extracts (0, 125, 250, 500 μg/ml) on HPBL was evaluated in vitro using trypan blue exclusion method and DNA single strand breaks (alkaline comet assay). Result revealed non-significant cytotoxic difference (P<0.001) between cultures especially at lower doses of GC and RC extracts except the highest dose of BC and GC extract which showed slightly significant damage (P<0.001). In conclusion, this study proved that GC and RC aqueous extracts were found to be selectively cytotoxic in vitro to cancerous cells (MCF-7 cell line) causing cell death with no cytotoxicity on normal human lymphocytes especially at lower doses. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Synthesis of some potent immunomodulatory and anti-inflammatory metabolites by fungal transformation of anabolic steroid oxymetholone

PubMed Central

2012-01-01

Background Biotransformation of organic compounds by using microbial whole cells provides an efficient approach to obtain novel analogues which are often difficult to synthesize chemically. In this manuscript, we report for the first time the microbial transformation of a synthetic anabolic steroidal drug, oxymetholone, by fungal cell cultures. Results Incubation of oxymetholone (1) with Macrophomina phaseolina, Aspergillus niger, Rhizopus stolonifer, and Fusarium lini produced 17β-hydroxy-2-(hydroxy-methyl)-17α-methyl-5α-androstan-1-en-3-one (2), 2α,17α-di(hydroxyl-methyl)-5α-androstan-3β,17β-diol (3), 17α-methyl-5α-androstan-2α,3β,17β-triol (4), 17β-hydroxy-2-(hydroxymethyl)-17α-methyl-androst-1,4-dien-3-one (5), 17β-hydroxy-2α-(hydroxy-methyl)-17α-methyl-5α-androstan-3-one (6), and 2α-(hydroxymethyl)-17α-methyl-5α-androstan-3β-17β-diol (7). Their structures were deduced by spectral analyses, as well as single-crystal X-ray diffraction studies. Compounds 2–5 were identified as the new metabolites of 1. The immunomodulatory, and anti-inflammatory activities and cytotoxicity of compounds 1–7 were evaluated by observing their effects on T-cell proliferation, reactive oxygen species (ROS) production, and normal cell growth in MTT assays, respectively. These compounds showed immunosuppressant effect in the T-cell proliferation assay with IC50 values between 31.2 to 2.7 μg/mL, while the IC50 values for ROS inhibition, representing anti-inflammatory effect, were in the range of 25.6 to 2.0 μg/mL. All the compounds were found to be non-toxic in a cell-based cytotoxicity assay. Conclusion Microbial transformation of oxymetholone (1) provides an efficient method for structural transformation of 1. The transformed products were obtained as a result of de novo stereoselective reduction of the enone system, isomerization of double bond, insertion of double bond and hydroxylation. The transformed products, which showed significant immunosuppressant and anti-inflammatory activities, can be further studied for their potential as novel drugs. PMID:23237028

In vitro antioxidant and cytotoxic properties of ethanol extract of Alpinia oxyphylla fruits.

PubMed

Wang, Cheng-zhong; Yuan, Hui-hui; Bao, Xiao-li; Lan, Min-bo

2013-11-01

Alpinia oxyphylla Miquel (Zingiberaceae) is a traditional Chinese herbal medicine widely used for the treatment of intestinal disorders, urosis and diuresis. However, information about antioxidant and cytotoxic properties of its fruits remains to be elucidated. The ethanol crude extract (CE) and its fractions [petroleum ether fraction (PF), ethyl acetate fraction (EF), n-butanol fraction (BF) and water fraction (WF) extracted by petroleum ether, ethyl acetate, n-butanol and water, respectively] of A. oxyphylla fruits were investigated for their antioxidant activity and cytotoxicity. The total phenolic content (TPC) and antioxidant activity of the extracts were determined by Folin-Ciocalteu reagent, 1,1-diphenyl-2-picrylhydrazyl (DPPH(•)), Trolox equivalent antioxidant capacity and reducing power assay. Cytotoxicity of the extracts (0-200 μg/mL) was tested on six human cancer cell lines (breast cancer cell line, cervix carcinoma cell line, lung adenocarcinoma cell line, liver carcinoma cell line, gastric cancer cell line and colon cancer cell line) using the sulforhodamine B assay. The TPC of extracts varied from 8.2 to 20.3 mg gallic acid equivalents/g dry weight. DPPH radical scavenging effect of extracts decreased in the order of EF > BF > CE > PF > WF, with IC50 values ranging from 74.7 to 680.8 μg/mL. 2,2-azo-bis(3-Ethylbenzothiazoline-6-sulfoic acid) diammonium salt scavenging activity ranged from 0.118 to 0.236 mmol Trolox equivalence/mg extract. The extracts exhibited concentration-dependent reducing power, and EF showed the highest reducing ability. A satisfactory correlation (R(2) > 0.826) between TPC and antioxidant activity was observed. In addition, EF, PF and CE exhibited potent anticancer effects on six cancer cell lines with IC50 values ranging from 40.1 to 166.3 μg/mL. The ethanol extract of A. oxyphylla fruit, especially the EF, was found to possess potent antioxidant and anticancer activities, and thus a great potential for the application in food and drug products.

Cytotoxic steroids from the leaves of Dysoxylum binectariferum.

PubMed

Yan, Hui-Jiao; Wang, Jun-Song; Kong, Ling-Yi

2014-08-01

Four new cholestane-type (1-4) and two new ergostane-type (5, 6) steroids were isolated from the leaves of Dysoxylum binectariferum. Their structures were elucidated on the basis of spectroscopic analysis, including 1D and 2D NMR techniques. The absolute configurations were established by comparison with the literature and Mo2(OAc)4-induced electronic circular dichroism (ECD) data. All the isolates were evaluated for cytotoxicity against A549 (lung carcinoma), MCF-7 (breast adenocarcinoma), and HepG2 (hepatocellular carcinoma) human cancer cell lines. Three of the new cholestane-type steroids displayed potent antiproliferative effects on the tumor cells with IC50 values ranging from 1.5 to 9.6μM, whereas the two new ergostane-type (5, 6) steroids were deemed inactive. Copyright © 2014 Elsevier Inc. All rights reserved.

Variability in P-Glycoprotein Inhibitory Potency (IC50) Using Various in Vitro Experimental Systems: Implications for Universal Digoxin Drug-Drug Interaction Risk Assessment Decision Criteria

PubMed Central

Bentz, Joe; O’Connor, Michael P.; Bednarczyk, Dallas; Coleman, JoAnn; Lee, Caroline; Palm, Johan; Pak, Y. Anne; Perloff, Elke S.; Reyner, Eric; Balimane, Praveen; Brännström, Marie; Chu, Xiaoyan; Funk, Christoph; Guo, Ailan; Hanna, Imad; Herédi-Szabó, Krisztina; Hillgren, Kate; Li, Libin; Hollnack-Pusch, Evelyn; Jamei, Masoud; Lin, Xuena; Mason, Andrew K.; Neuhoff, Sibylle; Patel, Aarti; Podila, Lalitha; Plise, Emile; Rajaraman, Ganesh; Salphati, Laurent; Sands, Eric; Taub, Mitchell E.; Taur, Jan-Shiang; Weitz, Dietmar; Wortelboer, Heleen M.; Xia, Cindy Q.; Xiao, Guangqing; Yabut, Jocelyn; Yamagata, Tetsuo; Zhang, Lei

2013-01-01

A P-glycoprotein (P-gp) IC50 working group was established with 23 participating pharmaceutical and contract research laboratories and one academic institution to assess interlaboratory variability in P-gp IC50 determinations. Each laboratory followed its in-house protocol to determine in vitro IC50 values for 16 inhibitors using four different test systems: human colon adenocarcinoma cells (Caco-2; eleven laboratories), Madin-Darby canine kidney cells transfected with MDR1 cDNA (MDCKII-MDR1; six laboratories), and Lilly Laboratories Cells—Porcine Kidney Nr. 1 cells transfected with MDR1 cDNA (LLC-PK1-MDR1; four laboratories), and membrane vesicles containing human P-glycoprotein (P-gp; five laboratories). For cell models, various equations to calculate remaining transport activity (e.g., efflux ratio, unidirectional flux, net-secretory-flux) were also evaluated. The difference in IC50 values for each of the inhibitors across all test systems and equations ranged from a minimum of 20- and 24-fold between lowest and highest IC50 values for sertraline and isradipine, to a maximum of 407- and 796-fold for telmisartan and verapamil, respectively. For telmisartan and verapamil, variability was greatly influenced by data from one laboratory in each case. Excluding these two data sets brings the range in IC50 values for telmisartan and verapamil down to 69- and 159-fold. The efflux ratio-based equation generally resulted in severalfold lower IC50 values compared with unidirectional or net-secretory-flux equations. Statistical analysis indicated that variability in IC50 values was mainly due to interlaboratory variability, rather than an implicit systematic difference between test systems. Potential reasons for variability are discussed and the simplest, most robust experimental design for P-gp IC50 determination proposed. The impact of these findings on drug-drug interaction risk assessment is discussed in the companion article (Ellens et al., 2013) and recommendations are provided. PMID:23620485

Effect of citral on the cytotoxicity of doxorubicin in human B-lymphoma cells.

PubMed

Dangkong, Darinee; Limpanasithikul, Wacharee

2015-02-01

Doxorubicin is a chemotherapy agent used in non-Hodgkin's lymphoma but side effects limit its use. Citral is a mixture of neral and geranial found in essential oils of lemon grass. We evaluated the activity of citral, doxorubicin, and combination on cytotoxicity, apoptosis, and anti-proliferative effects using human lymphoma Ramos cells. Cells were treated with doxorubicin alone or in combination with citral (10, 20, and 40 μM). Cytotoxic and apoptosis studies were done after 24 and 18 h incubations, respectively. Cytotoxic effects of citral on normal human peripheral blood mononuclear cells (PBMCs) were also investigated for its safety. Changes in the expression of BCL-2 family genes were analyzed by quantitative RT-PCR. Citral had cytotoxicity on cells with an IC50 value of 77.19 ± 4.95 µM. Citral at concentrations of 10, 20, and 40 µM additively increased the cytotoxic and apoptotic effects of doxorubicin, leading to decreased IC50 (µM) of the drug from 2.50 ± 0.01 to 2.16 ± 0.03, 1.90 ± 0.04, and 1.23 ± 0.04, respectively. Enhanced cytotoxicity was not observed in normal human PBMCs. Citral (40 µM) in combination with doxorubicin (1.5 µM) increased the expression of pro-apoptotic protein BAK but significantly decreased the expression of anti-apoptotic protein BCL-XL to 5.26-fold compared with doxorubicin-treated cells. It did not change the anti-proliferative activity of drug. Citral potentiated cytotoxicity of doxorubicin by increasing apoptotic effects. We conclude that citral may have beneficial effects in patients with B cell lymphoma treated with chemotherapy.

Phytochemical and biological evaluation of some Sargassum species from Persian Gulf

PubMed Central

Mehdinezhad, Negin; Ghannadi, Alireza; Yegdaneh, Afsaneh

2016-01-01

Sea algae are widely consumed in the world. There are several seaweeds including brown algae which are authorized for human consumption. These plants contain important phytochemical constituents and have various potential biological activities. The present study investigated the presence of phytochemical constituents and total phenolic quantity of the seaweeds Sargassum angustifolium, Sargassum oligocystum and Sargassum boveanum. Cytotoxicity of seaweeds was tested against HT-29, HeLa and MCF-7 cell lines. Antioxidant potential of these 3 Sargassum species was also analyzed. Cytotoxicity was characterized by IC50 of human cancer cell lines using sulforhodamine assay. Antioxidant activities were evaluated using 2,2-diphenyl-1- picrylhydrazil. The analysis revealed that tannins, saponins, sterols and triterpenes were the most abundant compounds in these Sargassum species while cyanogenic and cardiac glycosides were the least ones. Sargassum angustifolium had the highest content of total phenolics (0.061 mg/g) and showed the highest antioxidant activity (IC50 = 0.231). Cytotoxic results showed that all species could inhibit cell growth effectively, especially MCF-7 cell line (IC50 = 67.3, 56.9, 60.4 for S. oligocystum, S. angustifolium and S. boveanum respectively). Considerable phytochemicals and moderate cytotoxic activity of S. angustifolium, S. oligocystum and S. boveanum make them appropriate candidate for further studies and identification of their bioactive principles. PMID:27499794

A cytotoxic substance from Sangre de Grado.

PubMed

Itokawa, H; Ichihara, Y; Mochizuki, M; Enomori, T; Morita, H; Shirota, O; Inamatsu, M; Takeya, K

1991-04-01

Taspine has been isolated as a cytotoxic substance from Sangre de Grado, sap of Croton palanostigma (Euphorbiaceae), by bioassay guided fractionation. The cytotoxicity (IC50) of taspine was found to be 0.39 microgram/ml against KB cells and 0.17 microgram/ml against V-79 cells.

Brazilian Red Propolis Induces Apoptosis-Like Cell Death and Decreases Migration Potential in Bladder Cancer Cells

PubMed Central

Begnini, Karine Rech; Moura de Leon, Priscila Marques; Thurow, Helena; Schultze, Eduarda; Campos, Vinicius Farias; Borsuk, Sibele; Dellagostin, Odir Antônio; Savegnago, Lucielli; Moura, Sidnei; Padilha, Francine F.; Pêgas Henriques, João Antonio; Seixas, Fabiana Kömmling

2014-01-01

Natural products continue to be an invaluable resource of anticancer drug discovery in recent years. Propolis is known for its biological activities such as antimicrobial and antitumor effects. This study assessed the effects of Brazilian red propolis (BRP) on apoptosis and migration potential in human bladder cancer cells. The effect of BRP ethanolic extract (25, 50, and 100 μg/mL) on 5637 cells was determined by MTT, LIVE/DEAD, and migration (scratch assay) assays. Apoptosis induction was investigated through flow cytometry and gene expression profile was investigated by qRT-PCR. Results showed cytotoxicity on MTT and LIVE/DEAD assays, with IC50 values of 95 μg/mL in 24 h of treatment. Cellular migration of 5637 cells was significantly inhibited through lower doses of BRP ethanolic extract (25 and 50 μg/mL). Flow cytometry analyses showed that BRP induced cytotoxicity through apoptosis-like mechanisms in 5637 cells and qRT-PCR revealed increased levels of Bax/Bcl-2 ratio, p53, AIF, and antioxidant enzymes genes. Data suggest that BRP may be a potential source of drugs to bladder cancer treatment. PMID:25530785

Antioxidant Effect of Berberine and its Phenolic Derivatives Against Human Fibrosarcoma Cells.

PubMed

Pongkittiphan, Veerachai; Chavasiri, Warinthorn; Supabphol, Roongtawan

2015-01-01

Berberine (B1), isolated from stems of Coscinium fenestratum (Goetgh.) Colebr, was used as a principle structure to synthesize three phenolic derivatives: berberrubine (B2) with a single phenolic group, berberrubine chloride (B3) as a chloride counter ion derivative, and 2,3,9,10-tetra-hydroxyberberine chloride (B4) with four phenolic groups, to investigate their direct and indirect antioxidant activities. For DPPH assay, compounds B4, B3, and B2 showed good direct antioxidant activity (IC50 values=10.7±1.76, 55.2±2.24, and 87.4±6.65 μM, respectively) whereas the IC50 value of berberine was higher than 500 μM. Moreover, compound B4 exhibited a better DPPH scavenging activity than BHT as a standard antioxidant (IC50=72.7±7.22 μM) due to the ortho position of hydroxyl groups and its capacity to undergo intramolecular hydrogen bonding. For cytotoxicity assay against human fibrosarcoma cells (HT1080) using MTT reagent, the sequence of IC50 value at 7-day treatment stated that B1

Brazilian red propolis induces apoptosis-like cell death and decreases migration potential in bladder cancer cells.

PubMed

Begnini, Karine Rech; Moura de Leon, Priscila Marques; Thurow, Helena; Schultze, Eduarda; Campos, Vinicius Farias; Martins Rodrigues, Fernanda; Borsuk, Sibele; Dellagostin, Odir Antônio; Savegnago, Lucielli; Roesch-Ely, Mariana; Moura, Sidnei; Padilha, Francine F; Collares, Tiago; Pêgas Henriques, João Antonio; Seixas, Fabiana Kömmling

2014-01-01

Natural products continue to be an invaluable resource of anticancer drug discovery in recent years. Propolis is known for its biological activities such as antimicrobial and antitumor effects. This study assessed the effects of Brazilian red propolis (BRP) on apoptosis and migration potential in human bladder cancer cells. The effect of BRP ethanolic extract (25, 50, and 100 μg/mL) on 5637 cells was determined by MTT, LIVE/DEAD, and migration (scratch assay) assays. Apoptosis induction was investigated through flow cytometry and gene expression profile was investigated by qRT-PCR. Results showed cytotoxicity on MTT and LIVE/DEAD assays, with IC50 values of 95 μg/mL in 24 h of treatment. Cellular migration of 5637 cells was significantly inhibited through lower doses of BRP ethanolic extract (25 and 50 μg/mL). Flow cytometry analyses showed that BRP induced cytotoxicity through apoptosis-like mechanisms in 5637 cells and qRT-PCR revealed increased levels of Bax/Bcl-2 ratio, p53, AIF, and antioxidant enzymes genes. Data suggest that BRP may be a potential source of drugs to bladder cancer treatment.

A new alkaloid from the fruit of Nandina domestica Thunb.

PubMed

Peng, Cai-Ying; Liu, Jian-Qun; Zhang, Rui; Shu, Ji-Cheng

2014-01-01

A new steroidal alkaloid, (20S,22R,24R)-24-ethyl-3-oxocholest-4-en-22-amino, named as nandsterine (1), together with 10 known alkaloids, palmatine (2), O-methylbulbocapnine (3), nantenine (4), dehydronantenine (5), glaucine (6), didehydroglaucine (7), dehydrocorydaline (8), jatrorrhizine (9), magnoflorine (10) and berberine (11), was isolated from the fruit of Nandina domestica Thunb. Their structures were elucidated by using spectroscopic methods as well as by comparing with the published data. Compound 1 was a new class of steroidal alkaloid isolated from the family Berberidaceae, meanwhile compounds 2, 3, 6-8 and 10 were obtained from N. domestica for the first time. Compound 1 exhibited cytotoxicity against HL-60 cells (human leukaemia) with IC50 values of 52.1 μM.

Cytotoxic Withanolide Constituents of Physalis longifolia

PubMed Central

Zhang, Huaping; Samadi, Abbas K.; Gallagher, Robert J.; Araya, Juan J.; Tong, Xiaoqin; Day, Victor W.; Cohen, Mark S.; Kindscher, Kelly; Gollapudi, Rao; Timmermann, Barbara N.

2011-01-01

Fourteen new withanolides 1-14, named withalongolides A-N, respectively, were isolated from the aerial parts of Physalis longifolia together with eight known compounds (15-22). The structures of compounds 1-14 were elucidated through spectroscopic techniques and chemical methods. In addition, the structures of withanolides 1, 2, 3, and 6 were confirmed by X-ray crystallographic analysis. Using a MTS viability assays, eight withanolides (1, 2, 3, 7, 8, 15, 16, and 19) and four acetylated derivatives (1a, 1b, 2a, and 2b) showed potent cytotoxicity against human head and neck squamous cell carcinoma (JMAR and MDA-1986), melanoma (B16F10 and SKMEL-28), and normal fetal fibroblast (MRC-5) cells with IC50 values in the range between 0.067 and 9.3 μM. PMID:22098611

Influence of the π-coordinated arene on the anticancer activity of ruthenium(II) carbohydrate organometallic complexes

NASA Astrophysics Data System (ADS)

Hanif, Muhammad; Meier, Samuel; Nazarov, Alexey; Risse, Julie; Legin, Anton; Casini, Angela; Jakupec, Michael; Keppler, Bernhard; Hartinger, Christian

2013-10-01

The synthesis and in vitro cytotoxicity of a series of RuII(arene) complexes with carbohydrate-derived phosphite ligands and various arene co-ligands is described. The arene ligand has a strong influence on the in vitro anticancer activity of this series of compounds, which correlates fairly well with cellular accumulation. The most lipophilic compound bearing a biphenyl moiety and a cyclohexylidene-protected carbohydrate is the most cytotoxic with unprecedented IC50 values for the compound class in three human cancer cell lines. This compound shows reactivity to the DNA model nucleobase 9-ethylguanine, but does not alter the secondary structure of plasmid DNA indicating that other biological targets are responsible for its cytotoxic effect.

New cytotoxic diarylheptanoids from the rhizomes of Alpinia officinarum Hance.

PubMed

Liu, Dan; Liu, Yan-Wen; Guan, Fu-Qin; Liang, Jing-Yu

2014-07-01

Two new dimeric diarylheptanoids, named Alpinin C (1) and D (2), a new natural product of diarylheptanoid (3) along with three known diarylheptanoids (4-6) were isolated from the rhizomes of Alpinia officinarum Hance. Their structures were elucidated based on extensive spectroscopic analyses (1D and 2D NMR, HRTOFMS, IR). The isolated compounds were evaluated for their cytotoxicity against human tumor cell lines HepG2, MCF-7, T98G and B16-F10. Compound 1 showed selective cytotoxicity against cell lines of MCF-7 and T98G, while compound 6 showed significant cytotoxicity to the all tested tumor cell lines with IC50 in the range from 8.46 to 22.68 μmol/L. Copyright © 2014 Elsevier B.V. All rights reserved.

Phytochemical and biological evaluation of some Sargassum species from Persian Gulf.

PubMed

Mehdinezhad, Negin; Ghannadi, Alireza; Yegdaneh, Afsaneh

2016-01-01

Sea algae are widely consumed in the world. There are several seaweeds including brown algae which are authorized for human consumption. These plants contain important phytochemical constituents and have various potential biological activities. The present study investigated the presence of phytochemical constituents and total phenolic quantity of the seaweeds Sargassum angustifolium, Sargassum oligocystum and Sargassum boveanum. Cytotoxicity of seaweeds was tested against HT-29, HeLa and MCF-7 cell lines. Antioxidant potential of these 3 Sargassum species was also analyzed. Cytotoxicity was characterized by IC50 of human cancer cell lines using sulforhodamine assay. Antioxidant activities were evaluated using 2,2-diphenyl-1- picrylhydrazil. The analysis revealed that tannins, saponins, sterols and triterpenes were the most abundant compounds in these Sargassum species while cyanogenic and cardiac glycosides were the least ones. Sargassum angustifolium had the highest content of total phenolics (0.061 mg/g) and showed the highest antioxidant activity (IC50 = 0.231). Cytotoxic results showed that all species could inhibit cell growth effectively, especially MCF-7 cell line (IC50 = 67.3, 56.9, 60.4 for S. oligocystum, S. angustifolium and S. boveanum respectively). Considerable phytochemicals and moderate cytotoxic activity of S. angustifolium, S. oligocystum and S. boveanum make them appropriate candidate for further studies and identification of their bioactive principles.

Comparative cytotoxicity of artemisinin and cisplatin and their interactions with chlorogenic acids in MCF7 breast cancer cells.

PubMed

Suberu, John O; Romero-Canelón, Isolda; Sullivan, Neil; Lapkin, Alexei A; Barker, Guy C

2014-12-01

In parts of Africa and Asia, self-medication with a hot water infusion of Artemisia annua (Artemisia tea) is a common practice for a number of ailments including malaria and cancer. In our earlier work, such an extract showed better potency than artemisinin alone against both chloroquine-sensitive and -resistant parasites. In this study, in vitro tests of the infusion in MCF7 cells showed high IC50 values (>200 μM). The combination of artemisinin and 3-caffeoylquinic acid (3CA), two major components in the extract, was strongly antagonistic and gave a near total loss of cytotoxicity for artemisinin. We observed that the interaction of 3CAs with another cytotoxic compound, cisplatin, showed potentiation of activity by 2.5-fold. The chelation of cellular iron by 3CA is hypothesized as a possible explanation for the loss of artemisinin activity. © 2014 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Synthesis and biological evaluation of novel 6-hydroxy-benzo[d][1,3]oxathiol-2-one Schiff bases as potential anticancer agents.

PubMed

Chazin, Eliza de Lucas; Sanches, Paola de Souza; Lindgren, Eric Brazil; Vellasco Júnior, Walcimar Trindade; Pinto, Laine Celestino; Burbano, Rommel Mario Rodríguez; Yoneda, Julliane Diniz; Leal, Kátia Zaccur; Gomes, Claudia Regina Brandão; Wardell, James Lewis; Wardell, Solange Maria Silva Veloso; Montenegro, Raquel Carvalho; Vasconcelos, Thatyana Rocha Alves

2015-01-27

With the aim of discovering new anticancer agents, we have designed and synthesized novel 6-hydroxy-benzo[d][1,3]oxathiol-2-one Schiff bases. The synthesis started with the selective nitration at 5-position of 6-hydroxybenzo[d][1,3]oxathiol-2-one (1) leading to the nitro derivative 2. The nitro group of 2 was reduced to give the amino intermediate 3. Schiff bases 4a-r were obtained from coupling reactions between 3 and various benzaldehydes and heteroaromatic aldehydes. All the new compounds were fully identified and characterized by NMR (1H and 13C) and specifically for 4q by X-ray crystallography. The in vitro cytotoxicity of the compounds was evaluated against cancer cell lines (ACP-03, SKMEL-19 and HCT-116) by using MTT assay. Schiff bases 4b and 4o exhibited promising cytotoxicity against ACP-03 and SKMEL-19, respectively, with IC50 values lower than 5 μM. This class of compounds can be considered as a good starting point for the development of new lead molecules in the fight against cancer.

Safety assessment of sodium acetate, sodium diacetate and potassium sorbate food additives.

PubMed

Mohammadzadeh-Aghdash, Hossein; Sohrabi, Yousef; Mohammadi, Ali; Shanehbandi, Dariush; Dehghan, Parvin; Ezzati Nazhad Dolatabadi, Jafar

2018-08-15

Cytotoxicity and genotoxicity of sodium acetate (SA), sodium diacetate (SDA), and potassium sorbate (PS) was tested on Human Umbilical Vein Endothelial Cells (HUVEC). Cytotoxicity was investigated by MTT assay and flow cytometry analysis, while genotoxicity was evaluated using DNA fragmentation and DAPI staining assays. The growth of treated HUVECs with various concentrations of SA, SDA and PS decreased in a dose-and time-dependent manner. The IC50 of 487.71, 485.82 and 659.96 µM after 24 h and IC50 of 232.05, 190.19 and 123.95 µM after 48 h of treatment were attained for SA, SDA and PS, respectively. Flow cytometry analysis showed that early and late apoptosis percentage in treated cells was not considerable. Also neither considerable DNA fragmentation nor DNA smear was observed using DAPI staining and DNA ladder assays. Overall, it can be concluded that the aforementioned food additives can be used as safe additives at low concentration in food industry. Copyright © 2018 Elsevier Ltd. All rights reserved.

Antiplasmodial activities of gold(I) complexes involving functionalized N-heterocyclic carbenes.

PubMed

Hemmert, Catherine; Ramadani, Arba Pramundita; Boselli, Luca; Fernández Álvarez, Álvaro; Paloque, Lucie; Augereau, Jean-Michel; Gornitzka, Heinz; Benoit-Vical, Françoise

2016-07-01

A series of twenty five molecules, including imidazolium salts functionalized by N-, O- or S-containing groups and their corresponding cationic, neutral or anionic gold(I) complexes were evaluated on Plasmodium falciparum in vitro and then on Vero cells to determine their selectivity. Among them, eight new compounds were synthesized and fully characterized by spectroscopic methods. The X-ray structures of three gold(I) complexes are presented. Except one complex (18), all the cationic gold(I) complexes show potent antiplasmodial activity with IC50 in the micro- and submicromolar range, correlated with their lipophilicity. Structure-activity relationships enable to evidence a lead-complex (21) displaying a good activity (IC50=210nM) close to the value obtained with chloroquine (IC50=514nM) and a weak cytotoxicity. Copyright © 2016 Elsevier Ltd. All rights reserved.

Screening and HPLC-Based Activity Profiling for New Antiprotozoal Leads from European Plants

PubMed Central

Zimmermann, Stefanie; Thomi, Semira; Kaiser, Marcel; Hamburger, Matthias; Adams, Michael

2012-01-01

Based on a survey of remedies used in Renaissance Europe to treat malaria, we prepared and screened a library of 254 extracts from 61 plants for antiplasmodial activity in vitro. HPLC-based activity profiling was performed for targeted identification of active constituents in extracts. One of the most remarkable results was the identification of onopordopicrin, a germacranolide sesquiterpene lactone isolated from Arctium nemorosum as a potent inhibitor of P. falciparum with an IC50 of 6.9 μM. It was tested similarly against Trypanosoma brucei rhodesiense, the parasite which causes African sleeping sickness. With an IC50 of 0.37 μM, onopordopicrin was one of the most potent natural products reported so far. Cytotoxicity was determined against rat myoblast L6 cells (IC50: 3.06). PMID:22396915

Mapping Genes that Contribute to Daunorubicin-Induced Cytotoxicity

PubMed Central

Duan, Shiwei; Bleibel, Wasim K.; Huang, Rong Stephanie; Shukla, Sunita J.; Wu, Xiaolin; Badner, Judith A.; Dolan, M. Eileen

2009-01-01

Daunorubicin is an anthracycline antibiotic agent used in the treatment of hematopoietic malignancies. Toxicities associated with this agent include myelosuppression and cardiotoxicity; however, the genes or genetic determinants that contribute to these toxicities are unknown. We present an unbiased genome-wide approach that incorporates heritability, whole-genome linkage analysis, and linkage-directed association to uncover genetic variants contributing to the sensitivity to daunorubicin-induced cytotoxicity. Cell growth inhibition in 324 Centre d’ Etude du Polymorphisme Humain lymphoblastoid cell lines (24 pedigrees) was evaluated following treatment with daunorubicin for 72 h. Heritability analysis showed a significant genetic component contributing to the cytotoxic phenotypes (h2 = 0.18–0.63at 0.0125, 0.025, 0.05, 0.1, 0.2, and 1.0 µmol/L daunorubicin and at the IC50, the dose required to inhibit 50% cell growth). Whole-genome linkage scans at all drug concentrations and IC50 uncovered 11 regions with moderate peak LOD scores (>1.5), including 4q28.2 to 4q32.3 with a maximum LOD score of 3.18. The quantitative transmission disequilibrium tests were done using 31,312 high-frequency single-nucleotide polymorphisms (SNP) located in the 1 LOD confidence interval of these 11 regions. Thirty genes were identified as significantly associated with daunorubicin-induced cytotoxicity (P ≤ 2.0 × 10−4, false discovery rate ≤ 0.1). Pathway and functional gene ontology analysis showed that these genes were overrepresented in the phosphatidylinositol signaling system, axon guidance pathway, and GPI-anchored proteins family. Our findings suggest that a proportion of susceptibility to daunorubicin-induced cytotoxicity may be controlled by genetic determinants and that analysis using linkage-directed association studies with dense SNP markers can be used to identify the genetic variants contributing to cytotoxicity. PMID:17545624

Diterpenoids from Azorella compacta (Umbelliferae) active on Trypanosoma cruzi.

PubMed

Araya, Jorge E; Neira, Iván; da Silva, Solange; Mortara, Renato A; Manque, Patricio; Cordero, Esteban; Sagua, Hernán; Loyola, Alberto; Bórquez, Jorge; Morales, Glauco; González, Jorge

2003-04-01

The anti-Trypanosoma cruzi activity of natural products isolated from Azorella compacta was evaluated, with particular emphasis on their effect against intracellular amastigotes. Five diterpenoids from A. compacta derived from mulinane and azorellane were isolated and identified. Only two products, named azorellanol (Y-2) and mulin-11,3-dien-20-oic acid (Y-5), showed trypanocidal activity against all stages of T. cruzi including intracellular amastigotes. At 10 M, these compounds displayed a strong lytic activity. It ranged from 88.4 0.6 to 99.0 1 % for all strains and stages evaluate, with an IC50 /18 h values of 20-84 M and 41-87 M, respectively. The development of intracellular amastigotes was also inhibited by nearly 60% at 25 M. The trypanocidal molecules Y-2 and Y-5 did show different degrees of cytotoxicity depending on the cell line tested, with an IC50 /24 h ranging from 33.2 to 161.2 M. We evaluated the effect of diterpenoids against intracellular T. cruzi forms by immunofluorescent identification of a specific membrane molecular marker (Ssp-4 antigen) of the T. cruzi amastigote forms. The accuracy and reproducibility of the measurements were found to be outstanding when examined by confocal microscopy.

2-(3′-Indolyl)-N-arylthiazole-4-carboxamides: Synthesis and evaluation of antibacterial and anticancer activities

PubMed Central

Tantak, Mukund P.; Wang, Jing; Singh, Rajnish Prakash; Kumar, Anil; Shah, Kavita; Kumar, Dalip

2015-01-01

A new series of 2-(3′-indolyl)-N-arylthiazole-4-carboxamides 17a-p has been designed and synthesized. Initial reaction of readily available thioamides 15 with bromopyruvic acid under refluxing conditions produced different thiazole carboxylic acids 16 which upon coupling with arylamines by using EDCI.HCl and HOBt afforded diverse arylthiazole-4-carboxamides 17a-p in 78-87% yields. Antibacterial activity evaluation against Gram-positive and Gram-negative bacterial strains led to compounds 17i-k and 17o as potent and selectively (Gram-negative) antibacterial agents. The cytotoxicity of thiazole carboxamides 17a-p was also evaluated on a panel of human cancer cell lines. Among the tested derivatives, compounds 17i (IC50 = 8.64 μM; HEK293T) and 17l (IC50 = 3.41 μM; HeLa) were identified as the most potent analogues of the series. Preliminary mechanism of action studies of thiazole carboxamide 17i suggested that its cytotoxicity against HeLa cells involves the induction of cell death by apoptosis. PMID:26298501

Development of piperic acid derivatives from Piper nigrum as UV protection agents.

PubMed

Choochana, Piyapong; Moungjaroen, Jirapan; Jongkon, Nathjanan; Gritsanapan, Wandee; Tangyuenyongwatana, Prasan

2015-04-01

There is a need for the discovery of novel natural and semi-synthetic sunscreen that is safe and effective. Piperine has a UV absorption band of 230-400 nm with high molar absorptivity. This compound has a high potential to be developed to sunscreen. This study develops new UV protection compounds from piperine by using chemical synthesis. Piperine was isolated from Piper nigrum L. (Piperaceae) fruits, converted to piperic acid by alkaline hydrolysis, and prepared as ester derivatives by chemical synthesis. The piperate derivatives were prepared as 5% o/w emulsion, and the SPF values were evaluated. The best compound was submitted to cytotoxicity test using MTT assay. Piperic acid was prepared in 86.96% yield. Next, piperic acid was reacted with alcohols using Steglich reaction to obtain methyl piperate, ethyl piperate, propyl piperate, isopropyl piperate, and isobutyl piperate in 62.39-92.79% yield. All compounds were prepared as 5% oil in water emulsion and measured its SPF and UVA/UVB values using an SPF-290S analyzer. The SPF values (n = 6) of the piperate derivatives were 2.68 ± 0.17, 8.89 ± 0.46, 6.86 ± 0.91, 16.37 ± 1.8, and 9.68 ± 1.71. The UVA/UVB ratios of all compounds ranged from 0.860 to 0.967. Cytotoxicity of isopropyl piperate was evaluated using human skin fibroblast cells and the IC50 was equal to 120.2 μM. From the results, isopropyl piperate is an outstanding compound that can be developed into a UV protection agent.

In vitro antitumour activity of orsellinates.

PubMed

Bogo, Danielle; de Matos, Maria Fatima Cepa; Honda, Neli Kika; Pontes, Elenir Curi; Oguma, Patricia Midori; da Santos, Evelyn Cristina Silva; de Carvalho, João Ernesto; Nomizo, Auro

2010-01-01

Lichen phenolic compounds exhibit antioxidant, antimicrobial, antiproliferative, and cytotoxic activities. The purpose of this study was to evaluate the anticancer activity of lecanoric acid, a secondary metabolite of the lichen Parmotrema tinctorum, and its derivatives, orsellinates, obtained by structural modification. A cytotoxicity assay was carried out in vitro with sulforhodamine B (SRB) using HEp-2 larynx carcinoma, MCF7 breast carcinoma, 786-0 kidney carcinoma, and B16-F10 murine melanoma cell lines, in addition to a normal (Vero) cell line in order to calculate the selectivity index of the compounds. n-Butyl orsellinate was the most active compound, with IC50 values (the concentration that inhibits 50% of growth) ranging from 7.2 to 14.0 microg/mL, against all the cell lines tested. The compound was more active (IC50 = 11.4 microg/mL) against B16-F10 cells than was cisplatin (12.5 microg/mL). Conversely, lecanoric acid and methyl orsellinate were less active against all cell lines, having an IC50 value higher than 50 microg/mL. Ethyl orsellinate was more active against HEp-2 than against MCF7, 786-0, or B16-F10 cells. The same pattern was observed for n-propyl and n-butyl orsellinates. n-Pentyl orsellinate was less active than n-propyl or n-butyl orsellinates against HEp-2 cells. The orsellinate activity increased with chain elongation (from methyl to n-butyl), a likely consequence of an increase in lipophilicity. The results revealed that the structural modification of lecanoric acid increases the cytotoxic activity of the derivatives tested.

Cytotoxic activities of Coriolus versicolor (Yunzhi) extract on human leukemia and lymphoma cells by induction of apoptosis.

PubMed

Lau, C B S; Ho, C Y; Kim, C F; Leung, K N; Fung, K P; Tse, T F; Chan, H H L; Chow, M S S

2004-07-02

Coriolus versicolor (CV), also known as Yunzhi, is one of the commonly used Chinese medicinal herbs. Although recent studies have demonstrated its antitumour activities on cancer cells in vitro and in vivo, the exact mechanism is not fully elucidated. Hence, the objective of this study was to examine the in vitro cytotoxic activities of a standardized aqueous ethanol extract prepared from Coriolus versicolor on a B-cell lymphoma (Raji) and two human promyelocytic leukemia (HL-60, NB-4) cell lines using a MTT cytotoxicity assay, and to test whether the mechanism involves induction of apoptosis. Cell death ELISA was employed to quantify the nucleosome production resulting from nuclear DNA fragmentation during apoptosis. The present results demonstrated that CV extract at 50 to 800 microg/ml dose-dependently suppressed the proliferation of Raji, NB-4, and HL-60 cells by more than 90% (p < 0.01), with ascending order of IC50 values: HL-60 (147.3 +/- 15.2 microg/ml), Raji (253.8 +/- 60.7 microg/ml) and NB-4 (269.3 +/- 12.4 microg/ml). The extract however did not exert any significant cytotoxic effect on normal liver cell line WRL (IC50 > 800 microg/ml) when compared with a chemotherapeutic anticancer drug, mitomycin C (MMC), confirming the tumour-selective cytotoxicity. Nucleosome productions in HL-60, NB-4 and Raji cells were significantly increased by 3.6-, 3.6- and 5.6-fold respectively upon the treatment of CV extract, while no significant nucleosome production was detected in extract-treated WRL cells. The CV extract was found to selectively and dose-dependently inhibit the proliferation of lymphoma and leukemic cells possibly via an apoptosis-dependent pathway. Copyright 2004 Elsevier Inc.

Biological and Phytochemical Investigations on Caesalpinia benthamiana, a Plant Traditionally Used as Antimalarial in Guinea

PubMed Central

Loua, Jean; Traore, Mohamed Sahar; Camara, Aissata; Balde, Mamadou Aliou; Maes, Louis; Pieters, Luc

2017-01-01

Caesalpinia benthamiana is widely used as antimalarial in Guinean traditional medicine. Leaf extracts of the plant were tested for their in vitro antiprotozoal activity against Trypanosoma brucei brucei and T. cruzi and the chloroquine-sensitive Ghana strain of Plasmodium falciparum along with their cytotoxicity on MRC-5 cells. The methanolic extract showed the strongest antiprotozoal activity against P. falciparum (IC50 4 μg/ml), a good activity against T. brucei (IC50 13 μg/ml), and a moderate activity against T. cruzi (IC50 31 μg/ml) along with an IC50 on human MRC-5 cells of 32 μg/ml. Bioassay-guided fractionation from the methanolic extract led to antiplasmodially active subfractions. A prospective, placebo-controlled ethnotherapeutic trial assessed the antimalarial effectiveness and tolerability of C. benthamiana syrup administered orally to children with uncomplicated malaria as compared with chloroquine syrup. Phytochemical screening of the leaf extracts indicated the presence of flavonoids, terpenoids, tannins, saponins, and iridoids. PMID:29081823

New Dihydro-β-agarofuran Sesquiterpenes from Parnassia wightiana Wall: Isolation, Identification and Cytotoxicity against Cancer Cells

PubMed Central

Lv, Chao; Zheng, Zuo-Lue; Miao, Fang; Geng, Hui-Ling; Zhou, Le; Liu, La-Ping

2014-01-01

Five new (4–8) and three known (1–3) dihydro-β-agarofuran sesquiterpene polyesters were isolated from the whole plants of Parnassia wightiana. The structures of all compounds were elucidated through spectroscopic analysis including 2D-NMR and HR-MS. The absolute configuration of these compounds was established by X-ray diffraction analysis, comparison of NOESY spectra and biogenetic means. The cytotoxities of compounds 2–8 were evaluated in vitro against HL-60, SMMC-7721, A549, MCF-7 and SW480 cell lines. Compounds 5–7 exhibited the highest activities with IC50 values of 11.8–30.1 μM in most cases. The SAR revealed that the introduction of hydroxyl group was able to significantly improve the activities of the compounds for most of the cell lines. PMID:24955789

ICECAP: an integrated, general-purpose, automation-assisted IC50/EC50 assay platform.

PubMed

Li, Ming; Chou, Judy; King, Kristopher W; Jing, Jing; Wei, Dong; Yang, Liyu

2015-02-01

IC50 and EC50 values are commonly used to evaluate drug potency. Mass spectrometry (MS)-centric bioanalytical and biomarker labs are now conducting IC50/EC50 assays, which, if done manually, are tedious and error-prone. Existing bioanalytical sample preparation automation systems cannot meet IC50/EC50 assay throughput demand. A general-purpose, automation-assisted IC50/EC50 assay platform was developed to automate the calculations of spiking solutions and the matrix solutions preparation scheme, the actual spiking and matrix solutions preparations, as well as the flexible sample extraction procedures after incubation. In addition, the platform also automates the data extraction, nonlinear regression curve fitting, computation of IC50/EC50 values, graphing, and reporting. The automation-assisted IC50/EC50 assay platform can process the whole class of assays of varying assay conditions. In each run, the system can handle up to 32 compounds and up to 10 concentration levels per compound, and it greatly improves IC50/EC50 assay experimental productivity and data processing efficiency. © 2014 Society for Laboratory Automation and Screening.

(+)-rumphiin and polyalthurea, new compounds from the stems of Polyalthia rumphii.

PubMed

Wang, Tian-Shan; Luo, You-Ping; Wang, Jing; He, Meng-Xiong; Zhong, Ming-Guo; Li, Ying; Song, Xiao-Ping

2013-10-01

Two new compounds, (+)-rumphiin (3) and polyalthurea (7), together with seven known ones, 3,4,5-trimethoxy benzoic acid (1), (-)-seselinone (2), cannabisin D (4), allantoin (5), oxostephanine (6) and a mixture of beta-sitosterol (8) and stigmasterol (9) were isolated from the stems of Polyalthia rumphii. The chemical structures of 3 and 7 were elucidated by the combination of spectroscopic data, and the absolute configuration of 3 at C-2 was determined by the matrix method to be R. All compounds were evaluated for their cytotoxicity on four human cancer cell lines, which demonstrated that 3 was a moderate bioactive lignan, and 6 showed significant anticancer activity against SPC-A-1 and BEL-7402 cell lines with IC50 values of 1.47 and 1.73 microg/mL, respectively.

Further drimane sesquiterpenes from Drimys brasiliensis stem barks with cytotoxic potential.

PubMed

Fratoni, Eduarda; Claudino, Vanessa Duarte; Yunes, Rosendo Augusto; Franchi, Gilberto C; Nowill, Alexandre E; Filho, Valdir Cechinel; Monache, Franco Delle; Malheiros, Angela

2016-07-01

Drimys brasiliensis Miers (Winteraceae) is used in folk medicine for the treatment of cancer. Its anti-tumor activity has been demonstrated in vitro models using extracts and isolated compounds. This study investigates the cytotoxic effects of stem bark extracts of D. brasiliensis as well as isolated compounds that may be responsible for the activitys and evaluates them in leukemia cells. The stem bark extract were subjected to column chromatography, and the structures of compounds were elucidated based on spectroscopic methods by using NMR and infrared spectroscopy and GC/MS. The cytotoxicity of the isolated compounds was evaluated in chronic myeloid (K562) and acute B lymphoblastic (Nalm6) leukemia cells using tetrazolium assay (MTT). Two new compounds were isolated 1β-O-p-methoxy-E-cinnamoyl-5α-keto-11α-enol-albicanol (1a) and the isomer 1β-O-p-methoxy-E-cinnamoyl-5α-keto-11β-enol-albicanol (1b) and 1β-O-p-methoxy-E-cinnamoyl-isodrimeninol (2). The known compounds polygonal acid (3a) and the isomer isopolygonal acid (3b), fuegin (4a) and the isomer epifuegin (4b), the mixture drimanial (5) and 1β-O-(p-methoxy-E-cinnamoyl)-6α-hydroxypolygodial (6) were also isolated. The drimanes (1-4) and drimanial (5), 1β-(p-coumaroyloxy)-polygodial (7), 1β-(p-methoxycinnamoyl)-polygodial (8), and polygodial (9) isolated previously were assessed in tumor cells. The IC50 values were between 3.56 and 128.91 μM. 1-β-(p-cumaroiloxi)-polygodial showed the best result with IC50 8.18 and 3.56 μM by K562 and Nalm6, respectively. The chloroform extract of the stem bark of D. brasiliensis is a great source of drimane sesquiterpenes. Our experimental data suggest that drimanes are responsible for cytotoxicity activity demonstrated by this species, especially those with the aldehyde group linked to carbons C-11 and C-12.

Cecropin A-melittin mutant with improved proteolytic stability and enhanced antimicrobial activity against bacteria and fungi associated with gastroenteritis in vitro.

PubMed

Ji, Shengyue; Li, Weili; Zhang, Lei; Zhang, Yue; Cao, Binyun

2014-09-05

Cecropin A-melittin (CAM), a chimeric antimicrobial peptide with potent antimicrobial activity, is threatened by some special extracellular proteases when used to deal with certain drug-resistant pathogenic microbes in the gastrointestinal tract. Thus, a four-tryptophan-substitution mutant (CAM-W) from CAM was developed via the replacement of special amino acid residues to enhance the antimicrobial potency and to improve the proteolytic stability of this agent. The pharmaceutical index of CAM-W was investigated, with a focus on biological potency, cytotoxicity, and proteolytic stability, as well as pH and thermal resistance. CAM-W exhibited potent antimicrobial activity and was approximately 3-12 times higher than that of CAM. CAM-W also exhibited a strong antifungal activity against a series of common pathogenic fungi, in a lower IC50 range between 2.1mg/L and 3.3mg/L than that of its reference CAM ranging from 9.8mg/L to 14.2mg/L. Besides, CAM-W showed moderate cytotoxicity (IC50>300mg/L) in erythrocyte lysis test. In addition, CAM-W overcame challenges under various conditions, including specific temperatures (20, 30, 40, 50, 60, 70, 80, and 90°C), pH values (2.0, 3.0, 4.0, 5.0, 6.0, 7.0, 8.0, and 9.0), and proteases (trypsin, pepsin, human neutrophil elastase, Pseudomonas aeruginosa elastase, and Staphylococcus aureus V8 protease) that are commonly present in human gastrointestinal tract. These results suggest that the four-tryptophan-substitution can confer CAM-W with a high pharmaceutical index, which is important for CAM-W to become a potential alternative to conventional antibiotics against bacteria and fungi associated with gastroenteritis. Copyright © 2014 Elsevier Inc. All rights reserved.

Amantelides A and B, Polyhydroxylated Macrolides with Differential Broad Spectrum Cytotoxicity from a Guamanian Marine Cyanobacterium

PubMed Central

Salvador-Reyes, Lilibeth A.; Sneed, Jennifer; Paul, Valerie J.; Luesch, Hendrik

2016-01-01

Cytotoxicity-guided fractionation of a Guamanian cyanobacterial collection yielded the new compounds amantelides A (1) and B (2). These polyketides are characterized by a 40-membered macrolactone ring consisting of a 1,3-diol and contiguous 1,5-diol units and a tert-butyl substituent. Amantelide A (1) displayed potent cytotoxicity with sub-micromolar IC50 against HT29 colorectal adenocarcinoma and HeLa cervical carcinoma cell lines. Acetylation of the hydroxy group at C-33 in 2 caused a close to 10-fold decrease in potency. Exhaustive acetylation of the hydroxy groups abrogated the antiproliferative activity of amantelide A (1) by 20–67-fold. Further bioactivity assessment of 1 against bacterial pathogens and marine fungi indicated a broad spectrum of bioactivity. PMID:26204500

Anti-infective and cytotoxic properties of Bupleurum marginatum

PubMed Central

2014-01-01

Background Bupleurum marginatum Wall. ex DC (Apiaceae) is a perennial herb widely used in traditional Chinese and Kampo medicine for the treatment of various infectious diseases. The biological activities of B. marginatum have not been fully investigated. This study aims to investigate the antitrypanosomal, antimicrobial and antiviral activities of methanol (ME) and dichloromethane (DCM) extracts of B. marginatum aerial parts and the ability of both extracts to inhibit the growth of different cancer cell lines. Methods Phytochemical characterization of the extracts was performed by LC-MS profiling. The antitrypanosomal activity was evaluated using the resazurin method. The antimicrobial activity was assessed using agar diffusion and microdilution methods, and the minimum inhibitory concentration (MIC) values were determined. The antiviral activity was determined for 6.25, 12.5, and 50 μg/mL doses using a plaque reduction assay. Cytotoxicity was investigated in eight cancer cell lines (Caco-2, CCL-81, CCRF-CEM, COS-7, HL-60, MIA PaCa-2, MCF-7, and PANC-1) using the MTT assay and the caspase 3/7 activity was determined over the range of 62.5–1000 μg/mL. Results Phytochemical analyses resulted in the characterization of 15 components, mainly flavonoids and lignans. The DCM extract showed significant antitrypanosomal activity (IC50: 36.21 μg/mL) and moderate activity against Streptococcus pyogenes (MIC value: 0.25 mg/mL). At a dose of 12.5 μg/mL, the DCM extract inhibited 73.6% of the plaque production by hepatitis A virus. CCRF-CEM cells were the most sensitive to both extracts (IC50: 12.5–22.7 μg/mL). The cytotoxicity was mediated by induction of apoptosis (19-fold increase in the cellular caspase 3/7 level after treatment with the DCM extract at 1 mg/mL). Conclusions ME and DCM extract of B. marginatum showed anti-infective and antiproliferative effects. PMID:24438177

Discovery of Novel Hepatitis C Virus NS5B Polymerase Inhibitors by Combining Random Forest, Multiple e-Pharmacophore Modeling and Docking

PubMed Central

Wei, Yu; Li, Jinlong; Qing, Jie; Huang, Mingjie; Wu, Ming; Gao, Fenghua; Li, Dongmei; Hong, Zhangyong; Kong, Lingbao; Huang, Weiqiang; Lin, Jianping

2016-01-01

The NS5B polymerase is one of the most attractive targets for developing new drugs to block Hepatitis C virus (HCV) infection. We describe the discovery of novel potent HCV NS5B polymerase inhibitors by employing a virtual screening (VS) approach, which is based on random forest (RB-VS), e-pharmacophore (PB-VS), and docking (DB-VS) methods. In the RB-VS stage, after feature selection, a model with 16 descriptors was used. In the PB-VS stage, six energy-based pharmacophore (e-pharmacophore) models from different crystal structures of the NS5B polymerase with ligands binding at the palm I, thumb I and thumb II regions were used. In the DB-VS stage, the Glide SP and XP docking protocols with default parameters were employed. In the virtual screening approach, the RB-VS, PB-VS and DB-VS methods were applied in increasing order of complexity to screen the InterBioScreen database. From the final hits, we selected 5 compounds for further anti-HCV activity and cellular cytotoxicity assay. All 5 compounds were found to inhibit NS5B polymerase with IC50 values of 2.01–23.84 μM and displayed anti-HCV activities with EC50 values ranging from 1.61 to 21.88 μM, and all compounds displayed no cellular cytotoxicity (CC50 > 100 μM) except compound N2, which displayed weak cytotoxicity with a CC50 value of 51.3 μM. The hit compound N2 had the best antiviral activity against HCV, with a selective index of 32.1. The 5 hit compounds with new scaffolds could potentially serve as NS5B polymerase inhibitors through further optimization and development. PMID:26845440

Cucurbitane-type triterpenoids from the stems and leaves of Momordica charantia.

PubMed

Zhao, Gao-Ting; Liu, Jie-Qing; Deng, Yuan-Yuan; Li, Hai-Zhou; Chen, Jian-Chao; Zhang, Zhi-Run; Zhou, Lin; Qiu, Ming-Hua

2014-06-01

Six new cucurbitane-type triterpenoids, karavilagenin F (1), karavilosides XII and XIII (2, 3), momordicines VI, VII, and VIII (4, 5 and 6), along with four known ones, 5β,19-epoxy-25-methoxycucurbita-6,23-diene-3β,19-diol (7), 5β,19-epoxycucurbita-6, 23-diene-3β,19,25-triol (8), kuguacin R (9), and (19R,23E)-5β,19-epoxy-19-methoxycucurbita-6,23,25-trien-3β-ol (10), were isolated from the stems and leaves of Momordica charantia L. Their chemical structures were elucidated by extensive 1D NMR and 2D NMR (HSQC, HMBC, COSY, and ROESY), MS experiments, and CD spectrum. Compound 6 showed weak cytotoxicity against five human cancer cells lines with IC50 values of 14.3-20.5μmol/L. Copyright © 2014 Elsevier B.V. All rights reserved.

Phenylquinolinones with antitumor activity from the Indian Ocean-derived fungus Aspergillus versicolor Y31-2

NASA Astrophysics Data System (ADS)

Li, Peihai; Fan, Yaqin; Chen, Hao; Chao, Yaxi; Du, Ning; Chen, Junhui

2016-09-01

Two phenylquinolinones, including one new compound ( 1) and a previously isolated compound ( 2), were isolated from the ethyl acetate extracts of the fungus Aspergillus versicolor Y31-2, which was obtained from seawater samples collected from the Indian Ocean. The structures of these compounds were established by spectroscopic analyses. 4-(3-Hydroxyphenyl)-3-methoxyquinolin-2(1H)-one ( 1) exhibited moderate cytotoxicity against MCF-7 (human breast carcinoma cell line) and SMMC-7721 (human liver cancer cell line) cells with IC50 values of 16.6 and 18.2 μmol/L, respectively. To the best of our knowledge, this study represents the first reported account of the isolation of compounds 1 and 2 as the secondary metabolites of the seawater derived fungus Aspergillus versicolor from the Indian Ocean.

Cytotoxic bibenzyl dimers from the stems of Dendrobium fimbriatum Hook.

PubMed

Xu, Feng-Qing; Xu, Fang-Cheng; Hou, Bo; Fan, Wei-Wei; Zi, Cheng-Ting; Li, Yan; Dong, Fa-Wu; Liu, Yu-Qing; Sheng, Jun; Zuo, Zhi-Li; Hu, Jiang-Miao

2014-11-15

The bioassay-guided chemical investigation of the stems of Dendrobium fimbriatum Hook led to the isolation of seven first reported bibenzyl dimers with a linkage of a methylene moiety, fimbriadimerbibenzyls A-G (1-7), together with a new dihydrophenanthrene derivative (S)-2,4,5,9-tetrahydroxy-9,10-dihydrophenanthrene (8) and thirteen known compounds (9-21). The structure of the new compound was established by spectroscopic analysis. Biological evaluation of bibenzyl derivatives against five human cell lines indicated that seven of those compounds exhibited broad-spectrum and cytotoxic activities with IC50 values ranging from 2.2 to 21.2 μM. Those rare bibenzyl dimers exhibited cytotoxic activities in vitro and the cytotoxicity decreased as the number of oxygen-containing groups in the structure decreases. Copyright © 2014 Elsevier Ltd. All rights reserved.

Antitumor effect of the essential oil from leaves of Guatteria pogonopus (Annonaceae).

PubMed

do N Fontes, José Eraldo; Ferraz, Rosana P C; Britto, Anny C S; Carvalho, Adriana A; Moraes, Manoel O; Pessoa, Claudia; Costa, Emmanoel V; Bezerra, Daniel P

2013-04-01

Guatteria pogonopus Martius, a plant belonging to the Annonaceae family, is found in the remaining Brazilian Atlantic Forest. In this study, the chemical composition and antitumor effects of the essential oil isolated from leaves of G. pogonopus was investigated. The chemical composition of the oil was determined by GC-FID and GC/MS analyses. The in vitro cytotoxicity was evaluated against three different tumor cell lines (OVCAR-8, NCI-H358M, and PC-3M), and the in vivo antitumor activity was tested in mice bearing sarcoma 180 tumor. A total of 29 compounds was identified and quantified in the oil. The major compounds were γ-patchoulene (13.55%), (E)-caryophyllene (11.36%), β-pinene (10.37%), germacrene D (6.72%), bicyclogermacrene (5.97%), α-pinene (5.33%), and germacrene B (4.69%). The essential oil, but neither (E)-caryophyllene nor β-pinene, displayed in vitro cytotoxicity against all three tumor cell lines tested. The obtained average IC50 values ranged from 3.8 to 20.8 μg/ml. The lowest and highest values were obtained against the NCI-H358M and the OVCAR-8 cell lines, respectively. The in vivo tumor-growth-inhibition rates in the tumor-bearing mice treated with essential oil (50 and 100 mg/kg/d) were 25.3 and 42.6%, respectively. Hence, the essential oil showed significant in vitro and in vivo antitumor activity. Copyright © 2013 Verlag Helvetica Chimica Acta AG, Zürich.

Evaluation of in vitro cytotoxicity, biocompatibility, and changes in the expression of apoptosis regulatory proteins induced by cerium oxide nanocrystals

NASA Astrophysics Data System (ADS)

Khan, Shahanavaj; Ansari, Anees A.; Rolfo, Christian; Coelho, Andreia; Abdulla, Maha; Al-Khayal, Khayal; Ahmad, Rehan

2017-12-01

Cerium oxide nanocrystals (CeO2-NCs) exhibit superoxide dismutase and catalase mimetic activities. Based on these catalytic activities, CeO2-NCs have been suggested to have the potential to treat various diseases. The crystalline size of these materials is an important factor that influences the performance of CeO2-NCs. Previous reports have shown that several metal-based nanocrystals, including CeO2-NCs, can induce cytotoxicity in cancer cells. However, the underlying mechanisms have remained unclear. To characterize the anticancer activities of CeO2-NCs, several assays related to the mechanism of cytotoxicity and induction of apoptosis has been performed. Here, we have carried out a systematic study to characterize CeO2-NCs phase purity (X-ray diffraction), morphology (electron microscopy), and optical features (optical absorption, Raman scattering, and photoluminescence) to better establish their potential as anticancer drugs. Our study revealed anticancer effects of CeO2-NCs in HT29 and SW620 colorectal cancer cell lines with half-maximal inhibitory concentration (IC50) values of 2.26 and 121.18 μg ml-1, respectively. Reductions in cell viability indicated the cytotoxic potential of CeO2-NCs in HT29 cells based on inverted and florescence microscopy assessments. The mechanism of cytotoxicity confirmed by estimating possible changes in the expression levels of Bcl2, BclxL, Bax, PARP, cytochrome c, and β-actin (control) proteins in HT29 cells. Down-regulation of Bcl2 and BclxL and up-regulation of Bax, PARP, and cytochrome c proteins suggested the significant involvement of CeO2-NCs exposure in the induction of apoptosis. Furthermore, biocompatibility assay showed minimum effect of CeO2-NCs on human red blood cells.

A new 5-alkylresorcinol glucoside derivative from Cybianthus magnus.

PubMed

Cabanillas, B; Vásquez-Ocmín, P; Zebiri, I; Rengifo, E; Sauvain, M; Le, H L; Vaisberg, A; Voutquenne-Nazabadioko, L; Haddad, M

2016-01-01

One new 5-alkylresorcinol glucoside (1) was isolated from leaves of Cybianthus magnus, along with 12 known compounds (2-13), isolated from four plants belonging to Myrsinaceae family. Their structures were determined on the basis of spectroscopic analysis and by comparison of their spectral data with those reported in the literature. Among the tested molecules, only compound 2 displayed a strong cytotoxic activity with IC50 values ranging between 22 and 100 μM for all cell lines tested. One new 5-alkylresorcinol glucoside (1) was isolated from leaves of Cybianthus magnus, along with 12 known compounds, isolated from four plants belonging to Myrsinaceae family (2, 3 isolated from C. magnus; 4-7, 10 and 11 isolated from Myrsine latifolia; 4, 8 and 9 isolated from Myrsine sessiflora; 6, 7, 10, 12 and 13 isolated from Myrsine congesta). Their structures were determined on the basis of spectroscopic analysis and by comparison of their spectral data with those reported in the literature. So far, only nine 5-alkylresorcinol glucosides were isolated from leaves of Grevillea robusta. Since resorcinols are known to exhibit strong cytotoxic activity, compounds 1 and 2 were tested against cell lines 3T3, H460, DU145 and MCF-7 for cytotoxicity in vitro and compounds 3-13 were tested for their antileishmanial activity. Compound 2 displayed a strong cytotoxic activity with IC50 values ranging between 22 and 100 μM for all tested cell lines. Compounds 3-13 were not active against Leishmania amazonensis amastigotes.

Both plants Sebastiania chamaelea from Niger and Chrozophora senegalensis from Senegal used in African traditional medicine in malaria treatment share a same active principle.

PubMed

Garcia-Alvarez, M-C; Moussa, I; Njomnang Soh, P; Nongonierma, R; Abdoulaye, A; Nicolau-Travers, M-L; Fabre, A; Wdzieczak-Bakala, J; Ahond, A; Poupat, C; Ikhiri, K; Benoit-Vical, F

2013-10-07

Based on ethnobotanical data obtained from Nigerien and Senegalese traditional healers, two Euphorbiaceae plants, Sebastiania chamaelea and Chrozophora senegalensis, traditionally used to treat malaria, were selected for further investigations. Plant extracts were prepared with different solvents and tested both in vitro on several strains of Plasmodium falciparum, and in vivo to evaluate their antiplasmodial properties and isolate their active principles. With IC50 values around 6.5µg/ml and no significant cytotoxicity (>50µg/ml), the whole plant aqueous extract from S. chamaelea showed the best in vitro results. In vitro potentiation assays showed strong synergistic activity of S. chamaelea extract with the antiplasmodial drug chloroquine on the chloroquine-resistant P. falciparum strain W2-Indochina. In other respects, the aqueous crude extract of C. senegalensis leaves showed the most significant antiplasmodial activity in vitro (IC50 values less than 2µg/ml). We also demonstrated the prophylactic activity of C. senegalensis in vivo in a murine malaria model. Bioassay-guided fractionation of aqueous extracts of these plants enabled the isolation and identification of ellagic acid (EA, 1) as the main compound responsible for their antiplasmodial activity. Together with EA, other derivatives belonging to different chemical groups were isolated but showed moderate antimalarial activity: gallic acid (2), brevifolin carboxylic acid (3), protocatechuic acid (4), corillagin (5), rutin (6) and 3,4,8,9,10-pentahydroxy-dibenzo(b,d)pyran-6-one (7). The structures were determined by the usual spectroscopic methods and by comparison with published data. Furthermore, we report here the quantification of compound 1 (EA) by RP-HPLC in the dried extracts of these plants, reported for the first time in both these species, and possessing the highest in vitro antiplasmodial activity with IC50 values from 180 to 330nm. These in vitro and in vivo results support the traditional use in Africa of crude extracts of both S. chamaelea and C. senegalensis as an antimalarial treatment and prove the significant antiplasmodial property of EA. © 2013 Elsevier Ireland Ltd. All rights reserved.

Phytochemicals from Mangifera pajang Kosterm and their biological activities.

PubMed

Ahmad, Sadikah; Sukari, Mohd Aspollah; Ismail, Nurussaadah; Ismail, Intan Safinar; Abdul, Ahmad Bustamam; Abu Bakar, Mohd Fadzelly; Kifli, Nurolaini; Ee, Gwendoline C L

2015-03-26

Mangifera pajang Kosterm is a plant species from the mango family (Anacardiaceae). The fruits are edible and have been reported to have high antioxidant content. However, the detailed phytochemical studies of the plant have not been reported previously. This study investigates the phytochemicals and biological activities of different parts of Mangifera pajang. The plant samples were extracted with solvents of different polarity to obtain the crude extracts. The isolated compounds were characterized using spectroscopic methods. The extracts and isolated compounds were subjected to cytotoxicity tests using human breast cancer (MCF-7), human cervical cancer (HeLa) and human colon cancer (HT-29) cells. The free radical scavenging activity test was conducted using the DPPH assay. Antimicrobial activity tests were carried out by using the disc diffusion method. Phytochemical investigation on the kernel, stem bark and leaves of Mangifera pajang led to the isolation of methyl gallate (1), mixture of benzaldehyde (2) and benzyl alcohol (3), mangiferonic acid (4), 3β-hydroxy-cycloart-24-ene-26-oic acid (5), 3β,23-dihydroxy-cycloart-24-ene-26-oic acid (6), lupeol(7) lupenone(8), β-sitosterol(9), stigmasterol(10), trans-sobrerol(11) and quercitrin (12). Crude ethyl acetate and methanol extracts from the kernel indicated strong cytotoxic activity towards MCF-7 and HeLa cells with IC50 values of less than 10 μg/mL, while petroleum ether, chloroform and ethyl acetate extracts of the stem bark showed strong to moderate activity against MCF-7, HeLa and HT-29 cancer cell lines with IC50 values ranging from 5 to 30 μg/mL. As for the antimicrobial assays, only the ethyl acetate and methanol extracts from the kernel displayed some inhibition against the microbes in the antibacterial assays. The kernel extracts showed highest free radical scavenging activity with IC50 values of less than 10 μg/mL, while the ethyl acetate and methanol extracts of leaves displayed only weak activity in the DPPH assays. Phytochemical investigations on various parts of Mangifera pajang have identified terpenoids and a flavonol derivative as major constituents. Bioassay studies have indicated that the crude extracts and isolated compounds have potential as naturally-derived anticancer and antimicrobial agents, besides possess high free radical scavenging activity.

The in-vitro evaluation of antibacterial, antifungal and cytotoxic properties of Marrubium vulgare L. essential oil grown in Tunisia.

PubMed

Zarai, Zied; Kadri, Adel; Ben Chobba, Ines; Ben Mansour, Riadh; Bekir, Ahmed; Mejdoub, Hafedh; Gharsallah, Néji

2011-09-21

In order to validate its antiseptic and anticancer properties with respect to traditional uses, we have screened for the first time the antimicrobial activity of aerial parts of M. vulgare L. essential oil against different pathogenic microorganisms and the cytotoxic activity against HeLa cell lines. The agar disk diffusion method was used to study the antibacterial activity of M. vulgare essential oil against 12 bacterial and 4 fungi strains. The disc diameters of zone of inhibition (DD), the minimum inhibitory concentrations (MIC) and the concentration inhibiting 50% (IC50) were investigated to characterize the antimicrobial activities of this essential oil. The in vitro cytotoxicity of M. vulgare essential oil was examined using a modified MTT assay; the viability and the IC50 were used to evaluate this test. The antimicrobial activity of the essential oil was investigated in order to evaluate its efficacy against the different tested microorganisms. The present results results showed a significant activity against microorganisms especially Gram (+) bacteria with inhibition zones and minimal inhibitory concentration values in the range of 6.6-25.2 mm and 1120-2600 μg/ml, respectively, whereas Gram (-) bacteria exhibited a higher resistance. As far as the antifungal activity, among four strains tested, Botrytis cinerea exhibited the strongest activity with inhibition zones of 12.6 mm. However, Fusarium solani, Penicillium digitatum and Aspergillus niger were less sensitive to M. vulgare essential oil. About the citotoxicity assay, this finding indicate the capability of this essential oil to inhibited the proliferation of HeLa cell lines under some conditions with IC50 value of 0.258 μg/ml. This investigation showed that the M. vulgare essential oil has a potent antimicrobial activity against some Gram (+) pathogenic bacteria and Botrytis cinerea fungi. The present studies confirm the use of this essential oil as anticancer agent. Further research is required to evaluate the practical values of therapeutic applications.

In vitro antibacterial, antioxidant and cytotoxic activity of acetone leaf extracts of nine under-investigated Fabaceae tree species leads to potentially useful extracts in animal health and productivity.

PubMed

Dzoyem, Jean P; McGaw, Lyndy J; Eloff, Jacobus N

2014-05-05

The Fabaceae family is the second largest family of medicinal plants, containing more than 490 species which are being used as traditional medicine. The aim of this study was to determine the antioxidant and antibacterial activity as well as the cytotoxicity of acetone leaf extracts of nine tree species from the Fabaceae family that have not been investigated well previously for possible use in animal health and production. The antibacterial activity was determined by a serial microdilution method against three Gram-positive and three Gram-negative bacteria. Antioxidant activity was determined using free-radical scavenging assays. The safety of the extracts was ascertained using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay on Vero African green monkey kidney cells. Six of the nine acetone extracts had significant antibacterial activity against at least one of the six bacterial species with (MIC 20-80 μg/mL). The Crotalaria capensis extract had the highest activity against Salmonella typhimurium, followed by Indigofera cylindrica with MICs of 20 μg/mL and 40 μg/mL respectively. The Dalbergia nitidula extract had free radical scavenging capacity (IC50 of 9.31±2.14 μg/mL) close to that of the positive control Trolox in the DPPH assay. The Xylia torreana extract also had high activity (IC50 of 14.56±3.96 μg/mL) in the ABTS assay. There was a good correlation between antioxidant activity and total phenolic content (R2 values>0.8). The extracts had weak or no toxicity to Vero cells, compared to the positive control doxorubicin with the LC50 varying from 10.70±3.47 to 131.98±24.87 μg/mL at the concentrations tested. Extracts of D. nitidula, X. torreana, C. capensis and I. cylindrica had a low cytotoxicity and high antimicrobial and/or antioxidant activity. These species are therefore promising candidates for the development of useful antimicrobial/antioxidant preparations with a low cytotoxicity that may be useful in promoting animal health and productivity.

Synthesis, characterization, and anti-cancer activity of emodin-Mn(II) metal complex.

PubMed

Yang, Li; Tan, Jun; Wang, Bo-Chu; Zhu, Lian-Cai

2014-12-01

To synthesize and characterize a novel metal complex of Mn (II) with emodin, and evaluate its anti-cancer activity. The elemental analyses, IR, UV-vis, atomic absorption spectroscopy, TG-DSC, (1)H NMR, and (13)C NMR data were used to characterize the structure of the complex. The cytotoxicity of the complex against the human cancer cell lines HepG2, HeLa, MCF-7, B16, and MDA-MB-231 was tested by the MTT assay and flow cytometry. Emodin was coordinated with Mn(II) through the 9-C=O and 1-OH, and the general formula of the complex was Mn(II) (emodin)2·2H2O. In studies of the cytotoxicity, the complex exhibited significant activity, and the IC50 values of the complex against five cancer cell lines improved approximately three-fold compared with those of emodin. The complex could induce cell morphological changes, decrease the percentage of viability, and induce G0/G1 phase arrest and apoptosis in cancer cells. The coordination of emodin with Mn(II) can improve its anticancer activity, and the complex Mn(II) (emodin)2·2H2O could be studied further as a promising anticancer drug. Copyright © 2014 China Pharmaceutical University. Published by Elsevier B.V. All rights reserved.

HPLC analysis and cytotoxic activity of Vernonia cinerea.

PubMed

Khay, Mom; Toeng, Phirom; Mahiou-Leddet, Valérie; Mabrouki, Fathi; Sothea, Kim; Ollivier, Evelyne; Elias, Riad; Bun, Sok-Siya

2012-10-01

The extracts of five Cambodian medicinal plants (Aganosma marginata, Dracaena cambodiana, Harrisonia perforata, Hymenodictyon excelsum and Vernonia cinerea) were evaluated in vitro for their cytotoxic activity against HT29 colon adenocarcinoma cells and HepG2 hepatoma cells, using the MTT assay. Among these five plants, Vernonia cinerea displayed potent cytotoxicity. One main sesquiterpene lactone, 8alpha-tigloyloxy-hirsutinolide-13-O-acetate was isolated from the whole plant of V. cinerea. This compound was active against both cancer cell lines (IC50 = 3.50 microM for HT29 and IC50 = 4.27 microM for HepG2). To quantify this compound in the plant, an analytical high-performance liquid chromatography (HPLC) method was developed and validated.

Cytotoxicity of the Essential Oil of Fennel (Foeniculum vulgare) from Tajikistan

PubMed Central

Valiev, Abdujabbor; Satyal, Prabodh; Gulmurodov, Isomiddin; Yusufi, Salomudin; Setzer, William N.

2017-01-01

The essential oil of fennel (Foeniculum vulgare) is rich in lipophilic secondary metabolites, which can easily cross cell membranes by free diffusion. Several constituents of the oil carry reactive carbonyl groups in their ring structures. Carbonyl groups can react with amino groups of amino acid residues in proteins or in nucleotides of DNA to form Schiff’s bases. Fennel essential oil is rich in anise aldehyde, which should interfere with molecular targets in cells. The aim of the present study was to investigate the chemical composition of the essential oil of fennel growing in Tajikistan. Gas chromatographic-mass spectrometric analysis revealed that the main components of F. vulgare oil were trans-anethole (36.8%); α-ethyl-p-methoxy-benzyl alcohol (9.1%); p-anisaldehyde (7.7%); carvone (4.9%); 1-phenyl-penta-2,4-diyne (4.8%) and fenchyl butanoate (4.2%). The oil exhibited moderate antioxidant activities. The potential cytotoxic activity was studied against HeLa (human cervical cancer), Caco-2 (human colorectal adenocarcinoma), MCF-7 (human breast adenocarcinoma), CCRF-CEM (human T lymphoblast leukaemia) and CEM/ADR5000 (adriamycin resistant leukaemia) cancer cell lines; IC50 values were between 30–210 mg L−1 and thus exhibited low cytotoxicity as compared to cytotoxic reference compounds. PMID:28846628

Phloroglucinol derivatives from Hypericum species trigger mitochondrial dysfunction in Leishmania amazonensis.

PubMed

Dagnino, Ana Paula Aquistapase; Mesquita, Camila Saporiti; Dorneles, Gilson Pires; Teixeira, Vivian de Oliveira Nunes; de Barros, Francisco Maikon Corrêa; Vidal Ccana-Ccapatinta, Gari; Fonseca, Simone Gonçalves; Monteiro, Marta Chagas; Júnior, Luiz Carlos Rodrigues; Peres, Alessandra; von Poser, Gilsane Lino; Romão, Pedro Roosevelt Torres

2018-02-27

Bioactive molecules isolated from plants are promising sources for the development of new therapies against leishmaniasis. We investigated the leishmanicidal activity of cariphenone A (1), isouliginosin B (2) and uliginosin B (3) isolated from Hypericum species. Promastigotes and amastigotes of Leishmania amazonensis were incubated with compounds 1-3 at concentrations 1-100 µ m for 48 h. The anti-promastigote effect of compounds was also tested in combinations. The cytotoxicity against macrophages and human erythrocytes were determined using the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) method and hemolysis assay, respectively. The compounds 1-3 showed high leishmanicidal activity against promastigotes, IC50 values of 10.5, 17.5 and 11.3 µ m, respectively. Synergistic interactions were found to the associations of compounds 1 and 2 [Σ fractional inhibitory concentration (FIC) = 0.41], and 2 and 3 (ΣFIC = 0.28) on promastigotes. All Hypericum compounds induced mitochondrial hyperpolarization and reactive oxygen species production in promastigotes. The compounds showed low cytotoxicity toward mammalian cells, high selectivity index and killed intracellular amastigotes probably mediated by oxidative stress. These results indicate that these compounds are promising candidates for the development of drugs against leishmaniasis.

Guanidinium-based derivatives: searching for new kinase inhibitors.

PubMed

Diez-Cecilia, Elena; Kelly, Brendan; Perez, Concepcion; Zisterer, Daniela M; Nevin, Daniel K; Lloyd, David G; Rozas, Isabel

2014-06-23

Considering the structural similarities between the kinase inhibitor sorafenib and 4,4'-bis-guanidinium derivatives previously prepared by Rozas and co., which display interesting cytotoxicity in cancer cells, we have studied whether this activity could result from kinase inhibition. Five new families have been prepared consisting of unsubstituted and aryl-substituted 3,4'-bis-guanidiniums, 3,4'-bis-2-aminoimidazolinium and 3-acetamide-4'-(4-chloro-3-trifluoromethylphenyl)guanidinium derivatives. Cytotoxicity (measuring the IC50 values) and apoptosis studies in human HL-60 promyelocytic leukemia cells were carried out for these compounds. Additionally, their potential inhibitory effect was explored on a panel of kinases known to be involved in apoptotic pathways. The previously prepared cytotoxic 4,4'-bis-guanidiniums did not inhibit any of these kinases; however, some of the novel 3,4'-substituted derivatives showed a high percentage inhibition of RAF-1/MEK-1, for which the potential mode of binding was evaluated by docking studies. The interesting antitumour properties showed by these compounds open up new exciting lines of investigation for kinase inhibitors as anticancer agents and also highlights the relevance of the guanidinium moiety for protein kinase inhibitors chemical design. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Cytotoxic Activity of Extracts from Plants of Central Argentina on Sensitive and Multidrug-Resistant Leukemia Cells: Isolation of an Active Principle from Gaillardia megapotamica

PubMed Central

González, María Laura; Joray, Mariana Belén; Laiolo, Jerónimo; Crespo, María Inés; Palacios, Sara María; Ruiz, Gustavo Miguel

2018-01-01

Plants are a significant reservoir of cytotoxic agents, including compounds with the ability to interfere with multidrug-resistant (MDR) cells. With the aim of finding promising candidates for chemotherapy, 91 native and naturalized plants collected from the central region of Argentina were screened for their cytotoxic effect toward sensitive and MDR P-glycoprotein (P-gp) overexpressing human leukemia cells by means of MTT assays. The ethanol extracts obtained from Aldama tucumanensis, Ambrosia elatior, Baccharis artemisioides, Baccharis coridifolia, Dimerostemma aspilioides, Gaillardia megapotamica, and Vernonanthura nudiflora presented outstanding antiproliferative activity at 50 μg/mL, with inhibitory values from 93 to 100%, when tested on the acute lymphoblastic leukemia (ALL) cell line CCRF-CEM and the resistant derivative CEM-ADR5000, while 70–90% inhibition was observed against the chronic myelogenous leukemia (CML) cell K562 and its corresponding resistant subline, Lucena 1. Subsequent investigation showed these extracts to possess marked cytotoxicity with IC50 values ranging from 0.37 to 29.44 μg/mL, with most of them being below 7 μg/mL and with ALL cells, including the drug-resistant phenotype, being the most affected. G. megapotamica extract found to be one of the most effective and bioguided fractionation yielded helenalin (1). The sesquiterpene lactone displayed IC50 values of 0.63, 0.19, 0.74, and 0.16 μg/mL against K562, CCRF-CEM, Lucena 1, and CEM/ADR5000, respectively. These results support the potential of these extracts as a source of compounds for treating sensitive and multidrug-resistant leukemia cells and support compound 1 as a lead for developing effective anticancer agents. PMID:29861776

Synthesis, DNA-binding affinity and cytotoxicity of the dinuclear platinum(II) complexes with berenil and amines ligands.

PubMed

Bielawski, Krzysztof; Bielawska, Anna; Popławska, Bozena; Bołkun-Skórnicka, Urszula

2008-01-01

A series of platinium(II) complexes of formula [Pt2L4(berenil)2]Cl4.4HCl.2H2O where L is piperidine (1), 4-picoline (2), 3-picoline (3) or isopropylamine (4) was prepared and their cytotoxicity have been tested against the growth of human breast cancer cells. Evaluation of the cytotoxicity of these compounds employing a MTT assay and inhibition of [3H]thymidine incorporation into DNA in both MDA-MB-231 and MCF-7 breast cancer cells demonstrated that these compounds were more active than cisplatin. Data from the ethidium displacement assay indicated that these compounds show moderate specificity for AT base pairs of DNA. Compounds 1-4 were also potent topoisomerase II inhibitors, with 50% inhibitory concentrations (IC50) ranging from 5 to 50 microM.

The in-vitro evaluation of antibacterial, antifungal and cytotoxic properties of Marrubium vulgare L. essential oil grown in Tunisia

PubMed Central

2011-01-01

Background In order to validate its antiseptic and anticancer properties with respect to traditional uses, we have screened for the first time the antimicrobial activity of aerial parts of M. vulgare L. essential oil against different pathogenic microorganisms and the cytotoxic activity against HeLa cell lines. Methods The agar disk diffusion method was used to study the antibacterial activity of M. vulgare essential oil against 12 bacterial and 4 fungi strains. The disc diameters of zone of inhibition (DD), the minimum inhibitory concentrations (MIC) and the concentration inhibiting 50% (IC50) were investigated to characterize the antimicrobial activities of this essential oil. The in vitro cytotoxicity of M. vulgare essential oil was examined using a modified MTT assay; the viability and the IC50 were used to evaluate this test. Results The antimicrobial activity of the essential oil was investigated in order to evaluate its efficacy against the different tested microorganisms. The present results results showed a significant activity against microorganisms especially Gram (+) bacteria with inhibition zones and minimal inhibitory concentration values in the range of 6.6-25.2 mm and 1120-2600 μg/ml, respectively, whereas Gram (-) bacteria exhibited a higher resistance. As far as the antifungal activity, among four strains tested, Botrytis cinerea exhibited the strongest activity with inhibition zones of 12.6 mm. However, Fusarium solani, Penicillium digitatum and Aspergillus niger were less sensitive to M. vulgare essential oil. About the citotoxicity assay, this finding indicate the capability of this essential oil to inhibited the proliferation of HeLa cell lines under some conditions with IC50 value of 0.258 μg/ml. Conclusion This investigation showed that the M. vulgare essential oil has a potent antimicrobial activity against some Gram (+) pathogenic bacteria and Botrytis cinerea fungi. The present studies confirm the use of this essential oil as anticancer agent. Further research is required to evaluate the practical values of therapeutic applications. PMID:21936887

Proanthocyanidin Characterization, Antioxidant and Cytotoxic Activities of Three Plants Commonly Used in Traditional Medicine in Costa Rica: Petiveria alliaceae L., Phyllanthus niruri L. and Senna reticulata Willd.

PubMed Central

Navarro, Mirtha; Moreira, Ileana; Arnaez, Elizabeth; Quesada, Silvia; Azofeifa, Gabriela; Alvarado, Diego; Monagas, Maria J.

2017-01-01

The phenolic composition of aerial parts from Petiveria alliaceae L., Phyllanthus niruri L. and Senna reticulata Willd., species commonly used in Costa Rica as traditional medicines, was studied using UPLC-ESI-TQ-MS on enriched-phenolic extracts. Comparatively, higher values of total phenolic content (TPC), as measured by the Folin-Ciocalteau method, were observed for P. niruri extracts (328.8 gallic acid equivalents/g) than for S. reticulata (79.30 gallic acid equivalents/g) whereas P. alliaceae extract showed the lowest value (13.45 gallic acid equivalents/g). A total of 20 phenolic acids and proanthocyanidins were identified in the extracts, including hydroxybenzoic acids (benzoic, 4-hydroxybenzoic, gallic, prochatechuic, salicylic, syringic and vanillic acids); hydroxycinnamic acids (caffeic, ferulic, and p-coumaric acids); and flavan-3-ols monomers [(+)-catechin and (−)-epicatechin)]. Regarding proanthocyanidin oligomers, five procyanidin dimers (B1, B2, B3, B4, and B5) and one trimer (T2) are reported for the first time in P. niruri, as well as two propelargonidin dimers in S. reticulata. Additionally, P. niruri showed the highest antioxidant DPPH and ORAC values (IC50 of 6.4 μg/mL and 6.5 mmol TE/g respectively), followed by S. reticulata (IC50 of 72.9 μg/mL and 2.68 mmol TE/g respectively) and P. alliaceae extract (IC50 >1000 μg/mL and 1.32 mmol TE/g respectively). Finally, cytotoxicity and selectivity on gastric AGS and colon SW20 adenocarcinoma cell lines were evaluated and the best values were also found for P. niruri (SI = 2.8), followed by S. reticulata (SI = 2.5). Therefore, these results suggest that extracts containing higher proanthocyanidin content also show higher bioactivities. Significant positive correlation was found between TPC and ORAC (R2 = 0.996) as well as between phenolic content as measured by UPLC-DAD and ORAC (R2 = 0.990). These findings show evidence for the first time of the diversity of phenolic acids in P. alliaceae and S. reticulata, and the presence of proanthocyanidins as minor components in latter species. Of particular relevance is the occurrence of proanthocyanidin oligomers in phenolic extracts from P. niruri and their potential bioactivity. PMID:29048336

Microbial transformation of danazol with Cunninghamella blakesleeana and anti-cancer activity of danazol and its transformed products.

PubMed

Baydoun, Elias; Atia-tul-Wahab; Mehmood, Hina; Ahmad, Malik Shoaib; Malik, Rizwana; Smith, Colin; Choudhary, M Iqbal

2016-01-01

Biotransformation of danazol (1) (17β-hydroxy-17α-pregna-2,4-dien-20-yno-[2,3-d]-isoxazole) with Cunninghamella blakesleeana yielded three new metabolites 2-4 and a known metabolite 5. These metabolites were identified as 14β,17β-dihydroxy-2-(hydroxymethyl)-17α-pregn-4-en-20-yn-3-one (2), 1α,17β-dihydroxy-17α-pregna-2,4-dien-20-yno-[2,3-d]-isoxazole (3), 6β,17β-dihydroxy-17α-pregna-2,4-dien-20-yno-[2,3-d]-isoxazole (4), and 17β-hydroxy-2-(hydroxymethyl)-17α-pregn-1,4-dien-20-yn-3-one (5). Danazol (1) and its derivatives were evaluated against cervical cancer cell line (HeLa). Compound 1 showed a potent cytotoxicity with IC50=0.283±0.013 μM, as compared to doxorubicin (IC50=0.506±0.015 μM), where compound 3 was also found to be significantly active with IC50=13.427±0.819 μM. Copyright © 2015 Elsevier Inc. All rights reserved.

Spectrophotometric, voltammetric and cytotoxicity studies of 2-hydroxy-5-methoxyacetophenone thiosemicarbazone and its N(4)-substituted derivatives: A combined experimental-computational study

NASA Astrophysics Data System (ADS)

Akgemci, Emine Guler; Saf, Ahmet Ozgur; Tasdemir, Halil Ugur; Türkkan, Ercan; Bingol, Haluk; Turan, Suna Ozbas; Akkiprik, Mustafa

2015-02-01

In this study, 2-hydroxy-5-methoxyacetophenone thiosemicarbazone (HMAT) and its novel N(4) substituted derivatives were synthesized and characterized by different techniques. The optical band gap of the compounds and the energy of HOMO were experimentally examined by UV-vis spectra and cyclic voltammetry measurements, respectively. Furthermore, the conformational spaces of the compounds were scanned with molecular mechanics method. The geometry optimization, HOMO and LUMO energies, the energy gap of the HOMO-LUMO, dipole moment of the compounds were theoretically calculated by the density functional theory B3LYP/6-311++G(d,p) level. The minimal electronic excitation energy and maximum wavelength calculations of the compounds were also performed by TD-DFT//B3LYP/6-311++G(d,p) level of theory. Theoretically calculated values were compared with the related experimental values. The combined results exhibit that all compounds have good electron-donor properties which affect anti-proliferative activity. The cytotoxic effects of the compounds were also evaluated against HeLa (cervical carcinoma), MCF-7 (breast carcinoma) and PC-3 (prostatic carcinoma) cell lines using the standard MTT assay. All tested compounds showed antiproliferative effect having IC50 values in different range. In comparison with that of HMAT, it was obtained that while ethyl group on 4(N)-substituted position decreased in potent anti-proliferative effect, the phenyl group on the position increased in anti-proliferative effect for the tested cancer cell line. Considering the molecular energy parameters, the cytotoxicity activities of the compounds were discussed.

Cytotoxic oleanane-type triterpenoid saponins from the Rhizomes of Anemone rivularis var. flore-minore.

PubMed

Wang, Xiaoyang; Wang, Minchang; Xu, Min; Wang, Yi; Tang, Haifeng; Sun, Xiaoli

2014-02-18

Phytochemical investigation of the n-BuOH extract of the rhizomes of Anemone rivularis var. flore-minore led to the isolation of five new oleanane-type triterpenoid saponins 1-5, together with five known saponins 6-10. Their structures were determined by the extensive use of 1D and 2D NMR experiments, along with ESIMS analyses and acid hydrolysis. The aglycone of 4 and 5 was determined as 21α-hydroxyoleanolic acid, which was reported in this genus for the first time. The cytotoxicity of these compounds was evaluated against four human cancer cell line, including HL-60 (promyelocytic leukemia), HepG2 (hepatocellular carcinoma), A549 (lung carcinoma) and HeLa (cervical carcinoma). The monodesmosidic saponins 6-8 exhibited cytotoxic activity toward all tested cancer cell lines, with IC50 values in the 7.25-22.38 μM range.

Bifurcatriol, a New Antiprotozoal Acyclic Diterpene from the Brown Alga Bifurcaria bifurcata

PubMed Central

Smyrniotopoulos, Vangelis; Merten, Christian; Kaiser, Marcel; Tasdemir, Deniz

2017-01-01

Linear diterpenes that are commonly found in brown algae are of high chemotaxonomic and ecological importance. This study reports bifurcatriol (1), a new linear diterpene featuring two stereogenic centers isolated from the Irish brown alga Bifurcaria bifurcata. The gross structure of this new natural product was elucidated based on its spectroscopic data (IR, 1D and 2D-NMR, HRMS). Its absolute configuration was identified by experimental and computational vibrational circular dichroism (VCD) spectroscopy, combined with the calculation of 13C-NMR chemical shielding constants. Bifurcatriol (1) was tested for in vitro antiprotozoal activity towards a small panel of parasites (Plasmodium falciparum, Trypanosoma brucei rhodesiense, T. cruzi, and Leishmania donovani) and cytotoxicity against mammalian primary cells. The highest activity was exerted against the malaria parasite P. falciparum (IC50 value 0.65 μg/mL) with low cytotoxicity (IC50 value 56.6 μg/mL). To our knowledge, this is the first successful application of VCD and DP4 probability analysis of the calculated 13C-NMR chemical shifts for the simultaneous assignment of the absolute configuration of multiple stereogenic centers in a long-chain acyclic natural product. PMID:28767061

Synthesis, Characterization, Anticancer and Antibacterial Activity of Some Novel Pyrano[2,3-d]pyrimidinone Carbonitrile Derivatives.

PubMed

Aremu, Oluwole S; Gopaul, Kaalin; Kadam, Pramod; Singh, Moganavelli; Mocktar, Chunderika; Singh, Parvesh; Koorbanally, Neil A

2017-01-01

Pyrimidines have widespread activity and have shown potent antibacterial and anticancer activity. To synthesise a range of pyrimidine diones and test them for their antibacterial and anticancer activity. The pyranopyrimidin-2,4-dione derivatives (1-7) were synthesized in a one-pot reaction by reacting malononitrile and barbituric acid with several aromatic aldehydes in the presence of 1,4-diazabicyclo[2.2.2]octane (DABCO) in aqueous medium. The compounds were tested for their antibacterial activity using the broth microdilution method and for their cytotoxicity against three cell lines, HeLa (cervical cancer), Caco-2 (human colon adenocarcinoma) and HEK 293 (human embryonic kidney cells) using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide) assay. Compounds 1-7 were successfully synthesized in yields of >90%. The 3,4-dihydroxyaryl (3) and the 2,5- dimethoxyaryl (7) derivatives were novel. Compounds 3, 5 (4'-methoxy derivative) and 6 (2',3'-dimethoxy derivative) showed antibacterial activity comparable to or better than the standard ampicillin. All the test compounds 1-7 showed good anticancer activity. The IC50 values ranged from 3.46 to 37.13 μM (HeLa); 136.78 to 297.05 μM (Caco-2) and 137.84 to 333.81 μM (HEK293). The best activity was seen in the HeLa cell line when compared to the standard 5FU (5-Fluorouracil IC50 of 41.85 μM), with 1, 2, 5 and 7 having IC50 values of 10.64, 3.46, 4.36 and 4.44 μM respectively. Additionally, two representative compounds (1 and 7) found to be potent against the two cell lines (HeLa and HEK 293) were docked into the binding site of human kinesin Eg5 with the aim of predicting their binding propensities and to establish their mechanism of action. The Lipinski parameters of these compounds were also computed and analysed for their drug-likeness. Compound 6 is an excellent candidate for a broad spectrum antibiotic with MBCs of 45.6-365.2 μM, while both 3 and 6 have the potential to be developed into an antibiotic against MRSA, with MBCs of 183-199 μM. Since all synthesized compounds showed IC50 values of 10 μM or less especially against the HeLa cells, they can be considered good lead compounds for anticancer agents. Additionally, the docking simulations suggested a good binding affinity of the compounds with Eg5 and indicated their anti-cancer action, at least partially, through its inhibition. The predicted Lipinski descriptors also indicated the potential of these compounds as an orally active drug. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

A new spermidine macrocyclic alkaloid isolated from Gymnosporia arenicola leaf.

PubMed

da Silva, Gustavo; Martinho, Ana; Soengas, Raquel González; Duarte, Ana Paula; Serrano, Rita; Gomes, Elsa Teixeira; Silva, Olga

2015-10-01

The isolation and structural elucidation of a macrocyclic alkaloid, characterized by the presence of a 13-membered macrolactam ring containing a spermidine unit N-linked to a benzoyl group is hereby reported. The structure of this previously unknown spermidine alkaloid isolated from Gymnosporia arenicola (Celastraceae) leaves has been elucidated by (1)H and (13)C NMR spectroscopy (including bidimensional analysis) and further characterized by high-resolution mass spectrometry and polarimetry. A route for the biosynthesis of this new bioactive macrocycle is proposed and the cytotoxicity of the compound was evaluated against two ATCC cell lines - one normal-derived (MCF10A) and one cancer-derived cell line (MCF7) - using the MTT assay. The alkaloid revealed to be non-cytotoxic against both cell lines. The IC50 values from the cells were also determined. Copyright © 2015 Elsevier B.V. All rights reserved.

Antimicrobial peptides isolated from Phyllomedusa nordestina (Amphibia) alter the permeability of plasma membrane of Leishmania and Trypanosoma cruzi.

PubMed

Pinto, Erika Gracielle; Pimenta, Daniel C; Antoniazzi, Marta Maria; Jared, Carlos; Tempone, Andre Gustavo

2013-12-01

Nature has provided inspiration for Drug Discovery studies and amphibian secretions have been used as a promising source of effective peptides which could be explored as novel drug prototypes for neglected parasitic diseases as Leishmaniasis and Chagas disease. In this study, we isolated four antimicrobial peptides (AMPs) from Phyllomedusa nordestina secretion, and studied their effectiveness against Leishmania (L.) infantum and Trypanosoma cruzi. The antiparasitic fractions were characterized by mass spectrometry and Edman degradation, leading to the identification of dermaseptins 1 and 4 and phylloseptins 7 and 8. T. cruzi trypomastigotes were susceptible to peptides, showing IC50 values in the range concentration of 0.25-0.68 μM. Leishmania (L.) infantum showed susceptibility to phylloseptin 7, presenting an IC50 value of 10 μM. Except for phylloseptin 7 which moderate showed cytotoxicity (IC50=34 μM), the peptides induced no cellular damage to mammalian cells. The lack of mitochondrial oxidative activity of parasites detected by the MTT assay, suggested that peptides were leishmanicidal and trypanocidal. By using the fluorescent probe SYTOX(®) Green, dermaseptins 1 and 4 and phylloseptins 7 and 8 showed time-dependent plasma membrane permeabilization of T. cruzi; phylloseptin 7 also showed a similar effect in Leishmania parasites. The present study demonstrates for the first time that AMPs target the plasma membrane of Leishmania and T. cruzi, leading to cellular death. Considering the potential of amphibian peptides against protozoan parasites and the reduced mammalian toxicity, they may contribute as scaffolds for drug design studies. Copyright © 2013 Elsevier Inc. All rights reserved.

Evaluation of the In Vitro Antiplasmodial, Antileishmanial, and Antitrypanosomal Activity of Medicinal Plants Used in Saudi and Yemeni Traditional Medicine

PubMed Central

Mothana, Ramzi A.; Al-Musayeib, Nawal M.; Al-Ajmi, Mohamed F.; Cos, Paul; Maes, Louis

2014-01-01

The antiplasmodial, antileishmanial, and antitrypanosomal activity of twenty-five medicinal plants distributed in Saudi Arabia and Yemen was evaluated. The plants were extracted with methanol and screened in vitro against erythrocytic schizonts of Plasmodium falciparum, intracellular amastigotes of Leishmania infantum and Trypanosoma cruzi, and free trypomastigotes of T. brucei. To assess selectivity, cytotoxicity was determined on MRC-5 cells. Criteria for activity were an IC50 < 10 μg/mL and high selectivity (SI). Seven plants showed interesting antiprotozoal activity in one or more models. Extracts of Caralluma penicillata and Acalypha ciliata showed fairly good activity against P. falciparum with IC50 of 6.7 and 10.8 μg/mL and adequate selectivity (SI > 9.6 and >5.9). Interesting activity against L. infantum was obtained with Verbascum bottae (IC50 of 3.2 μg/mL, SI 10.2) and Solanum glabratum (IC50 8.1 μg/mL, SI 3.4). The extracts of C. penicillata, Leucas virgata, Loranthus regularis, and V. bottae exhibited moderate activity against T. brucei (IC50 8.5, 8.1, 8.3, and 2.3 μg/mL; SI > 7.6, 7.7, 4.3, and >14.1). These results partly support the traditional use of some of the selected medicinal plants and warrant further investigations into the putative active constituents. PMID:24963330

The effect of organic anion-transporting polypeptides 1B1, 1B3 and 2B1 on the antitumor activity of flavopiridol in breast cancer cells.

PubMed

Brenner, Stefan; Riha, Juliane; Giessrigl, Benedikt; Thalhammer, Theresia; Grusch, Michael; Krupitza, Georg; Stieger, Bruno; Jäger, Walter

2015-01-01

The contribution of organic anion transporting polypeptides (OATPs) to the cellular uptake of flavopiridol was investigated in OATP1B1-, OATP1B3- and OATP2B1-expressing Chinese hamster ovary (CHO) cells. Uptake of flavopiridol into these cells showed typical Michaelis-Menten kinetics with much higher transport capacity for OATP1B3 compared to OATP1B1 and OATP2B1 (Vmax/Km, 33.9 vs. 8.84 and 2.41 µl/mg/min, respectively). The predominant role of OATPs was further supported by a dramatic inhibition of flavopiridol uptake in the presence of the OATP substrate rifampicin. Uptake of flavopiridol by OATPs also seems to be an important determinant in breast cancer cells. The much higher mRNA level for OATP1B1 found in wild-type compared to ZR-75-1 OATP1B1 knockdown cells correlated with higher flavopiridol initial uptake leading to 4.6-fold decreased IC50 values in the cytotoxicity assay (IC50, 1.45 vs. 6.64 µM). Cell cycle profile also showed a clear incidence for a stronger cell cycle arrest in the G2/M phase for ZR-75-1 wild-type cells compared to OATP1B1 knockdown cells, further indicating an active uptake via OATP1B1. In conclusion, our results revealed OATP1B1, OATP1B3 and OATP2B1 as uptake transporters for flavopiridol in cancer cells, which may also apply in patients during cancer therapy.

7-Chloroquinolinotriazoles: synthesis by the azide-alkyne cycloaddition click chemistry, antimalarial activity, cytotoxicity and SAR studies.

PubMed

Pereira, Guilherme R; Brandão, Geraldo Célio; Arantes, Lucas M; de Oliveira, Háliton A; de Paula, Renata Cristina; do Nascimento, Maria Fernanda A; dos Santos, Fábio M; da Rocha, Ramon K; Lopes, Júlio César D; de Oliveira, Alaíde Braga

2014-02-12

Twenty-seven 7-chloroquinolinotriazole derivatives with different substituents in the triazole moiety were synthesized via copper-catalyzed cycloaddition (CuAAC) click chemistry between 4-azido-7-chloroquinoline and several alkynes. All the synthetic compounds were evaluated for their in vitro activity against Plasmodium falciparum (W2) and cytotoxicity to Hep G2A16 cells. All the products disclosed low cytotoxicity (CC50 > 100 μM) and five of them have shown moderate antimalarial activity (IC50 from 9.6 to 40.9 μM). As chloroquine analogs it was expected that these compounds might inhibit the heme polymerization and SAR studies were performed aiming to explain their antimalarial profile. New structural variations can be designed on the basis of the results obtained. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

Gastroprotective effect and cytotoxicity of natural and semisynthetic labdane diterpenes from Araucaria araucana resin.

PubMed

Schmeda-Hirschmann, Guillermo; Astudillo, Luis; Sepúlveda, Beatriz; Rodríguez, Jaime A; Theoduloz, Cristina; Yáñez, Tania; Palenzuela, José Antonio

2005-01-01

The resin of the tree Araucaria araucana (Araucariaceae) is used by the Mapuche Amerindians in southern Chile and Argentina to treat ulcers and has been shown to display a gastroprotective effect in animal models. A study was undertaken to isolate, identify and assess the gastroprotective effect of the resin constituents and its semisynthetic derivatives as well as to evaluate the cytotoxicity of the products in cell cultures. Eleven diterpenes (ten labdane and a pimarane) were isolated from a resin sample collected in Chile. The labdane derivatives 15-acetoxylabd-8(17)-en-19-ol as well as 15,19-diacetoxylabd-8(17)-en are reported for the first time as natural products. Six diterpenes previously described from other plant sources are reported for the first time for the A. araucana resin. The structure of all compounds was elucidated by spectroscopic means. Some 24 diterpenes isolated/prepared in amounts over 10 mg were evaluated for gastroprotective effects in the ethanol/HCl-induced ulcer model in mice at 100 mg/kg. The highest gastroprotective activities were provided by 15-hydroxyimbricatolal, 15-acetoxyimbricatolal, 15-acetoxylabd-8(17)-en-19-oic acid methyl ester and 15-acetoxy-19-labdanoic acid, all of them being as active as the reference drug lansoprazole at 20 mg/kg. The cytotoxicity of 30 diterpenes as well as lansoprazole was assessed towards human lung fibroblasts (MRC-5) and 26 compounds were evaluated on the human gastric epithelial cell line AGS by means of the neutral red uptake assay. A concentration-dependent cell viability inhibition was found with IC50 values ranging from 27 up to > 1000 microM. The relationship between the cytotoxicity data and lipophilicity of the products is also discussed.

Synthesis, β-glucuronidase inhibition and molecular docking studies of hybrid bisindole-thiosemicarbazides analogs.

PubMed

Taha, Muhammad; Ismail, Nor Hadiani; Imran, Syahrul; Rahim, Fazal; Wadood, Abdul; Khan, Huma; Ullah, Hayat; Salar, Uzma; Khan, Khalid Mohammed

2016-10-01

Hybrid bisindole-thiosemicarbazides analogs (1-18) were synthesized and screened for β-glucuronidase activity. All compounds showed varied degree of β-glucuronidase inhibitory potential when compared with standard d-saccharic acid 1,4-lactone (IC50=48.4±1.25μM). Compounds 4, 7, 9, 6, 5, 12, 17 and 18 showed exceptional β-glucuronidase inhibition with IC50 values ranging from 0.1 to 5.7μM. Compounds 1, 3, 8, 16, 13, 2 and 14 also showed better activities than standard with IC50 values ranging from 7.12 to 15.0μM. The remaining compounds 10, 11, and 15 showed good inhibitory potential with IC50 values 33.2±0.75, 21.4±0.30 and 28.12±0.25μM respectively. Molecular docking studies were carried out to confirm the binding interaction of the compounds. Copyright © 2016 Elsevier Inc. All rights reserved.

Development of Quantum Chemical Method to Calculate Half Maximal Inhibitory Concentration (IC50 ).

PubMed

Bag, Arijit; Ghorai, Pradip Kr

2016-05-01

Till date theoretical calculation of the half maximal inhibitory concentration (IC50 ) of a compound is based on different Quantitative Structure Activity Relationship (QSAR) models which are empirical methods. By using the Cheng-Prusoff equation it may be possible to compute IC50 , but this will be computationally very expensive as it requires explicit calculation of binding free energy of an inhibitor with respective protein or enzyme. In this article, for the first time we report an ab initio method to compute IC50 of a compound based only on the inhibitor itself where the effect of the protein is reflected through a proportionality constant. By using basic enzyme inhibition kinetics and thermodynamic relations, we derive an expression of IC50 in terms of hydrophobicity, electric dipole moment (μ) and reactivity descriptor (ω) of an inhibitor. We implement this theory to compute IC50 of 15 HIV-1 capsid inhibitors and compared them with experimental results and available other QASR based empirical results. Calculated values using our method are in very good agreement with the experimental values compared to the values calculated using other methods. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Cytotoxic prenylated flavones from the stem and root bark of Daphne giraldii.

PubMed

Sun, Qian; Wang, Di; Li, Fei-Fei; Yao, Guo-Dong; Li, Xue; Li, Ling-Zhi; Huang, Xiao-Xiao; Song, Shao-Jiang

2016-08-15

Three new prenylated flavones (1-3), along with three known analogues (4-6), were isolated from the stem and root bark of Daphne giraldii. Their structures were determined by comprehensive NMR and HRESIMS spectroscopic data analyses. The absolute configurations of compounds 2 and 3 were assigned by optical rotation comparison, CD and [Rh2(OCOCF3)4]-induced CD spectral methods. The in vitro cytotoxicity experiments carried out involving five cancer cell lines (U251, A549, HepG2, MCF-7 and Bcap37) showed that 2 markedly inhibited the proliferation of all tested cells with IC50 values ranging from 4.26 to 20.82μM. The preliminary structure-activity relationships of these flavones are discussed. In addition, compound 2 was found to effectively induce apoptosis in HepG2 cells according to a flow cytometry analysis. Copyright © 2016 Elsevier Ltd. All rights reserved.

Taxodione and Extracts from Salvia austriaca Roots as Human Cholinesterase Inhibitors.

PubMed

Kuźma, Łukasz; Wysokińska, Halina; Sikora, Joanna; Olszewska, Paulina; Mikiciuk-Olasik, Elżbieta; Szymański, Paweł

2016-02-01

Taxodione, an abietane diterpenoid, was isolated from Salvia austriaca transformed roots grown in in vitro conditions. The compound is known to have antibacterial, cytotoxic and anti-tumour properties. This study evaluates the ability of pure taxodione and extracts obtained from the S. austriaca hairy roots and roots from field-grown plants to inhibit human acetylcholinesterase and butyrylcholinesterase. Both extracts were found to have similar actions against acetylcholinesterase. The IC50 for extracts from transformed and untransformed roots were 142.5 and 139.5 µg ml(-1), respectively. The highest activity towards human acetylcholinesterase was demonstrated by taxodione (IC50  = 54.84 µg ml(-1)). With respect to BChE inhibition, the root extracts demonstrated stronger activity (IC50  = 23.6 µg ml(-1): field-grown plants and 41.6 µg ml(-1): transformed roots) than taxodione (IC50  = 195.9 µg ml(-1)). Taxodione showed significant cytotoxicity against A549 cell line (IC50  = 9.1 µg ml(-1)), whereas the activities for the extracts from S. austriaca roots of field-grown plants (IC50  = 75.7 µg ml(-1)) and hairy roots (IC50  = 86.2 µg ml(-1)) were lower. Computer modelling suggests that taxodione should not demonstrate cardiotoxic or genotoxic activity. It also indicates that taxodione should demonstrate very rapid transport from the body with very good blood-brain barrier penetration, but with no cumulative effect on the human body. The obtained results indicate that taxodione is a safe compound and may be used for further investigations in pharmacological activities. Copyright © 2015 John Wiley & Sons, Ltd.

Histone Deacetylase Inhibitors through Click Chemistry

PubMed Central

Shen, Jie; Woodward, Robert; Kedenburg, James Patrick; Liu, Xianwei; Chen, Min; Fang, Lanyan; Sun, Duxin; Wang, Peng George

2012-01-01

Histone deacetylase inhibitors (HDACi) are a relatively new class of chemotherapy agents. Herein, we report a click-chemistry based approach to the synthesis of HDACi. Fourteen agents were synthesized from the combination of two alkyne and seven azido precursors. The inhibition of HDAC1 and HDAC8 was then determined by in vitro enzymatic assays, after which the cytotoxicity was evaluated in the NCI human cancer cell line screen. A lead compound 5g (NSC746457) was discovered that inhibited HDAC1 at an IC50 value of 104 ± 30 nM and proved quite potent in the cancer cell line screen with GI50 values ranging from 3.92 μM to 10 nM. Thus, this click HDACi design has provided a new chemical scaffold that has not only revealed a lead compound, but one which is easily amendable to further structural modifications given the modular nature of this approach. PMID:19007204

Assessment of Antioxidant and Cytotoxicity Activities of Saponin and Crude Extracts of Chlorophytum borivilianum

PubMed Central

Abd Aziz, Maheran; Stanslas, Johnson; Abdul Kadir, Mihdzar

2013-01-01

The present paper focused on antioxidant and cytotoxicity assessment of crude and total saponin fraction of Chlorophytum borivilianum as an important medicinal plant. In this study, three different antioxidant activities (2,2-diphenyl-1-picrylhydrazyl radical scavenging (DPPH), ferrous ion chelating (FIC), and β-carotene bleaching (BCB) activity) of crude extract and total saponin fraction of C. borivilianum tubers were performed. Crude extract was found to possess higher free radical scavenging activity (ascorbic acid equivalents 2578 ± 111 mg AA/100 g) and bleaching activity (IC50 = 0.7 mg mL−1), while total saponin fraction displayed higher ferrous ion chelating (EC50 = 1 mg mL−1). Cytotoxicity evaluation of crude extract and total saponin fraction against MCF-7, PC3, and HCT-116 cancer cell lines using 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) cell viability assay indicated a higher cytotoxicity activity of the crude extract than the total saponin fraction on all cell lines, being most effective and selective on MCF-7 human breast cancer cell line. PMID:24223502

A cationic amphiphilic peptide ABP-CM4 exhibits selective cytotoxicity against leukemia cells.

PubMed

Chen, Yu Qing; Min, Cui; Sang, Ming; Han, Yang Yang; Ma, Xiao; Xue, Xiao Qing; Zhang, Shuang Quan

2010-08-01

Some cationic antibacterial peptides exhibit a broad spectrum of cytotoxic activity against cancer cells, which could provide a new class of anticancer drugs. In the present study, the anticancer activity of ABP-CM4, an antibacterial peptide from Bombyx mori, against leukemic cell lines THP-1, K562 and U937 was evaluated, and the cytotoxicity compared with the effects on non-cancerous mammalian cells, including peripheral blood mononuclear cells (PBMCs), HEK-293 and erythrocytes. ABP-CM4 reduced the number of viable cells of the leukemic cell lines after exposure for 24h. The reduction was concentration dependent, and the IC50 values ranged from 14 to 18 microM. Conversely, ABP-CM4, even at 120 microM, exhibited no cytotoxicity toward HEK-293 or PBMCs, indicating that there was no significant effect on these two types of non-cancer cells. ABP-CM4 at a concentration of 200 microM had no hemolytic activity on mammalian erythrocytes. Together, these results suggested a selective cytotoxicity in leukemia cells. Flow cytometry demonstrated that the binding activity of ABP-CM4 to leukemia cells was much higher than that to HEK-293 or PBMCs, and there was almost no binding to erythrocytes. FITC-labeled ABP-CM4 molecules were examined under a confocal microscope and found to be concentrated at the surface of leukemia cells and changes of the cell membrane were determined by a cell permeability assay, which led us to the conclusion that ABP-CM4 could act at the cell membrane for its anticancer activity on leukemia cells. Collectively, our results indicated that ABP-CM4 has the potential for development as a novel antileukemic agent. Copyright 2010 Elsevier Inc. All rights reserved.

Development of a BALB/c 3T3 neutral red uptake cytotoxicity test using a mainstream cigarette smoke exposure system

PubMed Central

2014-01-01

Background Tobacco smoke toxicity has traditionally been assessed using the particulate fraction under submerged culture conditions which omits the vapour phase elements from any subsequent analysis. Therefore, methodologies that assess the full interactions and complexities of tobacco smoke are required. Here we describe the adaption of a modified BALB/c 3T3 neutral red uptake (NRU) cytotoxicity test methodology, which is based on the Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM) protocol for in vitro acute toxicity testing. The methodology described takes into account the synergies of both the particulate and vapour phase of tobacco smoke. This is of particular importance as both phases have been independently shown to induce in vitro cellular cytotoxicity. Findings The findings from this study indicate that mainstream tobacco smoke and the gas vapour phase (GVP), generated using the Vitrocell® VC 10 smoke exposure system, have distinct and significantly different toxicity profiles. Within the system tested, mainstream tobacco smoke produced a dilution IC50 (dilution (L/min) at which 50% cytotoxicity is observed) of 6.02 L/min, whereas the GVP produced a dilution IC50 of 3.20 L/min. In addition, we also demonstrated significant dose-for-dose differences between mainstream cigarette smoke and the GVP fraction (P < 0.05). This demonstrates the importance of testing the entire tobacco smoke aerosol and not just the particulate fraction, as has been the historical preference. Conclusions We have adapted the NRU methodology based on the ICCVAM protocol to capture the full interactions and complexities of tobacco smoke. This methodology could also be used to assess the performance of traditional cigarettes, blend and filter technologies, tobacco smoke fractions and individual test aerosols. PMID:24935030

DNA damage evaluation of hydroxyapatite on fibroblast cell L929 using the single cell gel electrophoresis assay.

PubMed

Rajab, N F; Yaakob, T A; Ong, B Y; Hamid, M; Ali, A M; Annuar, B O; Inayat-Hussain, S H

2004-05-01

Hydroxyapatite is the main component of the bone which is a potential biomaterial substance that can be applied in orthopaedics. In this study, the biocompatibility of this biomaterial was assessed using an in vitro technique. The cytotoxicity and genotoxicity effect of HA2 and HA3 against L929 fibroblast cell was evaluated using the MTT Assay and Alkaline Comet Assay respectively. Both HA2 and HA3 compound showed low cytotoxicity effect as determined using MTT Assay. Cells viability following 72 hours incubation at maximum concentration of both HA2 and HA3 (200 mg/ml) were 75.3 +/- 8.8% and 86.7 +/- 13.1% respectively. However, the cytotoxicity effect of ZnSO4.7H2O as a positive control showed an IC50 values of 46 mg/ml (160 microM). On the other hand, both HA2 and HA3 compound showed a slight genotoxicity effect as determined using the Alkaline Comet Assay following incubation at the concentration 200 mg/ml for 72 hours. This assay has been widely used in genetic toxicology to detect DNA strand breaks and alkali-labile site. The percentage of the cells with DNA damage for both substance was 27.7 +/- 1.3% and 15.6 +/- 1.0% for HA2 and HA3 respectively. Incubation of the cells for 24 hours with 38 microg/ml (IC25) of positive control showed an increase in percentage of cells with DNA damage (67.5 +/- 0.7%). In conclusion, our study indicated that both hydroxyapatite compounds showed a good biocompatibility in fibroblast cells.

Antiparasitic activity and effect of casearins isolated from Casearia sylvestris on Leishmania and Trypanosoma cruzi plasma membrane.

PubMed

Bou, Diego Dinis; Tempone, André G; Pinto, Érika G; Lago, João Henrique G; Sartorelli, Patricia

2014-04-15

Leishmaniasis and Chagas disease are infectious diseases caused by parasite Leishmania sp. and Trypanosoma cruzi, respectively, and are included among the most neglected diseases in several underdeveloped and developing countries, with an urgent demand for new drugs. Considering the antiparasitic potential of MeOH extract from leaves of Casearia sylvestris Sw. (Salicaceae), a bioguided fractionation was conducted and afforded four active clerodane diterpenes (casearins A, B, G, and J). The obtained results indicated a superior efficacy of tested casearins against trypomastigotes of T. cruzi, with IC50 values ranging from 0.53 to 2.77 μg/ml. Leishmania infantum promastigotes were also susceptible to casearins, with IC50 values in a range between 4.45 and 9.48 μg/ml. These substances were also evaluated for mammalian cytotoxicity against NCTC cells resulting in 50% cytotoxic concentrations (CC50) ranging from 1.46 to 13.76 μg/ml. Additionally, the action of casearins on parasite membranes was investigated using the fluorescent probe SYTOX Green. The obtained results demonstrated a strong interaction of casearins A and B to the plasma membrane of T. cruzi parasites, corroborating their higher efficacy against these parasites. In contrast, the tested casearins induced no alteration in the permeability of plasma membrane of Leishmania parasites, suggesting that biochemical differences between Leishmania and T. cruzi plasma membrane might have contributed to the target effect of casearins on trypomastigotes. Thus, considering the importance of studying novel and selective drug candidates against protozoans, casearins A, B, G, and J could be used as tools to future drug design studies. Copyright © 2014 Elsevier GmbH. All rights reserved.

Leishmanicidal activity of lipophilic extracts of some Hypericum species.

PubMed

Dagnino, Ana Paula; Barros, Francisco Maikon Corrêa de; Ccana-Ccapatinta, Gari Vidal; Prophiro, Josiane Somariva; Poser, Gilsane Lino von; Romão, Pedro R T

2015-01-15

Leishmaniasis has emerged as the third most prevalent parasite-borne disease worldwide after malaria and filariasis, with about 350 million people at risk of infection. Antileishmanial drugs currently available have various limitations, mainly because of the parasite resistance and side effects. The search of new antileishmanial drugs is ventured throughout the world. The purpose of this study was to assess the leishmanicidal activity of lipophilic extracts of eight Hypericum species against promastigote forms of Leishmania (Leishmania) amazonensis. The dried and powered materials of aerial parts of H. andinum Gleason, H. brevistylum Choisy, H. caprifoliatum Cham. & Schltdl., H. carinatum Griseb., H. linoides A. St.-Hil., H. myrianthum Cham. & Schltdl., H. polyanthemum Klotzsch ex Reichardt and H. silenoides Juss. were extracted by static maceration with n-hexane. Extracts were evaporated to dryness under reduced pressure and stored at -20°C until biological evaluation and HPLC analysis. The metabolites investigated were dimeric phloroglucinol derivatives, benzophenones and benzopyrans. The yields were expressed as mean of three injections in mg of compound per g of extract (mg/g extract). The effect of Hypericum species on the viability of infective forms of L. (L.) amazonensis was determined using a hemocytometer. Amphotericin B was used as a standard drug. The 50% inhibitory concentration (IC50) values for each extract were determined by linear regression analysis. The cytotoxic effects of extracts were assessed on peritoneal macrophages of BALB/c mice by MTT assay. The concentration that causes 50% of macrophage cytotoxicity (CC50) was determined by linear regression analysis. The selectivity index (SI) of the extracts was determined considering the following equation: CC50 against mammalian cells/IC50 against L. amazonensis. We demonstrated that H. carinatum, H. linoides and H. polyanthemum were able to kill the parasites in a dose dependent manner. These extracts presented low cytotoxicity against murine macrophages. At 48h of incubation H. polyanthemum presented significant leishmanicidal activity with a 50% inhibitory concentration (IC50) of 36.1µg/ml. The leishmanicidal activity of H. myrianthum was significantly lower than that presented by H. polyanthemum, H. carinatum and H. linoides extracts. H. brevistylum and H. caprifoliatum showed significant leishmanicidal activity only at high concentrations (500 and 1000µg/ml), while H. andinum and H. silenoides were ineffective. The promising results demonstrate the importance of the species of the genus Hypericum as source of compounds potentially useful for the treatment of leishmaniasis. Copyright © 2014 Elsevier GmbH. All rights reserved.

Dextran-coated superparamagnetic nanoparticles as potential cancer drug carriers in vivo

NASA Astrophysics Data System (ADS)

Peng, Mingli; Li, Houli; Luo, Zhiyi; Kong, Jian; Wan, Yinsheng; Zheng, Lemin; Zhang, Qinlu; Niu, Hongxin; Vermorken, Alphons; van de Ven, Wim; Chen, Chao; Zhang, Xikun; Li, Fuqiang; Guo, Lili; Cui, Yali

2015-06-01

Dextran-coated superparamagnetic iron oxide nanoparticles (DSPIONs) have gained considerable interest, because of their biocompatibility and biosafety in clinics. Doxorubicin (Dox), a widely used chemotherapeutic drug, always has limited applications in clinical therapy due to its serious side effects of dose-limiting irreversible cardiotoxicity and myelo suppression. Herein, DSPIONs were synthesized and developed as magnetic carriers for doxorubicin. The Dox-DSPION conjugates were evaluated in the in vitro test of Dox release, which showed pH-dependence with the highest release percentage of 50.3% at pH 5.0 and the lowest release percentage of 11.8% in a physiological environment. The cytotoxicity of DSPIONs and Dox-DSPIONs evaluated by the MTT assay indicated that DSPIONs had no cytotoxicity and the conjugates had significantly reduced the toxicity (IC50 = 1.36 μg mL-1) compared to free Dox (IC50 = 0.533 μg mL-1). Furthermore, confocal microscopic data of cell uptake suggest that less cytotoxicity of Dox-DSPIONs may be attributed to the cellular internalization of the conjugates and sustainable release of Dox from the formulation in the cytoplasm. More importantly, the results from the rabbit VX2 liver tumor model test under an external magnetic field showed that the conjugates had approximately twice the anti-tumor activity and two and a half times the animal survival rate, respectively, compared to free Dox. Collectively, our data have demonstrated that Dox-DSPIONs have less toxicity with better antitumor effectiveness in in vitro and in vivo applications, suggesting that the conjugates have potential to be developed into chemo-therapeutic formulations.

Solid-phase total synthesis of cherimolacyclopeptide E and discovery of more potent analogues by alanine screening.

PubMed

Shaheen, Farzana; Rizvi, Tania S; Musharraf, Syed G; Ganesan, A; Xiao, Kai; Townsend, Jared B; Lam, Kit S; Choudhary, M Iqbal

2012-11-26

Cherimolacyclopeptide E (1) is a cyclic hexapeptide obtained from Annona cherimola, reported to be cytotoxic against the KB (human nasopharyngeal carcinoma) cell line. The solid-phase total syntheses of this cyclic peptide and its analogues were accomplished by employing FMOC/tert-butyl-protected amino acids and the Kenner sulfonamide safety-catch linker. The synthetic peptide 1 was found to be weakly cytotoxic against four cell lines (MOLT-4, Jurkat T lymphoma, MDA-MB-231, and KB). Analogues 3 and 7, where glycine at positions 2 and 6 of the parent compound was replaced by Ala, exhibited enhanced cytotoxicity against KB (3, IC50 6.3 μM; 7, IC50 7.8 μM) and MDA-MB-231 breast cancer cells (3, IC50 10.2 μM; 7, IC50 7.7 μM), thereby suggesting possible selective targeting of these cancer cells by these peptides. The spectral data of synthetic peptide 1 was found to be similar to that reported for the natural product. However, a striking difference in biological activity was noted, which warrants the re-evaluation of the original natural product for purity and the existence of conformational differences.

Discovery of a Series of Acridinones as Mechanism-Based Tubulin Assembly Inhibitors with Anticancer Activity

PubMed Central

Magalhaes, Luma G.; Marques, Fernando B.; da Fonseca, Marina B.; Rogério, Kamilla R.; Graebin, Cedric S.; Andricopulo, Adriano D.

2016-01-01

Microtubules play critical roles in vital cell processes, including cell growth, division, and migration. Microtubule-targeting small molecules are chemotherapeutic agents that are widely used in the treatment of cancer. Many of these compounds are structurally complex natural products (e.g., paclitaxel, vinblastine, and vincristine) with multiple stereogenic centers. Because of the scarcity of their natural sources and the difficulty of their partial or total synthesis, as well as problems related to their bioavailability, toxicity, and resistance, there is an urgent need for novel microtubule binding agents that are effective for treating cancer but do not have these disadvantages. In the present work, our lead discovery effort toward less structurally complex synthetic compounds led to the discovery of a series of acridinones inspired by the structure of podophyllotoxin, a natural product with important microtubule assembly inhibitory activity, as novel mechanism-based tubulin assembly inhibitors with potent anticancer properties and low toxicity. The compounds were evaluated in vitro by wound healing assays employing the metastatic and triple negative breast cancer cell line MDA-MB-231. Four compounds with IC50 values between 0.294 and 1.7 μM were identified. These compounds showed selective cytotoxicity against MDA-MB-231 and DU-145 cancer cell lines and promoted cell cycle arrest in G2/M phase and apoptosis. Consistent with molecular modeling results, the acridinones inhibited tubulin assembly in in vitro polymerization assays with IC50 values between 0.9 and 13 μM. Their binding to the colchicine-binding site of tubulin was confirmed through competitive assays. PMID:27508497

Antioxidant and Hepatoprotective Potential of Phenol-Rich Fraction of Juniperus communis Linn. Leaves

PubMed Central

Ved, Akash; Gupta, Amresh; Rawat, Ajay Kumar Singh

2017-01-01

Background: Juniperus communis Linn. is an important plant in India traditional system of medicine which is widely used by different tribes in many countries. Objective: In the present study, the antioxidant, cytotoxic and hepatoprotective activities of Juniperus communis leaves were investigated against various models. Materials and Methods: ethanolic extract (70% v/v) of J. communis leaves was successively extracted using hexane and ethyl acetate to prepare various fractions. Total phenol content was resolute by the Folin-Ciocalteau's process. The antioxidant properties of the different fractions/extract of leaves of J. communis were examined by 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity and Fe2+ chelating ability. Cytotoxic activity was examined by cell viability assay on HepG2 cells. Hepatoprotective activity of ethyl acetate fraction (EAF) evaluated against PCM-Paracetamol-induced hepatic damage in Wistar albino rats. Results: Total phenol content was found maximum 315.33 mg/GAE/g in EAF. Significant scavenging activity were found for EAF (IC50 = 177 μg/ml) as compared to standard BHT (IC50 = 138 μg/ml), while EAF showed good Fe2+ chelating ability having an IC50 value of 261 mg/ML compared to standard ethylenediaminetetraacetic acid (7.7 mg/mL). It was found that EAF treated group shows remarkable decrease in serum Aspartate aminotransferase, serum Alanine aminotransferase, total bilirubin, direct bilirubin, and alkaline phosphatase level in treatment group as compared to the hepatotoxic group. Conclusion: EAF of J. communis leaves is found to be potent antioxidant and hepatoprotective without any cytotoxicity and it can also be included in nutraceuticals with notable benefits for mankind or animal health. SUMMARY Phenol-rich fraction (PRF) and other fractions/extract of Juniperus communis leaves were screened for antioxidant, cytotoxic, and hepatoprotective activity.Significant antioxidant and hepatoprotective activity without any cytotoxicity were found while treating with ethyl acetate fraction (EAF). Abbreviations used: HepG2: Liver hepatocellular carcinoma, BHT: Butylated hydroxytoluene, PCM: Paracetamol, IC50: Half maximal inhibitory concentration, RSA: Radical Scavenging Activity, WST: Water-soluble tetrazolium. PMID:28216892

Potential of 2-hydroxy-3-phenylsulfanylmethyl-[1,4]-naphthoquinones against Leishmania (L.) infantum: biological activity and structure-activity relationships.

PubMed

Pinto, Erika G; Santos, Isabela O; Schmidt, Thomas J; Borborema, Samanta E T; Ferreira, Vitor F; Rocha, David R; Tempone, Andre G

2014-01-01

Naphtoquinones have been used as promising scaffolds for drug design studies against protozoan parasites. Considering the highly toxic and limited therapeutic arsenal, the global negligence with tropical diseases and the elevated prevalence of co-morbidities especially in developing countries, the parasitic diseases caused by various Leishmania species (leishmaniasis) became a significant public health threat in 98 countries. The aim of this work was the evaluation of antileishmanial in vitro potential of thirty-six 2-hydroxy-3-phenylsulfanylmethyl-[1,4]-naphthoquinones obtained by a three component reaction of lawsone, the appropriate aldehyde and thiols adequately substituted, exploiting the in situ generation of o-quinonemethides (o-QM) via the Knoevenagel condensation. The antileishmanial activity of the naphthoquinone derivatives was evaluated against promastigotes and intracellular amastigotes of Leishmania (Leishmania) infantum and their cytotoxicity was verified in mammalian cells. Among the thirty-six compounds, twenty-seven were effective against promastigotes, with IC50 values ranging from 8 to 189 µM; fourteen compounds eliminated the intracellular amastigotes, with IC50 values ranging from 12 to 65 µM. The compounds containing the phenyl groups at R1 and R2 and with the fluorine substituent at the phenyl ring at R2, rendered the most promising activity, demonstrating a selectivity index higher than 15 against amastigotes. A QSAR (quantitative structure activity relationship) analysis yielded insights into general structural requirements for activity of most compounds in the series. Considering the in vitro antileishmanial potential of 2-hydroxy-3-phenylsulfanylmethyl-[1,4]-naphthoquinones and their structure-activity relationships, novel lead candidates could be exploited in future drug design studies for leishmaniasis.

Synergistic suppression of human breast cancer cells by combination of plumbagin and zoledronic acid In vitro.

PubMed

Qiao, Han; Wang, Ting-yu; Yan, Wei; Qin, An; Fan, Qi-ming; Han, Xiu-guo; Wang, Yu-gang; Tang, Ting-ting

2015-09-01

Zoledronic acid (ZA), a bisphosphonate, is currently used in combination with chemotherapeutic agents to suppress breast cancer cell proliferation or breast cancer-induced osteolysis. The aim of this study was to investigate the effects of ZA combined with a natural anticancer compound plumbagin (PL) against human breast cancer cells in vitro. Human breast cancer MDA-MB-231SArfp cells were treated with ZA, PL or a combination of ZA and PL. The cell growth, apoptosis and migration were evaluated using CCK-8 assay, flow cytometry and transwell assay, respectively. The expression of apoptosis-related proteins was measured using real-time PCR and Western blotting. Synergism was evaluated using Compusyn software, and the combination index (CI) and drug reduction index (DRI) values were determined. PL or ZA alone caused mild cytotoxicity (the IC50 value at 24 h was 12.18 and above 100 μmol/L, respectively). However, the combination of ZA and PL caused a synergistic cytotoxicity (CI=0.26). The DRI values also showed a synergistic effect between PL and ZA, with actual values of 5.52 and 3.59, respectively. Furthermore, PL and ZA synergistically induced apoptosis and inhibited migration of the breast cancer cells. Moreover, the combination of ZA and PL decreased the expression of Notch-1, cleaved PARP, Bcl-2 and Bcl-xl, and increased the expression of cleaved caspase-3, CDKN1A and ID1. When the breast cancer cells were transfected with specific siRNA against Notch-1, the combination of ZA and PL markedly increased the expression of Bcl-2. Combination of ZA and PL synergistically suppresses human breast cancer MDA-MB-231SArfp cells in vitro. PL can inhibit ZA-induced activation of the Notch-1 signaling pathway and subsequently reduce the expression of Bcl-2, thus potentiating cancer cell apoptosis.

Comparison of inhibition of murine leukaemia cell growth by 9-isothiocyanatoacridine and its cytosine adduct: involvement of thiols.

PubMed

Bajdichova, M; Paulikova, H; Jakubikova, J; Sabolova, D

2007-01-01

Cytotoxicity of two fluorescent acridine derivatives - 9-isothiocyanatoacridine (AcITC) and N-(9-acridinylthiocarbamoyl) cytosine (AcTCC) - a novel acridine compound, were investigated. Both substances have cytotoxic activity against the L1210 cellular line, IC50 values were in the micromolar range. Despite the high reactivity of AcITC towards thiols, its effects on leukemia cells were similar to naturally occurring isothiocyanates. AcITC changed the intracellular level of glutathione (GSH), and induced apoptosis. Arrest of cell cycle (G2/M-phase) was also observed. AcITC primarily reacted with -SH groups on cellular surface, and the study of the interaction of the isotiocyanate with human erythrocyte ghosts confirmed that the plasma membrane was the first place where AcITC bound. AcTCC does not react with cellular thiols; images obtained with fluorescent microscopy confirmed interaction of AcTCC with chromatine. Although AcTCC induced cellular arrest in the G2/M phase, apoptosis was not confirmed.

Triterpenoid saponins from the roots of Clematis argentilucida.

PubMed

Zhao, Mei; Ma, Ning; Qiu, Feng; Tian, Xiangrong; Zhang, Yan; Tang, Haifeng; Liu, Xinyou

2014-09-01

Reinvestigation of the n-BuOH extract of the roots of Clematis argentilucida led to the isolation of a new ursane-type triterpenoid saponin 1 and a new taraxerane-type saponin 2, four known saponins 3-6 first isolated from the species, together with seven saponins 7-13 reported in the previous papers. The structures of saponins 1-6 were elucidated by extensive spectroscopic analysis and chemical evidences. The ursane-type and taraxerane-type triterpenoid saponins were obtained from genus Clematis for the first time, and the aglycone of saponin 1, 3β,28-dihydroxy-18αH-ursan-20-en was first encountered. The cytotoxicity of all the saponins was evaluated against human glioblastoma U251MG cell lines. The monodesmosidic saponins 1, 2 and 4-8 exhibited cytotoxic activity against the cells with IC50 values ranging from 6.95 to 38.51 μM. Copyright © 2014 Elsevier B.V. All rights reserved.

Chemical constituents from Piper hainanense and their cytotoxicities.

PubMed

Shi, Yan-Ni; Xin, Ying; Ling, Yi; Li, Xing-Cong; Hao, Chao-Yun; Zhu, Hong-Tao; Wang, Dong; Yang, Chong-Ren; Xu, Min; Zhang, Ying-Jun

2016-08-01

Two new compounds, (Z,R)-1-phenylethylcinnamate (1) and (1R,2R,3R,6S)-pipoxide (2) were isolated from the aerial part of Piper hainanense, along with 12 known compounds, including nine benzene derivatives (4-11), one isobutylamide (12), and two polyoxygenated cyclohexene derivatives (13-14). Their structures were elucidated on the basis of the HRESIMS, 1D and 2D NMR spectroscopic analyses, and ECD in cases of 2 and 3. The absolute configuration of ellipeiopsol B (3) was determined for the first time. All these compounds 1-14 were reported from the titled plant for the first time. Most of the isolates were tested for their cytotoxicities against five human cancer cell lines. Four of which, 2, 3, 9, 14 showed moderate bioactivities. Among them, the new compound 2 showed potential cytotoxicity against SMMC-7721, MCF-7, and SW-480 with IC50 values of 9.7, 15.0, and 13.2 μM, respectively.

Antiviral anthraquinones and azaphilones produced by an endophytic fungus Nigrospora sp. from Aconitum carmichaeli.

PubMed

Zhang, Shou-Peng; Huang, Rong; Li, Fang-Fang; Wei, Hong-Xia; Fang, Xiao-Wei; Xie, Xiao-Song; Lin, Dong-Guo; Wu, Shao-Hua; He, Jian

2016-07-01

A new hydroanthraquinone derivative, 6-O-demethyl-4-dehydroxyaltersolanol A (1), and two new azaphilones, 8,11-didehydrochermesinone B (6) and (7S)-7-hydroxy-3,7-dimethyl-isochromene-6,8-dione (8), along with five known analogues (2-5 and 7), were isolated from the culture broth of Nigrospora sp. YE3033, an endophytic fungus obtained from Aconitum carmichaeli. Their structures were elucidated on the basis of spectroscopic analyses. Biological activity test indicated that compounds 1-3, and 7 exhibited the inhibitory effects on influenza viral strain of A/Puerto Rico/8/34 (H1N1) with the IC50 values of 2.59, 8.35, 7.82, and 0.80μg/mL, respectively, while the low cytotoxicity of 7 with the CC50 value of 184.75μg/mL, displaying a promising potential of 7 in the development of anti-influenza A virus drugs. Copyright © 2016 Elsevier B.V. All rights reserved.

Triterpene Esters and Biological Activities from Edible Fruits of Manilkara subsericea (Mart.) Dubard, Sapotaceae

PubMed Central

Fernandes, Caio P.; Corrêa, Arthur L.; Lobo, Jonathas F. R.; Caramel, Otávio P.; de Almeida, Fernanda B.; Castro, Elaine S.; Souza, Kauê F. C. S.; Burth, Patrícia; Amorim, Lidia M. F.; Santos, Marcelo G.; Ferreira, José Luiz P.; Falcão, Deborah Q.; Carvalho, José C. T.; Rocha, Leandro

2013-01-01

Manilkara subsericea (Mart.) Dubard (Sapotaceae) is popularly known in Brazil as “guracica.” Studies with Manilkara spp indicated the presence of triterpenes, saponins, and flavonoids. Several activities have been attributed to Manilkara spp such as antimicrobial, antiparasitic and antitumoral, which indicates the great biological potential of this genus. In all, 87.19% of the hexanic extract from fruits relative composition were evaluated, in which 72.81% were beta- and alpha-amyrin esters, suggesting that they may be chemical markers for M. subsericea. Hexadecanoic acid, hexadecanoic acid ethyl ester, (E)-9-octadecenoic acid ethyl ester, and octadecanoic acid ethyl ester were also identified. Ethanolic crude extracts from leaves, stems, and hexanic extract from fruits exhibited antimicrobial activity against Staphylococcus aureus ATCC25923. These extracts had high IC50 values against Vero cells, demonstrating weak cytotoxicity. This is the first time, to our knowledge, that beta- and alpha-amyrin caproates and caprylates are described for Manilkara subsericea. PMID:23509702

Fucoidan cytotoxicity against human breast cancer T47D cell line increases with higher level of sulfate ester group

NASA Astrophysics Data System (ADS)

Saepudin, Endang; Alfita Qosthalani, Fildzah; Sinurat, Ellya

2018-01-01

The anticancer activity of different sulfate ester group content in different molecular weight was examined. The anticancer activity was achieved in vitro on human breast cancer T47D cell line. Fucoidan with lower molecular weight (5.79 kDa) tends to have lower sulfate ester group content (8.69%) and resulted in higher IC50 value (184.22 μg/mL). While fucoidan with higher molecular weight (785.12 kDa) tends to have higher sulfate level (18.63%) and achieved lower IC50 value (75.69 μg/mL). The result showed that in order to maintain fucoidan cytotoxic activity against human breast cancer T47D cell line, the sulfate content should be remain high. Keywords: fucoidan, sulfate ester group, human breast cancer

Apogossypol Derivatives as Pan-active Inhibitors of Anti-apoptotic B-cell lymphoma/leukemia-2 (Bcl-2) Family Proteins

PubMed Central

Wei, Jun; Kitada, Shinichi; Rega, Michele F.; Stebbins, John L.; Zhai, Dayong; Cellitti, Jason; Yuan, Hongbin; Emdadi, Aras; Dahl, Russell; Zhang, Ziming; Yang, Li; Reed, John C.; Pellecchia, Maurizio

2009-01-01

Guided by nuclear magnetic resonance (NMR) binding assays and computational docking studies, a series of 5, 5′ substituted Apogossypol derivatives was synthesized that resulted in potent pan-active inhibitors of anti-apoptotic Bcl-2 family proteins. Compound 8r inhibits the binding of BH3 peptides to Bcl-XL, Bcl-2, Mcl-1 and Bfl-1 with IC50 values of 0.76, 0.32, 0.28 and 0.73 μM, respectively. The compound also potently inhibits cell growth of human lung cancer and BP3 human B-cell lymphoma cell lines with EC50 values of 0.33 and 0.66 μM, respectively. Compound 8r shows little cytotoxicity against bax−/−bak−/− cells, indicating that it kills cancers cells via the intented mechanism. The compound also displays in vivo efficacy in transgenic mice in which Bcl-2 is overexpressed in splenic B-cells. Together with its improved chemical, plasma and microsomal stability relative to compound 2 (Apogossypol), compound 8r represents a promising drug lead for the development of novel apoptosis-based therapies for cancer. PMID:19555126

Erythrocytes and cell line-based assays to evaluate the cytoprotective activity of antioxidant components obtained from natural sources.

PubMed

Botta, Albert; Martínez, Verónica; Mitjans, Montserrat; Balboa, Elena; Conde, Enma; Vinardell, M Pilar

2014-02-01

Oxidative stress can damage cellular components including DNA, proteins or lipids, and may cause several skin diseases. To protect from this damage and addressing consumer's appeal to natural products, antioxidants obtained from algal and vegetal extracts are being proposed as antioxidants to be incorporated into formulations. Thus, the development of reliable, quick and economic in vitro methods to study the cytoactivity of these products is a meaningful requirement. A combination of erythrocyte and cell line-based assays was performed on two extracts from Sargassum muticum, one from Ulva lactuca, and one from Castanea sativa. Antioxidant properties were assessed in erythrocytes by the TBARS and AAPH assays, and cytotoxicity and antioxidant cytoprotection were assessed in HaCaT and 3T3 cells by the MTT assay. The extracts showed no antioxidant activity on the TBARS assay, whereas their antioxidant capacity in the AAPH assay was demonstrated. On the cytotoxicity assays, extracts showed low toxicity, with IC50 values higher than 200μg/mL. C. sativa extract showed the most favourable antioxidant properties on the antioxidant cytoprotection assays; while S. muticum and U. lactuca extracts showed a slight antioxidant activity. This battery of methods was useful to characterise the biological antioxidant properties of these natural extracts. Copyright © 2013 Elsevier Ltd. All rights reserved.

Betulinic acid derivatives NVX-207 and B10 for treatment of glioblastoma--an in vitro study of cytotoxicity and radiosensitization.

PubMed

Bache, Matthias; Bernhardt, Stephan; Passin, Sarina; Wichmann, Henri; Hein, Anja; Zschornak, Martin; Kappler, Matthias; Taubert, Helge; Paschke, Reinhard; Vordermark, Dirk

2014-10-30

Betulinic acid (BA), a pentacyclic triterpene, represents a new therapeutic substance that has potential benefits for treating glioblastoma. Recently, new strategies for producing BA derivatives with improved properties have evolved. However, few studies have examined the combination of BA or BA derivatives using radiotherapy. The effects of two BA derivatives, NVX-207 and B10, on cellular and radiobiological behavior were analyzed using glioblastoma cell lines (U251MG, U343MG and LN229). Based on IC50 values under normoxic conditions, we detected a 1.3-2.9-fold higher cytotoxicity of the BA derivatives B10 and NVX-207, respectively, compared to BA. Incubation using both BA derivatives led to decreased cell migration, cleavage of PARP and decreased protein expression levels of Survivin. Weak radiation sensitivity enhancement was observed in U251MG cells after treatment with both BA derivatives. The enhancement factors at an irradiation dose of 6 Gy after treatment with 5 µM NVX-207 and 5 µM B10 were 1.32 (p=0.029) and 1.55 (p=0.002), respectively. In contrast to BA, neither NVX-207 nor B10 had additional effects under hypoxic conditions. Our results suggest that the BA derivatives NVX-207 and B10 improve the effects of radiotherapy on human malignant glioma cells, particularly under normoxic conditions.

Role of reactive oxygen species in the synergistic cytotoxicity of safingol-based combination regimens with conventional chemotherapeutics

PubMed Central

Ling, Leong-Uung; Tan, Kuan-Boone; Chiu, Gigi N.C.

2011-01-01

Exploiting the sensitivity of cancer cells to reactive oxygen species (ROS) has been suggested as a strategy for the selective elimination of cancer cells. In this study, the ROS-generating sphingolipid safingol was combined with various conventional chemotherapeutics, and the potential synergism of the safingol-based combination regimen was assessed using a panel of cancer cell lines. The IC50 values of safingol using as a single agent were 1.4-6.3 µM, which are concentrations that are clinically achievable. While synergism was dependent on the drug molar ratios, a 4:1 molar ratio of safingol to conventional chemotherapeutics exhibited a moderate to strong synergism in MDA-MB-231, JIMT-1, SKOV-3, U937 and KB cells, with combination indices ranging from 0.07 to 0.77. Furthermore, the addition of safingol may reduce the concentrations of conventional chemotherapeutics required to achieve 90% cell-kill by 1 to >3 log-folds. A significant reduction in the cytotoxicity of safingol-based drug combinations was observed in the presence of N-acetyl-L-cysteine, suggesting that ROS is an important factor in mediating the observed synergism. Taken together, our results suggest that the use of safingol-based drug combinations is promising as an effective strategy for cancer therapy and should be investigated. PMID:22866148

Nickel(II) and palladium(II) triphenylphosphine complexes incorporating tridentate Schiff base ligands: Synthesis, characterization and biocidal activities

NASA Astrophysics Data System (ADS)

Shabbir, Muhammad; Akhter, Zareen; Ashraf, Ahmad Raza; Ismail, Hammad; Habib, Anum; Mirza, Bushra

2017-12-01

Nickel(II) and palladium(II) triphenylphosphine complexes incorporating tridentate Schiff bases have been prepared and characterized by elemental analysis as well as by spectroscopic techniques (FTIR & NMR). The synthesized compounds were assessed to check their potential biocidal activity by using different biological assays (brine shrimp cytotoxicity, antimicrobial, antioxidant, antitumor and drug-DNA interaction). Results of brine shrimp cytotoxicity assay showed that ligand molecules are more bioactive than metal complexes with LD50 as low as 12.4 μg/mL. The prominent antitumor activity was shown by nickel complexes while the palladium complexes exhibited moderate activity. The synthesized compounds have shown high propensity for DNA binding either through intercalation or groove binding which represents the mechanism of antitumor effect of these compounds. Additionally, ligand molecules and nickel metal complexes showed significant antioxidant activity with IC50 values as low as 3.1 μg/mL and 18.9 μg/mL respectively while palladium complexes exhibited moderate activity. Moreover, in antimicrobial assays H2L1, Ni(L1)PPh3 and H2L3 showed dual inhibition against bacterial and fungal strains while for the rest of the compounds varying degree of activity was recorded against different strains. Overall comparison of results suggests that the synthesized compounds can be promising candidate for drug formulation and development.

Tunable Biodegradable Nanocomposite Hydrogel for Improved Cisplatin Efficacy on HCT-116 Colorectal Cancer Cells and Decreased Toxicity in Rats.

PubMed

Abdel-Bar, Hend Mohamed; Osman, Rihab; Abdel-Reheem, Amal Youssef; Mortada, Nahed; Awad, Gehanne A S

2016-02-08

This work describes the development of a modified nanocomposite thermosensitive hydrogel for controlled cisplatin release and improved cytotoxicity with decreased side effects. The system was characterized in terms of physical properties, morphological architecture and in vitro cisplatin release. Cytotoxicity was tested against human colorectal carcinoma HCT-116. In vivo studies were conducted to evaluate the acute toxicity in terms of rats' survival rate and body weight loss. Nephro and hepatotoxicities were evaluated followed by histopathological alterations of various tissue organs. Nanocomposite thermosensitive hydrogel containing nanosized carrier conferred density and stiffness allowing a zero order drug release for 14 days. Enhanced cytotoxicity with 2-fold decrease in cisplatin IC50 was accomplished. A linear in vivo-in vitro correlation was proved for the system degradation. Higher animal survival rate and lower tissue toxicities proved the decreased toxicity of cisplatin nanocomposite compared to its solution.

Characterizations of coal fly ash nanoparticles and induced in vitro toxicity in cell lines

NASA Astrophysics Data System (ADS)

Sambandam, Bharathi; Palanisami, Eganathan; Abbugounder, Rajasekar; Prakhya, Balakrishnamurthy; Thiyagarajan, Devasena

2014-02-01

The present study illustrates the characterization and cytotoxicity studies of coal fly ash nanoparticles (CFA-NPs). The coal fly ash (CFA) collected from electrostatic precipitator of a coal-fired power plant and the average size of the CFA-NPs was found to be 9-50 nm. Imaging techniques showed predominantly homogenous spherical shaped nanoparticles. The X-ray diffraction analysis and energy dispersive X-ray (EDAX) analysis spectra reveal the elemental constituents of the CFA-NPs contain several toxic heavy metals. Cytotoxicity of CFA-NPs was determined by MTT assay. Cellular metabolism is inhibited in a dose dependent manner by CFA concentrations varying from 13 to 800 μg mL-1. After 48 h exposure, the Hep2, A549 and HepG2 cell lines prove more sensitive to CFA-NPs at varying levels which results in IC50 (50 % inhibitory concentration) cytotoxicity end point.

Zephycandidine A, the First Naturally Occurring Imidazo[1,2-f]phenanthridine Alkaloid from Zephyranthes candida, Exhibits Significant Anti-tumor and Anti-acetylcholinesterase Activities

NASA Astrophysics Data System (ADS)

Zhan, Guanqun; Qu, Xiaolan; Liu, Junjun; Tong, Qingyi; Zhou, Junfei; Sun, Bin; Yao, Guangmin

2016-09-01

Zephycandidine A (1), the first naturally occurring imidazo[1,2-f]phenanthridine alkaloid, was isolated from Zephyranthes candida (Amaryllidaceae). The structure of 1 was elucidated by spectroscopic analyses and NMR calculation, and a plausible biogenetic pathway for zephycandidine A (1) was proposed. Zephycandidine A (1) exhibited significant cytotoxicity against five cancer cell lines with IC50 values ranging from 1.98 to 7.03 μM with selectivity indices as high as 10 when compared to the normal Beas-2B cell. Further studies suggested that zephycandidine A (1) induces apoptosis in leukemia cells by the activation of caspase-3, upregulation of Bax, downregulation of Bcl-2, and degradation of PARP expression. In addition, zephycandidine A (1) showed acetylcholinesterase (AChE) inhibitory activity, and the docking studies of zephycandidine A (1) and galanthamine (2) with AChE revealed that interactions with W286 and Y337 are necessary.

Unsymmetric Mono- and Dinuclear Platinum(IV) Complexes Featuring an Ethylene Glycol Moiety: Synthesis, Characterization, and Biological Activity

PubMed Central

Pichler, Verena; Heffeter, Petra; Valiahdi, Seied M.; Kowol, Christian R.; Egger, Alexander; Berger, Walter; Jakupec, Michael A.; Galanski, Markus; Keppler, Bernhard K.

2014-01-01

Eight novel mononuclear and two dinuclear platinum(IV) complexes were synthesized and characterized by elemental analysis, one- and two-dimensional NMR spectroscopy, mass spectrometry, and reversed-phase HPLC (log kw) and in one case by X-ray diffraction. Cytotoxicity of the compounds was studied in three human cancer cell lines (CH1, SW480, and A549) by means of the MTT assay, featuring IC50 values to the low micromolar range. Furthermore a selected set of compounds was investigated in additional cancer cell lines (P31 and P31/cis, A2780 and A2780/cis, SW1573, 2R120, and 2R160) with regard to their resistance patterns, offering a distinctly different scheme compared to cisplatin. To gain further insights into the mode of action, drug uptake, DNA synthesis inhibition, cell cycle effects, and induction of apoptosis were determined for two characteristic substances. PMID:23194425

Cytotoxicity of arctigenin and matairesinol against the T-cell lymphoma cell line CCRF-CEM.

PubMed

Su, Shan; Cheng, Xinlai; Wink, Michael

2015-09-01

Arctigenin and matairesinol possess a diversity of bioactivities. Here we investigated the cytotoxicity of arctigenin and matairesinol against a T-cell lymphoma cell line CCRF-CEM and the underlying mechanisms that have not been explored before. The cytotoxic activity was investigated using MTT assay. The cell cycle arrest and reactive oxygen species (ROS) accumulation were determined by flow cytometric analysis. The apoptosis induction was assessed using Annexin V/Propidium Iodide assay. The gene quantification analysis was measured through real-time polymerase chain reaction. Arctigenin and matairesinol exhibited significant antiproliferative activity against CCRF-CEM cells after 72 h treatment with IC50 values of 1.21 ± 0.15 μm and 4.27 ± 0.41 μm, respectively. In addition, both lignans arrest CCRF-CEM cells in the S phase. Furthermore, they could induce apoptosis in CCRF-CEM cells in a concentration- and time-dependent manner. Interestingly, the lignans differentially regulated the expression of several key genes involved in apoptosis pathways, including Bax, Bad and caspase-9. Moreover, both lignans could increase ROS levels in CCRF-CEM cells. Our study provides an insight into the potential of arctigenin and matairesinol as good candidates for the development of novel agents against T-cell lymphoma. © 2015 Royal Pharmaceutical Society.

Induction of apoptosis and cell cycle arrest in human colon carcinoma cells by Corema album leaves.

PubMed

León-González, Antonio J; Manson, Margaret M; López-Lizaro, Miguel; Navarro, Inmaculada; Martín-Cordero, Carmen

2014-01-01

The leaves of Corema album (Ericaceae), an endemic shrub which grows in Atlantic coastal areas of the Iberian Peninsula, are rich in flavonoids and other secondary metabolites. Silica gel column chromatography of the ethyl acetate extract from dried leaves was performed and a flavonic active fraction was obtained. The cytotoxic activity of this fraction was assessed using the colon cancer cell lines HCT116 and HT29. After 48 hours of treatment, cell viability was determined with luminescence-based ATPLite assay, showing IC50 values of 7.2 +/- 0.7 and 6.8 +/- 1.2 microg/mL, respectively. The study by flow cytometry revealed that the cytotoxicity of this fraction was mediated, at least in part, by induction of apoptosis and G2/M cell cycle arrest. The active fraction was then subjected to Sephadex LH-20 chromatography and two flavonoids were separated and identified as the flavanone pinocembrin and 2',4'-dihydroxychalcone after UV, MS and NMR analysis.

Cytotoxic epimeric withaphysalins from leaves of Acnistus arborescens.

PubMed

Veras, Maria Leopoldina; Bezerra, Maria Zeneide B; Braz-Filho, Raimundo; Pessoa, Otilia Deusdênia L; Montenegro, Raquel Carvalho; do O Pessoa, Cláudia; de Moraes, Manoel Odorico; Costa-Lutufo, Letícia Veras

2004-06-01

Phytochemical analysis of the leaves of Acnistus arborescens (Solanaceae) resulted in the isolation of two new epimeric withaphysalins (17S,20R,22R)-5beta,6beta: 18,20-diepoxy-4beta,18-dihydroxy-1-oxowitha-24-enolide (2, 18R and 18S), together with the known withaphysalin F (1, 18R and 18S). Their structures were established by spectroscopic methods, including 2D NMR data and comparison with literature data. Compounds 1 and 2 dis-played potent cytotoxic activities against several cancer cell lines with IC50 values in the range of 0.20 to 1.46 microg/mL for 1 and 0.89 to 8.08 microg/mL for 2. The strong cytotoxicity presented by 1 suggests that in this series of compounds, the 2,3-unsaturated ketone moiety is an important pharmacophoric unit. The cytotoxic activity seemed to be related to DNA synthesis inhibition, as revealed by the reduction of 5-bromo-2'-deoxyuridine incorporation after 24 hours of incubation on leukemic cells.

The slow cell death response when screening chemotherapeutic agents.

PubMed

Blois, Joseph; Smith, Adam; Josephson, Lee

2011-09-01

To examine the correlation between cell death and a common surrogate of death used in screening assays, we compared cell death responses to those obtained with the sulforhodamine B (SRB) cell protein-based "cytotoxicity" assay. With the SRB assay, the Hill equation was used to obtain an IC50 and final cell mass, or cell mass present at infinite agent concentrations, with eight adherent cell lines and four agents (32 agent/cell combinations). Cells were treated with high agent concentrations (well above the SRB IC50) and the death response determined as the time-dependent decrease in cells failing to bind both annexin V and vital fluorochromes by flow cytometry. Death kinetics were categorized as fast (5/32) (similar to the reference nonadherent Jurkat line), slow (17/32), or none (10/32), despite positive responses in the SRB assay in all cases. With slow cell death, a single exposure to a chemotherapeutic agent caused a slow, progressive increase in dead (necrotic) and dying (apoptotic) cells for at least 72 h. Cell death (defined by annexin and/or fluorochrome binding) did not correlate with the standard SRB "cytotoxicity" assay. With the slow cell death response, a single exposure to an agent caused a slow conversion from vital to apoptotic and necrotic cells over at least 72 h (the longest time point examined). Here, increasing the time of exposure to agent concentrations modestly above the SRB IC50 provides a method of maximizing cell kill. If tumors respond similarly, sustained low doses of chemotherapeutic agents, rather than a log-kill, maximum tolerated dose strategy may be an optimal strategy of maximizing tumor cell death.

Cytotoxic withanolides from Physalis angulata L.

PubMed

He, Qing-Ping; Ma, Lei; Luo, Jie-Ying; He, Fu-Yuan; Lou, Li-Guang; Hu, Li-Hong

2007-03-01

Four new withanolides, physagulins L-O (1-4), were isolated from the MeOH extract of the aerial parts of Physalis angulata L. (Solanaceae), together with seven known withanolides, compounds 5-11. Their structures were determined by spectroscopic techniques, including 1H-, 13C-NMR (DEPT), and 2D-NMR (HMBC, HMQC, 1H,1H-COSY, NOESY) experiments, as well as by HR-MS. All eleven compounds were tested for their antiproliferative activities towards human colorectal-carcinoma (HCT-116) and human non-small-cell lung-cancer (NCI-H460) cells. Compound 5 exhibited the highest anticancer activity against the HCT-116 cell line, with an IC50 value of 1.64+/-0.06 microM. Compound 9 exhibited the highest cytotoxicity towards the NCI-H460 cell line, with an IC50 value of 0.43+/-0.02 microM.

Biological activity of neosergeolide and isobrucein B (and two semi-synthetic derivatives) isolated from the Amazonian medicinal plant Picrolemma sprucei (Simaroubaceae).

PubMed

Silva, Ellen C C; Cavalcanti, Bruno C; Amorim, Rodrigo C N; Lucena, Jorcilene F; Quadros, Dulcimar S; Tadei, Wanderli P; Montenegro, Raquel C; Costa-Lotufo, Letícia V; Pessoa, Cláudia; Moraes, Manoel O; Nunomura, Rita C S; Nunomura, Sergio M; Melo, Marcia R S; Andrade-Neto, Valter F de; Silva, Luiz Francisco R; Vieira, Pedro Paulo R; Pohlit, Adrian M

2009-02-01

In the present study, in vitro techniques were used to investigate a range of biological activities of known natural quassinoids isobrucein B (1) and neosergeolide (2), known semi-synthetic derivative 1,12-diacetylisobrucein B (3), and a new semi-synthetic derivative, 12-acetylneosergeolide (4). These compounds were evaluated for general toxicity toward the brine shrimp species Artemia franciscana, cytotoxicity toward human tumour cells, larvicidal activity toward the dengue fever mosquito vector Aedes aegypti, haemolytic activity in mouse erythrocytes and antimalarial activity against the human malaria parasite Plasmodium falciparum. Compounds 1 and 2 exhibited the greatest cytotoxicity against all the tumor cells tested (IC50 = 5-27 microg/L) and against multidrug-resistant P. falciparum K1 strain (IC50 = 1.0-4.0 g/L) and 3 was only cytotoxic toward the leukaemia HL-60 strain (IC50 = 11.8 microg/L). Quassinoids 1 and 2 (LC50 = 3.2-4.4 mg/L) displayed greater lethality than derivative 4 (LC50 = 75.0 mg/L) toward A. aegypti larvae, while derivative 3 was inactive. These results suggest a novel application for these natural quassinoids as larvicides. The toxicity toward A. franciscana could be correlated with the activity in several biological models, a finding that is in agreement with the literature. Importantly, none of the studied compounds exhibited in vitro haemolytic activity, suggesting specificity of the observed cytotoxic effects. This study reveals the biological potential of quassinoids 1 and 2 and to a lesser extent their semi-synthetic derivatives for their in vitro antimalarial and cytotoxic activities.

Betulinic Acid Derivatives NVX-207 and B10 for Treatment of Glioblastoma—An in Vitro Study of Cytotoxicity and Radiosensitization

PubMed Central

Bache, Matthias; Bernhardt, Stephan; Passin, Sarina; Wichmann, Henri; Hein, Anja; Zschornak, Martin; Kappler, Matthias; Taubert, Helge; Paschke, Reinhard; Vordermark, Dirk

2014-01-01

Betulinic acid (BA), a pentacyclic triterpene, represents a new therapeutic substance that has potential benefits for treating glioblastoma. Recently, new strategies for producing BA derivatives with improved properties have evolved. However, few studies have examined the combination of BA or BA derivatives using radiotherapy. The effects of two BA derivatives, NVX-207 and B10, on cellular and radiobiological behavior were analyzed using glioblastoma cell lines (U251MG, U343MG and LN229). Based on IC50 values under normoxic conditions, we detected a 1.3–2.9-fold higher cytotoxicity of the BA derivatives B10 and NVX-207, respectively, compared to BA. Incubation using both BA derivatives led to decreased cell migration, cleavage of PARP and decreased protein expression levels of Survivin. Weak radiation sensitivity enhancement was observed in U251MG cells after treatment with both BA derivatives. The enhancement factors at an irradiation dose of 6 Gy after treatment with 5 µM NVX-207 and 5 µM B10 were 1.32 (p = 0.029) and 1.55 (p = 0.002), respectively. In contrast to BA, neither NVX-207 nor B10 had additional effects under hypoxic conditions. Our results suggest that the BA derivatives NVX-207 and B10 improve the effects of radiotherapy on human malignant glioma cells, particularly under normoxic conditions. PMID:25361208

Arylthioindole inhibitors of tubulin polymerization. 3. Biological evaluation, structure-activity relationships and molecular modeling studies.

PubMed

La Regina, Giuseppe; Edler, Michael C; Brancale, Andrea; Kandil, Sahar; Coluccia, Antonio; Piscitelli, Francesco; Hamel, Ernest; De Martino, Gabriella; Matesanz, Ruth; Díaz, José Fernando; Scovassi, Anna Ivana; Prosperi, Ennio; Lavecchia, Antonio; Novellino, Ettore; Artico, Marino; Silvestri, Romano

2007-06-14

The new arylthioindole (ATI) derivatives 10, 14-18, and 21-24, which bear a halogen atom or a small size ether group at position 5 of the indole moiety, were compared with the reference compounds colchicine and combretastatin A-4 for biological activity. Derivatives 10, 11, 16, and 21-24 inhibited MCF-7 cell growth with IC50 values <50 nM. A halogen atom (14-17) at position 5 caused a significant reduction in the free energy of binding of compound to tubulin, with a concomitant reduction in cytotoxicity. In contrast, methyl (21) and methoxy (22) substituents at position 5 caused an increase in cytotoxicity. Compound 16, the most potent antitubulin agent, led to a large increase (56%) in HeLa cells in the G2/M phase at 24 h, and at 48 h, 26% of the cells were hyperploid. Molecular modeling studies showed that, despite the absence of the ester moiety present in the previously examined analogues, most of the compounds bind in the colchicine site in the same orientation as the previously studied ATIs. Binding to beta-tubulin involved formation of a hydrogen bond between the indole and Thr179 and positioning of the trimethoxy phenyl group in a hydrophobic pocket near Cys241.

Design of multi-target compounds as AChE, BACE1, and amyloid-β(1-42) oligomerization inhibitors: in silico and in vitro studies.

PubMed

Hernández-Rodríguez, Maricarmen; Correa-Basurto, José; Martínez-Ramos, Federico; Padilla-Martínez, Itzia Irene; Benítez-Cardoza, Claudia G; Mera-Jiménez, Elvia; Rosales-Hernández, Martha Cecilia

2014-01-01

Despite great efforts to develop new therapeutic strategies against Alzheimer's disease (AD), the acetylcholinesterase inhibitors (AChEIs): donepezil, rivastigmine, and galantamine, have been used only as a palliative therapeutic approach. However, the pathogenesis of AD includes several factors such as cholinergic hypothesis, amyloid-β (Aβ) aggregation, and oxidative stress. For this reason, the design of compounds that target the genesis and progression of AD could offer a therapeutic benefit. We have designed a set of compounds (M-1 to M-5) with pharmacophore moieties to inhibit the release, aggregation, or toxicity of Aβ, act as AChEIs and have antioxidant properties. Once the compounds were designed, we analyzed their physicochemical parameters and performed docking studies to determine their affinity values for AChE, β-site amyloid-protein precursor cleaving enzyme 1 (BACE1), and the Aβ monomer. The best ligands, M-1 and M-4, were then synthesized, chemically characterized, and evaluated in vitro. The in vitro studies showed that these compounds inhibit AChE (M-1 Ki = 0.12 and M-4 Ki = 0.17 μM) and BACE1 (M-1 IC50 = 15.1 and M-4 IC50 = 15.4 nM). They also inhibit Aβ oligomerization and exhibit antioxidant activity. In addition, these compounds showed low cytotoxicity in microglial cells. For these reasons, they are promising for future use as drugs in AD mice transgenic models.

Cytotoxic responses of selected insecticides in chick ganglia cultures.

PubMed Central

Sharma, R P; Obersteiner, E J

1981-01-01

Various agricultural chemicals, e.g. pesticides, are known to cause different toxic effects in man and animals. Some of these produce responses involving the nervous tissue. Total of 52 such chemicals, representing organophosphates, carbamates and other miscellaneous insecticides were evaluated to determine their relative cytotoxic effects in avian dorsal root ganglia cultures. Many of these chemicals caused a slight stimulation of cellular growth at very low concentrations. At toxic concentrations, a dose-related but nonspecific inhibition of cell growth occurred. The cytotoxic changes included the decreased migration of cells from the culture implant, varicosities in and shortening of various cells and vacuolization and rounding of neuroglial cells. At high concentrations, pigmentary degeneration and complete abolition of cell growth were observed. The toxic effects were numerically scored in a random blind fashion and the concentrations of individual chemicals to produce a half maximal effect (IC50) in culture were determined from the dose-response curves. The IC50 values for various chemicals ranged from approximately 10(-6) M for compounds like methylparathion, diazinon, paraoxon and Vendex to greater than 10(-2) M for chlorpyriphos and methylchlorpyriphos. No significant correlations of nerve fiber or glial cell cytotoxicity were apparent with other toxic or physico-chemical properties such as lethal dose in animals, cholinesterase inhibition, lipophilicity or water solubility of chemicals. Clinically neurotoxic and nonneurotoxic compounds caused similar cytotoxic effects in ganglia cultures. Images Fig. 3. Fig. 4. Fig. 5. Fig. 6. PMID:7272842

Evaluation of Antileishmanial Activity of Selected Brazilian Plants and Identification of the Active Principles

PubMed Central

Filho, Valdir Cechinel; Meyre-Silva, Christiane; Niero, Rivaldo; Bolda Mariano, Luisa Nathália; Gomes do Nascimento, Fabiana; Vicente Farias, Ingrid; Gazoni, Vanessa Fátima; dos Santos Silva, Bruna; Giménez, Alberto; Gutierrez-Yapu, David; Salamanca, Efrain; Malheiros, Angela

2013-01-01

This study evaluated extracts, fractions, and isolated compounds from some selected Brazilian medicinal plants against strains of promastigotes of Leishmania amazonensis and L. brasiliensis in vitro. The cell viability was determined, comparing the results with reference standards. The dichloromethane fractions of the roots, stems, and leaves of Allamanda schottii showed IC50 values between 14.0 and 2.0 μg/mL. Plumericin was the main active compound, with IC50 of 0.3 and 0.04 μg/mL against the two species of Leishmania analyzed. The hexane extract of Eugenia umbelliflora fruits showed IC50 of 14.3 and 5.7 μg/mL against L. amazonensis and L. brasiliensis, respectively. The methanolic extracts of the seeds of Garcinia achachairu and guttiferone A presented IC50 values of 35.9 and 10.4 μg/mL, against L. amazonensis, respectively. The ethanolic extracts of the stem barks of Rapanea ferruginea and the isolated compound, myrsinoic acid B, presented activity against L. brasiliensis with IC50 of 24.1 and 6.1 μg/mL. Chloroform fraction of Solanum sisymbriifolium exhibited IC50 of 33.8 and 20.5 μg/mL, and cilistol A was the main active principle, with IC50 of 6.6 and 3.1 μg/mL against L. amazonensis and L. brasiliensis, respectively. It is concluded that the analyzed plants are promising as new and effective antiparasitic agents. PMID:23840252

Phenolic, flavonoid contents, anticholinesterase and antioxidant evaluation of Iris germanica var; florentina.

PubMed

Ullah, Farhat; Ayaz, Muhammad; Sadiq, Abdul; Hussain, Abid; Ahmad, Sajjad; Imran, Muhammad; Zeb, Anwar

2016-06-01

This study was designed to investigate antioxidant and anticholinesterase potential of Iris germanica var; florentina. Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory potential of plant samples were investigated by Ellman's assay. Antioxidant activity was performed using DPPH, H2O2 and ABTS free radical scavenging assays. Total phenolics and flavonoids contents were expressed in mg GAE/g dry weight and mg RTE/g, respectively. In AChE inhibition assay, Ig.Fl, Ig.Sp and Ig.Cf fractions exhibited highest activity with IC50 values of < 0.1, 5.64 and 19 μg/mL, respectively. In BChE inhibitory assay, Ig.Fl, Ig.Sp, Ig.Cf and Ig.Cr were most active with IC50 of < 0.1, < 0.1, 31 and 78 μg/mL, respectively. In DPPH assay, Ig.Fl and Ig.Cf exhibited highest inhibition of free radicals, 80.52% (IC50 = 9 μg/mL) and 78.30% (IC50 = 8 μg/mL), respectively. In ABTS assay Ig.Cr, Ig.Cf, Ig.Fl and Ig.Sp exhibited IC50 values of < 0.1, 2, 2 and 3 μg/mL, respectively.

Synthesis, crystal structures and properties of new homoleptic Ni(II)/Pd(II) β-oxodithioester chelates

NASA Astrophysics Data System (ADS)

Yadav, Chote L.; Manar, Krishna K.; Yadav, Manoj K.; Tiwari, Neeraj; Singh, Rakesh K.; Drew, Michael G. B.; Singh, Nanhai

2018-05-01

Six new cis-chelate complexes, [M(L)2] (L = methyl-3-hydroxy-3-(furyl)-2-propenedithioate L1, M = Ni(II) 1, Pd(II) 4; methyl-3-hydroxy-3-(thiophenyl)-2-propenedithioate L2, M = Ni(II) 2, Pd(II) 5 and methyl-3-hydroxy-3-(phenyl)-2-propenedithioate L3, M = Ni(II) 3, Pd(II) 6 have been prepared and characterized by elemental analyses, spectroscopy (IR, UV-Vis., 1H and 13C{1H} NMR). The structures of 2-6 have been revealed by X-ray crystallography. In all the crystal structures, the metal has four-coordinate slightly distorted square planar geometry with a cis-configuration of the ligands. Anti-leishmanial properties of the complexes have been studied; 2, 3 and 6 showed potential anti-promastigote and anti-amastigote activities with IC50 values of 1.70 ± 0.50, 1.62 ± 0.19, 9.20 ± 2.16 μg/mL and IC50 2.50 ± 0.10, 2.05 ± 0.40, 12.84 ± 3.46 μg/mL respectively. Cytotoxicity assays on these complexes showed toxicity on the promastigotes but less toxicity against RAW 264.7 cell lines at different concentrations. Palladium complexes 4, 5 and 6 show luminescent characteristics in CH2Cl2 solution at room temperature. Complexes 1-6 are weakly conducting (σrt = 10-4-10-6 S cm-1, Ea = 0.19-1.13 eV) but show semiconducting behavior in the solid phase.

Isolation, structural determination, and evaluation of the biological activity of 20(S)-25-methoxyl-dammarane-3beta, 12beta, 20-triol [20(S)-25-OCH3-PPD], a novel natural product from Panax notoginseng.

PubMed

Zhao, Y; Wang, W; Han, L; Rayburn, E R; Hill, D L; Wang, H; Zhang, R

2007-01-01

Ginseng has been used extensively for medicinal purposes, with suggested utility for indications as diverse as diabetes, cardiovascular disease and cancer. Herein we report the discovery and characterization of 20(S)-25-OCH3-PPD, a ginsenoside that inhibits growth and survival of cancer cells. The novel dammarane triterpene sapogenin (C31H56O4; molecular weight 492) was isolated from the total hydrolyzed saponins extracted from the leaves of Panax notoginseng using conventional and reverse-phase silica gel chromatography. Based on physicochemical characteristics and NMR data, the compound was identified as 20(S)-25-OCH3-PPD. The biological activities of 20(S)-25-OCH3-PPD and its known analogs, 20(S)-PPD and Rg3, were evaluated in 12 human cancer cell lines. In all cell lines, the order of cytotoxicity of the test compounds was 20(S)-25-OCH3-PPD > 20(S)-PPD > Rg3. 20(S)-25-OCH3-PPD also induced apoptosis and cell cycle arrest in the G1 phase, and inhibited proliferation in breast cancer cell lines, demonstrating its potent biological effects. In regard to cytotoxicity, the IC50 values of 20(S)-25-OCH3-PPD for most cell lines were in the lower microM range, a 5-15-fold greater cytotoxicity relative to 20(S)-PPD and a 10-100-fold increase over Rg3. These findings suggest a structure-activity relationship among dammarane-type sapogenins. The data presented here may provide a basis for the future development of 20(S)-25-OCH3-PPD as a novel anti-cancer agent.

New Ferrocene Compounds as Selective Cyclooxygenase (COX-2) Inhibitors: Design, Synthesis, Cytotoxicity and Enzyme-inhibitory Activity.

PubMed

Farzaneh, Shabnam; Zeinalzadeh, Elnaz; Daraei, Bahram; Shahhosseini, Soraya; Zarghi, Afshin

2018-01-01

Due to the astonishing properties of ferrocene and its derivatives, it has a broad application in diverse areas. Numerous ferrocene derivatives demonstrated anti-proliferative activity. Also COX-2, as a key isoenzyme for production of prostaglandins, is frequently overexpressed in various cancers. It is now recognized that COX-2 over expression promotes tumorigenic functions which can be suppressed by COX-2 inhibitors, a phenomenon useful for the preventing of tumor progression. The combination of COX-2 inhibitors with other anti-cancer or cancer prevention drugs may reduce their side effects in future cancer prevention and treatment. Owing to high anticancer potential of ferrocene derivatives and considerable COX-2 inhibitory and cytotoxicity effects of our previously synthesized chalcones, we decided to incorporate the ferrocenyl moiety into appropriate COX-2 inhibitor chalcone based scaffold, to evaluate COX-2 inhibitory activity as well as anticancer activities. Chalcones were synthesized via clasien-schmidt condensation of methylsulfonyl aldehyde and acetyl ferrocene. Further different amines with solvent free and ultra sound condition were reacted with chalcones to have different 1-ferrocenyl-3-amino carbonyl compounds. Docking study was carried out with Auto Dock vina software. All the newly-synthesized compounds were evaluated for their cyclooxygenase-2 (COX-2) inhibitory activity using chemiluminescent enzyme assays as well as cytotoxicity activity against MCF-7 and T47D and fibroblast cell lines by MTT assay. In vitro COX-1/COX-2 inhibition studies demonstrated that all compounds were selective inhibitors of the COX-2 isozyme with IC50 values in the highly potent 0.05-0.12 µM range, and COX-2 selectivity indexes (SI) in the 148.3-313.7 range. These results indicated that either potency or selectivity of COX-2 inhibitory activity was affected by the nature and size of the substituents on C-3 of propane-1-one. Also anti-proliferative and toxicity activities of synthesized compounds against breast cancer cell lines MCF-7 and T47D and fibroblast cell lines showed that the synthesized compounds had mild to moderate cytotoxicity against MCT7 and T47D breast cancer cell lines at 10 µM concentration. In vitro COX-1/COX-2 inhibition studies and anticancer activity against MCF-7, identified 1-ferrocenyl-3-(4-methylsulfonylphenyl) propen-1-one as a potent compound (IC50 COX-2 = 0.05 µM, MCF-7: % inhibition (at concentration of 10 µM) = 32.7%), and also 1-ferrocenyl-3- (propan-1-amine)-3-(4-methylsulfonylphenyl) propan-1-one showed the most selectivity on COX-2 inhibition (selectivity index= 313.7). A novel group of ferrocene compounds, possessing a methyl sulfonyl COX-2 pharmacophore were synthesized to investigate the effect of different substituents on selectivity and potency of COX-2 inhibitory activity and their cytotoxicity effects. This study indicates that 1-ferrocenyl-3-amino carbonyl compounds having ferrocene motif and methyl sulfonyl COX-2 pharmacophore is a suitable scaffold to design COX-2 inhibitors and anti-cancer agents. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Improved photodynamic efficacy of Zn(II) phthalocyanines via glycerol substitution.

PubMed

Chin, Yunni; Lim, Siang Hui; Zorlu, Yunus; Ahsen, Vefa; Kiew, Lik Voon; Chung, Lip Yong; Dumoulin, Fabienne; Lee, Hong Boon

2014-01-01

Phthalocyanines are excellent photosensitizers for photodynamic therapy as they have strong absorbance in the near infra-red region which is most relevant for in vivo activation in deeper tissular regions. However, most phthalocyanines present two major challenges, ie, a strong tendency to aggregate and low water-solubility, limiting their effective usage clinically. In the present study, we evaluated the potential enhancement capability of glycerol substitution on the photodynamic properties of zinc (II) phthalocyanines (ZnPc). Three glycerol substituted ZnPc, 1-3, (tetra peripherally, tetra non-peripherally and mono iodinated tri non-peripherally respectively) were evaluated in terms of their spectroscopic properties, rate of singlet oxygen generation, partition coefficient (log P), intracellular uptake, photo-induced cytotoxicity and vascular occlusion efficiency. Tetrasulfonated ZnPc (ZnPcS4) was included as a reference compound. Here, we showed that 1-3 exhibited 10-100 nm red-shifted absorption peaks with higher molar absorptivity, and at least two-fold greater singlet oxygen generation rates compared to ZnPcS4. Meanwhile, phthalocyanines 1 and 2 showed more hydrophilic log P values than 3 consistent with the number of glycerol attachments but 3 was most readily taken up by cells compared to the rest. Both phthalocyanines 2 and 3 exhibited potent phototoxicity against MCF-7, HCT-116 and HSC-2 cancer cell-lines with IC50 ranging 2.8-3.2 µM and 0.04-0.06 µM respectively, while 1 and ZnPcS4 (up to 100 µM) failed to yield determinable IC50 values. In terms of vascular occlusion efficiency, phthalocyanine 3 showed better effects than 2 by causing total occlusion of vessels with diameter <70 µm of the chorioallantoic membrane. Meanwhile, no detectable vascular occlusion was observed for ZnPcS4 with treatment under similar experimental conditions. These findings provide evidence that glycerol substitution, in particular in structures 2 and 3, is able to improve the photodynamic properties of ZnPc.

Antioxidant and antiproliferative potentials of methanol extract of Xylopia aethiopica (Dunal) A. Rich in PC-3 and LNCaP cells.

PubMed

Adaramoye, Oluwatosin Adekunle; Erguen, Bettina; Nitzsche, Bianca; Höpfner, Michael; Jung, Klaus; Rabien, Anja

2017-07-26

Our previous studies showed that fruit methanol extract from Xylopia aethiopica (MEXA) exhibited antiproliferative activity in human cervical cancer cells via the induction of apoptosis. The present study was designed to assess the antiproliferative, antiangiogenic and antioxidant effects of MEXA on prostate cancer (PCa) cells (PC-3 and LNCaP). PC-3 and LNCaP cells were cultured and treated with MEXA (10, 50 and 100 μg/mL). The sodium 3'-[1-(phenylaminocarbonyl)-3,4-tetrazolium]-bis (4-methoxy-6-nitro) benzene sulfonic acid hydrate (XTT) and lactate dehydrogenase (LDH) assays were used to evaluate cell viability and cytotoxicity, respectively. DNA fragmentation was determined by cell death detection ELISA plus, and angiogenesis was assessed by chicken chorioallantoic membrane (CAM) assay. The antioxidant activities of MEXA were determined by DPPH and hydroxyl (OH) radicals' scavenging methods as well as through the inhibition of lipid peroxidation (LPO) in rats' liver homogenate. MEXA at 100, 250 and 500 μg/mL scavenged DPPH by 48%, 62%, 70% and OH radical by 39%, 58%, 67%, respectively. MEXA significantly (p<0.05) inhibited LPO in a concentration-dependent manner. In addition, MEXA had antiproliferative effects on PC-3 and LNCaP with IC50 of 62.1 and 73.6 μg/mL, respectively, at 96 h. The LDH assay showed that MEXA had low toxicity in vitro at its IC50 values. The extent of DNA fragmentation by MEXA showed higher values in PC-3 and LNCaP, suggesting the possible induction of apoptosis. In contrast, MEXA did not affect the network of vessels in CAM, thus lacking anti-angiogenic property. These findings suggest that MEXA induces antiproliferative activity in PCa cells through a mechanism that involves apoptosis. Therefore, MEXA may be a potential therapeutic agent for PCa.

Synthesis, fluorescence properties and the promising cytotoxicity of pyrene-derived aminophosphonates.

PubMed

Lewkowski, Jarosław; Rodriguez Moya, Maria; Wrona-Piotrowicz, Anna; Zakrzewski, Janusz; Kontek, Renata; Gajek, Gabriela

2016-01-01

A large series of variously substituted amino(pyren-1-yl)methylphosphonic acid derivatives was synthesized using a modified aza-Pudovik reaction in 20-97% yields. The fluorescence properties of the obtained compounds were investigated revealing that N-alkylamino(pyren-1-yl)methylphosphonic derivatives are stronger emissive compounds than the corresponding N-aryl derivatives. N-Benzylamino(pyren-1-yl)methylphosphonic acid displayed strong fluorescence (ΦF = 0.68) in phosphate-buffered saline (PBS). The influence of a series of derivatives on two colon cancer cell lines HT29 and HCT116 was also investigated. The most promising results were obtained for N-(4-methoxyphenyl)amino(pyren-1-yl)methylphosphonate, which was found to be cytotoxic for the HCT116 cancer cell line (IC50 = 20.8 μM), simultaneously showing weak toxicity towards normal lymphocytes (IC50 = 230.8 µM).

The Anti-Inflammatory Activity of Boron Derivatives in Rodents

PubMed Central

Hall, Iris H.; Burnham, Bruce S.; Chen, Shang Y.; Sood, Anup; Spielvogel, Bernard F.; Morse, Karen W.

1995-01-01

Acyclic amine-carboxyboranes were effective anti-inflammatory agents in mice at 8 mg/kg x 2. These amine-carboxyboranes were more effective than the standard indomethacin at 8 mg/kg x 2, pentoxifylline at 50 mg/kg x 2, and phenylbutazone at 50 mg/kg x 2. The heterocyclic amine derivatives as well as amine-carbamoylboranes, carboalkoxyboranes, and cyanoboranes were generally less active. However, selected aminomethyl-phosphonate-N-cyanoboranes demonstrated greater than 60% reduction of induced inflammation. The boron compounds were also active in the rat induced edema, chronic arthritis, and pleurisy screens, demonstrating activity similar to the standard indomethacin. The compounds were effecive in reducing local pain and decreased the tail flick reflex to pain. The derivatives which demonstrated good anti-inflammatory activity were effective inhibitors of hydrolytic lysosomal, and proteolytic enzyme activities with IC50 50 values equal to -6M in mouse macrophages, human leukocytes, and Be Sal osteofibrolytic cells. In these same cell lines, the agents blocked prostaglandin cyclooxygenase activity with IC50 values of -6M. In mouse macrophage and human leukocytes, 5′ lipoxygenase activity was also inhibited by the boron derivatives with IC50 values of 10-6M. These IC50 values for inhibition of these enzyme activities are consistent with published values of known anti-inflammatory agents which target these enzymes. PMID:18472741

Interaction of Silymarin Flavonolignans with Organic Anion-Transporting Polypeptides

PubMed Central

Köck, Kathleen; Xie, Ying; Oberlies, Nicholas H.; Brouwer, Kim L. R.

2013-01-01

Organic anion-transporting polypeptides (OATPs) are multispecific transporters mediating the uptake of endogenous compounds and xenobiotics in tissues that are important for drug absorption and elimination, including the intestine and liver. Silymarin is a popular herbal supplement often used by patients with chronic liver disease; higher oral doses than those customarily used (140 mg three times/day) are being evaluated clinically. The present study examined the effect of silymarin flavonolignans on OATP1B1-, OATP1B3-, and OATP2B1-mediated transport in cell lines stably expressing these transporters and in human hepatocytes. In overexpressing cell lines, OATP1B1- and OATP1B3-mediated estradiol-17β-glucuronide uptake and OATP2B1-mediated estrone-3-sulfate uptake were inhibited by most of the silymarin flavonolignans investigated. OATP1B1-, OATP1B3-, and OATP2B1-mediated substrate transport was inhibited efficiently by silymarin (IC50 values of 1.3, 2.2 and 0.3 µM, respectively), silybin A (IC50 values of 9.7, 2.7 and 4.5 µM, respectively), silybin B (IC50 values of 8.5, 5.0 and 0.8 µM, respectively), and silychristin (IC50 values of 9.0, 36.4, and 3.6 µM, respectively). Furthermore, silymarin, silybin A, and silybin B (100 µM) significantly inhibited OATP-mediated estradiol-17β-glucuronide and rosuvastatin uptake into human hepatocytes. Calculation of the maximal unbound portal vein concentrations/IC50 values indicated a low risk for silymarin-drug interactions in hepatic uptake with a customary silymarin dose. The extent of silymarin-drug interactions depends on OATP isoform specificity and concentrations of flavonolignans at the site of drug transport. Higher than customary doses of silymarin, or formulations with improved bioavailability, may increase the risk of flavonolignan interactions with OATP substrates in patients. PMID:23401473

A novel application of t-statistics to objectively assess the quality of IC50 fits for P-glycoprotein and other transporters.

PubMed

O'Connor, Michael; Lee, Caroline; Ellens, Harma; Bentz, Joe

2015-02-01

Current USFDA and EMA guidance for drug transporter interactions is dependent on IC50 measurements as these are utilized in determining whether a clinical interaction study is warranted. It is therefore important not only to standardize transport inhibition assay systems but also to develop uniform statistical criteria with associated probability statements for generation of robust IC50 values, which can be easily adopted across the industry. The current work provides a quantitative examination of critical factors affecting the quality of IC50 fits for P-gp inhibition through simulations of perfect data with randomly added error as commonly observed in the large data set collected by the P-gp IC50 initiative. The types of errors simulated were (1) variability in replicate measures of transport activity; (2) transformations of error-contaminated transport activity data prior to IC50 fitting (such as performed when determining an IC50 for inhibition of P-gp based on efflux ratio); and (3) the lack of well defined "no inhibition" and "complete inhibition" plateaus. The effect of the algorithm used in fitting the inhibition curve (e.g., two or three parameter fits) was also investigated. These simulations provide strong quantitative support for the recommendations provided in Bentz et al. (2013) for the determination of IC50 values for P-gp and demonstrate the adverse effect of data transformation prior to fitting. Furthermore, the simulations validate uniform statistical criteria for robust IC50 fits in general, which can be easily implemented across the industry. A calibration of the t-statistic is provided through calculation of confidence intervals associated with the t-statistic.

Molecularly Characterized Solvent Extracts and Saponins from Polygonum hydropiper L. Show High Anti-Angiogenic, Anti-Tumor, Brine Shrimp, and Fibroblast NIH/3T3 Cell Line Cytotoxicity

PubMed Central

Ayaz, Muhammad; Junaid, Muhammad; Ullah, Farhat; Sadiq, Abdul; Subhan, Fazal; Khan, Mir Azam; Ahmad, Waqar; Ali, Gowhar; Imran, Muhammad; Ahmad, Sajjad

2016-01-01

Polygonum hydropiper is used as anti-cancer and anti-rheumatic agent in folk medicine. This study was designed to investigate the anti-angiogenic, anti-tumor, and cytotoxic potentials of different solvent extracts and isolated saponins. Samples were analyzed using GC, Gas Chromatography–Mass Spectrometry (GC–MS) to identify major and bioactive compounds. Quantitation of antiangiogenesis for the plant's samples including methanolic extract (Ph.Cr), its subsequent fractions; n-hexane (Ph.Hex), chloroform (Ph.Chf), ethyl acetate (Ph.EtAc), n-Butanol (Ph.Bt), aqueous (Ph.Aq), saponins (Ph.Sp) were performed using the chick embryo chorioallantoic membrane (CAM) assay. Potato disc anti-tumor assay was performed on Agrobacterium tumefaciens containing tumor inducing plasmid. Cytotoxicity was performed against Artemia salina and mouse embryonic fibroblast NIH/3T3 cell line following contact toxicity and MTT cells viability assays, respectively. The GC–MS analysis of Ph.Cr, Ph.Hex, Ph.Chf, Ph.Bt, and Ph.EtAc identified 126, 124, 153, 131, and 164 compounds, respectively. In anti-angiogenic assay, Ph.Chf, Ph.Sp, Ph.EtAc, and Ph.Cr exhibited highest activity with IC50 of 28.65, 19.21, 88.75, and 461.53 μg/ml, respectively. In anti-tumor assay, Ph.Sp, Ph.Chf, Ph.EtAc, and Ph.Cr were most potent with IC50 of 18.39, 73.81, 217.19, and 342.53 μg/ml, respectively. In MTT cells viability assay, Ph.Chf, Ph.EtAc, Ph.Sp were most active causing 79.00, 72.50, and 71.50% cytotoxicity, respectively, at 1000 μg/ml with the LD50 of 140, 160, and 175 μg/ml, respectively. In overall study, Ph.Chf and Ph.Sp have shown overwhelming results which signifies their potentials as sources of therapeutic agents against cancer. PMID:27065865

Synthesis and discovery of highly functionalized mono- and bis-spiro-pyrrolidines as potent cholinesterase enzyme inhibitors.

PubMed

Kia, Yalda; Osman, Hasnah; Suresh Kumar, Raju; Basiri, Alireza; Murugaiyah, Vikneswaran

2014-04-01

Novel mono and bis spiropyrrolidine derivatives were synthesized via an efficient ionic liquid mediated, 1,3-dipolar cycloaddition methodology and evaluated in vitro for their AChE and BChE inhibitory activities in search for potent cholinesterase enzyme inhibitors. Most of the synthesized compounds displayed remarkable AChE inhibitory activities with IC50 values ranging from 1.68 to 21.85 μM, wherein compounds 8d and 8j were found to be most active inhibitors against AChE and BChE with IC50 values of 1.68 and 2.75 μM, respectively. Molecular modeling simulation on Torpedo californica AChE and human BChE receptors, showed good correlation between IC50 values and binding interaction template of the most active inhibitors docked into the active site of their relevant enzymes. Copyright © 2014 Elsevier Ltd. All rights reserved.

Immunotoxicological effects of streptozotocin and alloxan: in vitro and in vivo studies.

PubMed

Diab, Randa A Hadi; Fares, Mona; Abedi-Valugerdi, Manuchehr; Kumagai-Braesch, Makiko; Holgersson, Jan; Hassan, Moustapha

2015-02-01

Streptozotocin (STZ) and alloxan (ALX), widely used to induce diabetes in experimental animals, have different structures and mechanisms of action. We investigated those effects of these drugs on the immune system that might influence engraftment efficiency and graft survival in transplantation models, and their cytotoxicity on hematopoietic cell lines. We used the minimum dose to induce diabetes in a mouse, i.e. 180 mg/kg i.v. STZ and 75 mg/kg i.v. ALX. Both groups exhibited significant decrease in body weight during 4 days post-treatment as compared to controls. We found that blood glucose in ALX-injected mice increased faster than in STZ-injected mice. The total number of recovered splenocytes was lower in STZ-injected animals than in ALX-injected animals. The survival periods of rat islet grafts in recipient mice were longer and more diverse in STZ-injected recipients (7-24 days) compared to ALX-injected recipients (6-7 days). The in vitro study showed that ALX was less cytotoxic in cell lines with IC50 values of 2809, 3679 and >4000 μg/ml for HL60, K562 and C1498 cells respectively. STZ was more toxic, especially in HL60 cells, with IC50 values of 11.7, 904 and 1024 μg/ml for HL60, K562 and C1498 cells respectively. Furthermore, in response to concanavalin A (Con-A), splenocytes from STZ-injected mice produced higher amounts of interferon-gamma (IFN-γ) than those from ALX-injected mice. In conclusion, STZ was more cytotoxic than ALX in vitro and in vivo. STZ caused lymphocytopenia, which may result in longer graft survival in STZ-treated animals than in ALX-treated animals. Copyright © 2015 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.

Rational Design, Synthesis, and Biological Evaluation of Third Generation α-Noscapine Analogues as Potent Tubulin Binding Anti-Cancer Agents

PubMed Central

Manchukonda, Naresh Kumar; Naik, Pradeep Kumar; Santoshi, Seneha; Lopus, Manu; Joseph, Silja; Sridhar, Balasubramanian; Kantevari, Srinivas

2013-01-01

Systematic screening based on structural similarity of drugs such as colchicine and podophyllotoxin led to identification of noscapine, a microtubule-targeted agent that attenuates the dynamic instability of microtubules without affecting the total polymer mass of microtubules. We report a new generation of noscapine derivatives as potential tubulin binding anti-cancer agents. Molecular modeling experiments of these derivatives 5a, 6a-j yielded better docking score (-7.252 to -5.402 kCal/mol) than the parent compound, noscapine (-5.505 kCal/mol) and its existing derivatives (-5.563 to -6.412 kCal/mol). Free energy (ΔG bind) calculations based on the linear interaction energy (LIE) empirical equation utilizing Surface Generalized Born (SGB) continuum solvent model predicted the tubulin-binding affinities for the derivatives 5a, 6a-j (ranging from -4.923 to -6.189 kCal/mol). Compound 6f showed highest binding affinity to tubulin (-6.189 kCal/mol). The experimental evaluation of these compounds corroborated with theoretical studies. N-(3-brormobenzyl) noscapine (6f) binds tubulin with highest binding affinity (KD, 38 ± 4.0 µM), which is ~ 4.0 times higher than that of the parent compound, noscapine (KD, 144 ± 1.0 µM) and is also more potent than that of the first generation clinical candidate EM011, 9-bromonoscapine (KD, 54 ± 9.1 µM). All these compounds exhibited substantial cytotoxicity toward cancer cells, with IC50 values ranging from 6.7 µM to 72.9 µM; compound 6f showed prominent anti-cancer efficacy with IC50 values ranging from 6.7 µM to 26.9 µM in cancer cells of different tissues of origin. These compounds perturbed DNA synthesis, delayed the cell cycle progression at G2/M phase, and induced apoptotic cell death in cancer cells. Collectively, the study reported here identified potent, third generation noscapinoids as new anti-cancer agents. PMID:24205049

Preliminary phytochemical analysis, Antioxidant and cytotoxicity test of Carissa edulis Vahl dried fruits

NASA Astrophysics Data System (ADS)

Fowsiya, J.; Madhumitha, G.

2017-11-01

Plants are the main source of medicine which is used in traditional as well as modern medicine in recent years for curing many diseases. Carissa edulis Vahl is one of the traditional plants which have healing property on diarrhea, toothache and chest pain. The present work aims on phytochemical, antioxidant and in vitro cytotoxicity test of C. edulis dried fruits. The different solvent extracts obtained from petroleum ether, ethyl acetate, chloroform, ethanol and water have been evaluated the presence of phytochemicals. Several assays were carried out like total antioxidant, DPPH, reducing power and thiobarbituric acid to investigate the free radical scavenging property. In addition, the cytotoxicity study also carried out on human lung cancer cells (A549). Among different solvent extract, ethanol exhibited strong antioxidant activity. Additionally, the in vitro cytotoxicity test of C. edulis on human lung cancer cell (A549) showed IC50 value 405.704 ± 2.42 μg/mL. Therefore, C. edulis could be useful as a potential preventive intervention for free radicals mediated diseases as well as an antioxidant drug in the pharmaceutical industry.

Direct led-fluorescence method for Mao-B inactivation in the treatment of Parkinson's

NASA Astrophysics Data System (ADS)

Castillo, Jimmy A.; Hung, Jannett; Rodriguez, M.; Bastidas, E.; Laboren, I.; Jaimes, A.

2004-10-01

A led-fluorescence spectroscopy method determinate the inhibitory effects of probe compounds on MAO-B activity is described. In this assay, we demonstrate the possibility of determinate the activity of MAO-B efficiently and rapidly without the use of reference substrate. Measuring variations in fluorescence intensity of MAO-B enzyme during the reaction with inhibitors, L-deprenyl and berberine IC50 and KI values were obtained. For L-deprenyl (IC50 = 0.017 μM and KI = 0.019 μM) and berberine (IC50 = 90 μM and KI = 47 μM) were in agreement to the values obtained with a standard method and literature reported.

Preformulation and formulation development of a bioactive nitroaromatic compound

NASA Astrophysics Data System (ADS)

Sena, Camila F. A.; Apolinário, Lívia S.; Duarte, Jaqueline A.; dos Santos, Giovanna C.; Monteiro, Liziane O. F.; de Oliveira, Mônica C.; Leite, Elaine A.; de Oliveira, Renata B.

2017-11-01

The N-(butanoyloxyethyl)-4-(chloromethyl)-3-nitrobenzamide (BNB) is a nitroaromatic derivative with significant antitumor activity. Preformulation, forced degradation (distilled water, acid and base hydrolysis, oxidation, and light), and formulation studies were performed to investigate the chemical behavior of the molecule, the physicochemical properties, and the impact of formulation variables. Pharmacokinetic properties for BNB were estimated in silico. Solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) containing BNB were developed by a hot melt homogenization method for parenteral administration. Degradation studies demonstrated that this compound is sensitive to hydrolysis. BNB was predicted to have a favorable absorption, distribution, metabolism, and excretion profile. The nanocarriers developed were characterized for particle size (PS = 61 to 85 nm), polydispersity index (PI < 0.3), zeta potential (ZP = - 22 to - 34 mV), and encapsulation efficiency (EE = 66 to 90%) and remained stable for 30 days of storage. These studies indicated that BNB (inhibitory concentration (IC50) 21.8 μM) and BNB-loaded NLC (IC50 33.7 μM) showed moderate cytotoxicity against breast cancer cell line. Blank formulations did not induce cytotoxicity and BNB-loaded SLN was able to potentiate the action of BNB (lC50 12.4 μM). BNB is a promising antitumor agent and it is possible to modulate its activity based on the particle size of the formulation.

Cytotoxic Activity of Kenaf Seed Oils from Supercritical Carbon Dioxide Fluid Extraction towards Human Colorectal Cancer (HT29) Cell Lines.

PubMed

Abd Ghafar, Siti Aisyah; Ismail, Maznah; Saiful Yazan, Latifah; Fakurazi, Sharida; Ismail, Norsharina; Chan, Kim Wei; Md Tahir, Paridah

2013-01-01

Kenaf (Hibiscus cannabinus) from the family Malvaceae, is a valuable fiber plant native to India and Africa and is currently planted as the fourth commercial crop in Malaysia. Kenaf seed oil contains alpha-linolenic acid, phytosterol such as β -sitosterol, vitamin E, and other antioxidants with chemopreventive properties. Kenaf seeds oil (KSO) was from supercritical carbon dioxide extraction fluid (SFE) at 9 different permutations of parameters based on range of pressures from 200 to 600 bars and temperature from 40 to 80°C. They were 200/40, 200/60, 200/80, 400/40, 400/60, 400/80, 600/40, 600/60, and 600/80. Extraction from 9 parameters of KSO-SFE was screened for cytotoxicity towards human colorectal cancer cell lines (HT29) and mouse embryonic fibroblast (NIH/3T3) cell lines using MTS assay. KSO-SFE at 600/40 showed the strongest cytotoxicity towards HT29 with IC50 of 200 µg/mL. The IC50 for NIH/3T3 was not detected even at highest concentration employed. Cell cycle analysis showed a significant increase in the accumulation of KSO-SFE-treated cells at sub-G1 phase, indicating the induction of apoptosis by KSO-SFE. Further apoptosis induction was confirmed by Annexin V/PI and AO/PI staining.

Leucocontextins A-R, lanostane-type triterpenoids from Ganoderma leucocontextum.

PubMed

Zhao, Zhen-Zhu; Chen, He-Ping; Li, Zheng-Hui; Dong, Ze-Jun; Bai, Xue; Zhou, Zhong-Yu; Feng, Tao; Liu, Ji-Kai

2016-03-01

Eighteen new lanostane-type triterpenoids, namely leucocontextins A-R (1-18) were isolated from the fruiting bodies of Ganoderma leucocontextum. Their structures were established by 1D and 2D NMR data in conjunction with HRESIMS/HREIMS, X-ray single crystal diffraction analysis. Compound 18 exhibited weak cytotoxicity against K562 and MCF-7 cell lines with IC50 of 20-30 μM. Copyright © 2015 Elsevier B.V. All rights reserved.

Abietane-Type Diterpenoid Amides with Highly Potent and Selective Activity against Leishmania donovani and Trypanosoma cruzi.

PubMed

Pirttimaa, Minni; Nasereddin, Abedelmajeed; Kopelyanskiy, Dmitry; Kaiser, Marcel; Yli-Kauhaluoma, Jari; Oksman-Caldentey, Kirsi-Marja; Brun, Reto; Jaffe, Charles L; Moreira, Vânia M; Alakurtti, Sami

2016-02-26

Dehydroabietylamine (1) was used as a starting material to synthesize a small library of dehydroabietyl amides by simple and facile methods, and their activities against two disease-causing trypanosomatids, namely, Leishmania donovani and Trypanosoma cruzi, were assayed. The most potent compound, 10, an amide of dehydroabietylamine and acrylic acid, was found to be highly potent against these parasites, displaying an IC50 value of 0.37 μM against L. donovani axenic amastigotes and an outstanding selectivity index of 63. Moreover, compound 10 fully inhibited the growth of intracellular amastigotes in Leishmania donovani-infected human macrophages with a low IC50 value of 0.06 μM. This compound was also highly effective against T. cruzi amastigotes residing in L6 cells with an IC50 value of 0.6 μM and high selectivity index of 58, being 3.5 times more potent than the reference compound benznidazole. The potent activity of this compound and its relatively low cytotoxicity make it attractive for further development in pursuit of better drugs for patients suffering from leishmaniasis and Chagas disease.

PTP1B, α-glucosidase, and DPP-IV inhibitory effects for chromene derivatives from the leaves of Smilax china L.

PubMed

Zhao, Bing Tian; Le, Duc Dat; Nguyen, Phi Hung; Ali, Md Yousof; Choi, Jae-Sue; Min, Byung Sun; Shin, Heung Mook; Rhee, Hae Ik; Woo, Mi Hee

2016-06-25

Two new flavonoids, bismilachinone (11) and smilachinin (14), were isolated from the leaves of Smilax china L. together with 14 known compounds. Their structures were elucidated using spectroscopic methods. The PTP1B, α-glucosidase, and DPP-IV inhibitory activities of compounds 1-16 were evaluated at the molecular level. Among them, compounds 4, 7, and 10 showed moderate DPP-IV inhibitory activities with IC50 values of 20.81, 33.12, and 32.93 μM, respectively. Compounds 3, 4, 6, 11, 12, and 16 showed strong PTP1B inhibitory activities, with respective IC50 values of 7.62, 10.80, 0.92, 2.68, 9.77, and 24.17 μM compared with the IC50 value for the positive control (ursolic acid: IC50 = 1.21 μM). Compounds 2-7, 11, 12, 15, and 16 showed potent α-glucosidase inhibitory activities, with respective IC50 values of 8.70, 81.66, 35.11, 35.92, 7.99, 26.28, 11.28, 62.68, 44.32, and 70.12 μM. The positive control, acarbose, displayed an IC50 value of 175.84 μM. In the kinetic study for the PTP1B enzyme, compounds 6, 11, and 12 displayed competitive inhibition with Ki values of 3.20, 8.56, and 5.86 μM, respectively. Compounds 3, 4, and 16 showed noncompetitive inhibition with Ki values of 18.75, 5.95, and 22.86 μM, respectively. Molecular docking study for the competitive inhibitors (6, 11, and 12) radically corroborates the binding affinities and inhibition of PTP1B enzymes. These results indicated that the leaves of Smilax china L. may contain compounds with anti-diabetic activity. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Inhibitory Effects of Respiration Inhibitors on Aflatoxin Production

PubMed Central

Sakuda, Shohei; Prabowo, Diyan Febri; Takagi, Keiko; Shiomi, Kazuro; Mori, Mihoko; Ōmura, Satoshi; Nagasawa, Hiromichi

2014-01-01

Aflatoxin production inhibitors, which do not inhibit the growth of aflatoxigenic fungi, may be used to control aflatoxin without incurring a rapid spread of resistant strains. A respiration inhibitor that inhibits aflatoxin production was identified during a screening process for natural, aflatoxin-production inhibitors. This prompted us to evaluate respiration inhibitors as potential aflatoxin control agents. The inhibitory activities of four natural inhibitors, seven synthetic miticides, and nine synthetic fungicides were evaluated on aflatoxin production in Aspergillus parasiticus. All of the natural inhibitors (rotenone, siccanin, aptenin A5, and antimycin A) inhibited fungal aflatoxin production with IC50 values around 10 µM. Among the synthetic miticides, pyridaben, fluacrypyrim, and tolfenpyrad exhibited strong inhibitory activities with IC50 values less than 0.2 µM, whereas cyflumetofen did not show significant inhibitory activity. Of the synthetic fungicides, boscalid, pyribencarb, azoxystrobin, pyraclostrobin, and kresoxim-methyl demonstrated strong inhibitory activities, with IC50 values less than 0.5 µM. Fungal growth was not significantly affected by any of the inhibitors tested at concentrations used. There was no correlation observed between the targets of respiration inhibitors (complexes I, II, and III) and their IC50 values for aflatoxin-production inhibitory activity. This study suggests that respiration inhibitors, including commonly used pesticides, are useful for aflatoxin control. PMID:24674936

A new cytotoxic sterol methoxymethyl ether from a deep water marine sponge Scleritoderma sp. cf. paccardi.

PubMed

Gunasekera, S P; Kelly-Borges, M; Longley, R E

1996-02-01

24(R)-Methyl-5 alpha-cholest-7-enyl 3 beta-methoxymethyl ether (1), a new sterol ether, has been isolated from a deep-water marine sponge Scleritoderma sp. cf. paccardi. Compound 1 exhibited in vitro cytotoxicity against the cultured murine P-388 tumor cell line with an IC50 of 2.3 micrograms/mL. The isolation and structure elucidation of 1 by NMR spectroscopy is described.

Cytotoxic Activity of Kenaf Seed Oils from Supercritical Carbon Dioxide Fluid Extraction towards Human Colorectal Cancer (HT29) Cell Lines

PubMed Central

Abd Ghafar, Siti Aisyah; Ismail, Maznah; Saiful Yazan, Latifah; Fakurazi, Sharida; Chan, Kim Wei; Md Tahir, Paridah

2013-01-01

Kenaf (Hibiscus cannabinus) from the family Malvaceae, is a valuable fiber plant native to India and Africa and is currently planted as the fourth commercial crop in Malaysia. Kenaf seed oil contains alpha-linolenic acid, phytosterol such as β-sitosterol, vitamin E, and other antioxidants with chemopreventive properties. Kenaf seeds oil (KSO) was from supercritical carbon dioxide extraction fluid (SFE) at 9 different permutations of parameters based on range of pressures from 200 to 600 bars and temperature from 40 to 80°C. They were 200/40, 200/60, 200/80, 400/40, 400/60, 400/80, 600/40, 600/60, and 600/80. Extraction from 9 parameters of KSO-SFE was screened for cytotoxicity towards human colorectal cancer cell lines (HT29) and mouse embryonic fibroblast (NIH/3T3) cell lines using MTS assay. KSO-SFE at 600/40 showed the strongest cytotoxicity towards HT29 with IC50 of 200 µg/mL. The IC50 for NIH/3T3 was not detected even at highest concentration employed. Cell cycle analysis showed a significant increase in the accumulation of KSO-SFE-treated cells at sub-G1 phase, indicating the induction of apoptosis by KSO-SFE. Further apoptosis induction was confirmed by Annexin V/PI and AO/PI staining. PMID:23606884

Synthesis and anticancer evaluation of 1,3,4-oxadiazoles, 1,3,4-thiadiazoles, 1,2,4-triazoles and Mannich bases.

PubMed

Megally Abdo, Nadia Youssef; Kamel, Mona Monir

2015-01-01

A series of 5-(pyridin-4-yl)-N-substituted-1,3,4-oxadiazol-2-amines (3a-d), 5-(pyridin-4-yl)-N-substituted-1,3,4-thiadiazol-2-amines (4a-d) and 5-(pyridin-4-yl)-4-substituted-1,2,4-triazole-3-thiones (5a-d) were obtained by the cyclization of hydrazinecarbothioamide derivatives 2a-d derived from isonicotinic acid hydrazide. Aminoalkylation of compounds 5a-d with formaldehyde and various secondary amines furnished the Mannich bases 6a-p. The structures of the newly synthesized compounds were confirmed on the basis of their spectral data and elemental analyses. All the compounds were screened for their in vitro anticancer activity against six human cancer cell lines and normal fibroblast cells. Sixteen of the tested compounds exhibited significant cytotoxicity against most cell lines. Among these derivatives, the Mannich bases 6j, 6m and 6p were found to exhibit the most potent activity. The Mannich base 6m showed more potent cytotoxic activity against gastric cancer NUGC (IC50=0.021 µM) than the standard CHS 828 (IC50=0.025 µM). Normal fibroblast cells WI38 were affected to a much lesser extent (IC50>10 µM).

Docetaxel-albumin conjugates: preparation, in vitro evaluation and biodistribution studies.

PubMed

Esmaeili, Farnaz; Dinarvand, Rassoul; Ghahremani, Mohammad Hossein; Amini, Mohsen; Rouhani, Hasti; Sepehri, Nima; Ostad, Seyed Nasser; Atyabi, Fatemeh

2009-08-01

Docetaxel (DTX) is one of the most active chemotherapeutic agents for treating metastatic breast cancer. Its aqueous solubility is very low, hence the available formulation of DTX for clinical use consists of high concentrations of tween80, which has been associated with several hypersensitivity reactions. To reduce the systemic toxicity of DTX as well as to avoid the use of tween80, in this study DTX was chemically conjugated with human serum albumin via a succinic spacer. A high-performance liquid chromatography method was developed for the determination of DTX-albumin conjugate. T47D and SKOV3 cells were used for the evaluation of the in vitro cytotoxicity of the conjugate by MTT assay. Studies were then done on balb/c mice to elucidate the tissue distribution of conjugates after intravenous administration. The albumin-conjugated formulation of DTX with the particle size of 90-110 nm showed enhanced solubility and in vivo characteristics and significantly higher cytotoxicity against tumor cells, for example, IC50 of 6.30 +/- 0.73 nM for T47D cell line compared to free DTX with IC50 of 39.4 +/- 1.75 nM. Conjugation also maintained DTX plasma level at 16.19% up to 2 h after injection compared with 2.51% for Taxotere, hence increasing the chance of nanoparticles uptake by tumor cells. Copyright 2009 Wiley-Liss, Inc.

A novel application of t-statistics to objectively assess the quality of IC50 fits for P-glycoprotein and other transporters

PubMed Central

O'Connor, Michael; Lee, Caroline; Ellens, Harma; Bentz, Joe

2015-01-01

Current USFDA and EMA guidance for drug transporter interactions is dependent on IC50 measurements as these are utilized in determining whether a clinical interaction study is warranted. It is therefore important not only to standardize transport inhibition assay systems but also to develop uniform statistical criteria with associated probability statements for generation of robust IC50 values, which can be easily adopted across the industry. The current work provides a quantitative examination of critical factors affecting the quality of IC50 fits for P-gp inhibition through simulations of perfect data with randomly added error as commonly observed in the large data set collected by the P-gp IC50 initiative. The types of errors simulated were (1) variability in replicate measures of transport activity; (2) transformations of error-contaminated transport activity data prior to IC50 fitting (such as performed when determining an IC50 for inhibition of P-gp based on efflux ratio); and (3) the lack of well defined “no inhibition” and “complete inhibition” plateaus. The effect of the algorithm used in fitting the inhibition curve (e.g., two or three parameter fits) was also investigated. These simulations provide strong quantitative support for the recommendations provided in Bentz et al. (2013) for the determination of IC50 values for P-gp and demonstrate the adverse effect of data transformation prior to fitting. Furthermore, the simulations validate uniform statistical criteria for robust IC50 fits in general, which can be easily implemented across the industry. A calibration of the t-statistic is provided through calculation of confidence intervals associated with the t-statistic. PMID:25692007

Antiproliferative Activity of Xanthones Isolated from Artocarpus obtusus

PubMed Central

Hashim, Najihah Mohd; Rahmani, Mawardi; Ee, Gwendoline Cheng Lian; Sukari, Mohd Aspollah; Yahayu, Maizatulakmal; Oktima, Winda; Ali, Abd Manaf; Go, Rusea

2012-01-01

An investigation of the chemical constituents in Artocarpus obtusus species led to the isolation of three new xanthones, pyranocycloartobiloxanthone A (1), dihydroartoindonesianin C (2), and pyranocycloartobiloxanthone B (3). The compounds were subjected to antiproliferative assay against human promyelocytic leukemia (HL60), human chronic myeloid leukemia (K562), and human estrogen receptor (ER+) positive breast cancer (MCF7) cell lines. Pyranocycloartobiloxanthone A (1) consistently showed strong cytotoxic activity against the three cell lines compared to the other two with IC50 values of 0.5, 2.0 and 5.0 μg/mL, respectively. Compound (1) was also observed to exert antiproliferative activity and apoptotic promoter towards HL60 and MCF7 cell lines at respective IC50 values. The compound (1) was not toxic towards normal cell lines human nontumorigenic breast cell line (MCF10A) and human peripheral blood mononuclear cells (PBMCs) with IC50 values of more than 30 μg/mL. PMID:21960741

Inhibitory Effects of Commonly Used Herbal Extracts on UDP-Glucuronosyltransferase 1A4, 1A6, and 1A9 Enzyme Activities

PubMed Central

Mohamed, Mohamed-Eslam F.

2011-01-01

The aim of this study was to investigate the effect of commonly used botanicals on UDP-glucuronosyltransferase (UGT) 1A4, UGT1A6, and UGT1A9 activities in human liver microsomes. The extracts screened were black cohosh, cranberry, echinacea, garlic, ginkgo, ginseng, milk thistle, saw palmetto, and valerian in addition to the green tea catechin epigallocatechin gallate (EGCG). Formation of trifluoperazine glucuronide, serotonin glucuronide, and mycophenolic acid phenolic glucuronide was used as an index reaction for UGT1A4, UGT1A6, and UGT1A9 activities, respectively, in human liver microsomes. Inhibition potency was expressed as the concentration of the inhibitor at 50% activity (IC50) and the volume in which the dose could be diluted to generate an IC50-equivalent concentration [volume/dose index (VDI)]. Potential inhibitors were EGCG for UGT1A4, milk thistle for both UGT1A6 and UGT1A9, saw palmetto for UGT1A6, and cranberry for UGT1A9. EGCG inhibited UGT1A4 with an IC50 value of (mean ± S.E.) 33.8 ± 3.1 μg/ml. Milk thistle inhibited both UGT1A6 and UGT1A9 with IC50 values of 59.5 ± 3.6 and 33.6 ± 3.1 μg/ml, respectively. Saw palmetto and cranberry weakly inhibited UGT1A6 and UGT1A9, respectively, with IC50 values >100 μg/ml. For each inhibition, VDI was calculated to determine the potential of achieving IC50-equivalent concentrations in vivo. VDI values for inhibitors indicate a potential for inhibition of first-pass glucuronidation of UGT1A4, UGT1A6, and UGT1A9 substrates. These results highlight the possibility of herb-drug interactions through modulation of UGT enzyme activities. Further clinical studies are warranted to investigate the in vivo extent of the observed interactions. PMID:21632963

pH-Dependent doxorubicin release from terpolymer of starch, polymethacrylic acid and polysorbate 80 nanoparticles for overcoming multi-drug resistance in human breast cancer cells.

PubMed

Shalviri, Alireza; Raval, Gaurav; Prasad, Preethy; Chan, Carol; Liu, Qiang; Heerklotz, Heiko; Rauth, Andrew Michael; Wu, Xiao Yu

2012-11-01

This work investigated the capability of a new nanoparticulate system, based on terpolymer of starch, polymethacrylic acid and polysorbate 80, to load and release doxorubicin (Dox) as a function of pH and to evaluate the anticancer activity of Dox-loaded nanoparticles (Dox-NPs) to overcome multidrug resistance (MDR) in human breast cancer cells in vitro. The Dox-NPs were characterized by Fourier transform infrared spectroscopy (FTIR), isothermal titration calorimetry (ITC), transmission electron microscopy (TEM), and dynamic light scattering (DLS). The cellular uptake and cytotoxicity of the Dox-loaded nanoparticles were investigated using fluorescence microscopy, flow cytometry, and a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) (MTT) assay. The nanoparticles were able to load up to 49.7±0.3% of Dox with a high loading efficiency of 99.9±0.1%, while maintaining good colloidal stability. The nanoparticles released Dox at a higher rate at acidic pH attributable to weaker Dox-polymer molecular interactions evidenced by ITC. The Dox-NPs were taken up by the cancer cells in vitro and significantly enhanced the cytotoxicity of Dox against human MDR1 cells with up to a 20-fold decrease in the IC50 values. The results suggest that the new terpolymeric nanoparticles are a promising vehicle for the controlled delivery of Dox for treatment of drug resistant breast cancer. Copyright © 2012 Elsevier B.V. All rights reserved.

Physalin B from Physalis angulata triggers the NOXA-related apoptosis pathway of human melanoma A375 cells.

PubMed

Hsu, Chia-Chun; Wu, Yang-Chang; Farh, Lynn; Du, Ying-Chi; Tseng, Wei-Kung; Wu, Chau-Chung; Chang, Fang-Rong

2012-03-01

Melanoma is a lethal form of skin cancer that can metastasize rapidly. While surgery and radiation therapy provide palliative therapy for local tumor growth, systemic therapy is the mainstay of treatment for metastatic melanoma. However, limited chemotherapeutic agents are available for melanoma treatment. In this study, we investigated the anti-melanoma effect of physalin B, the major active compound from a widely used herb medicine, Physalis angulata L. This study demonstrated that physalin B exhibits cytotoxicity towards v-raf murine sarcoma viral oncogene homolog B1 (BRAF)-mutated melanoma A375 and A2058 cells (the IC50 values are lower than 4.6 μg/ml). Cytotoxicity is likely resulted from apoptosis since the apoptotic marker phosphatidylserine are detected immediately under physalin B treatment and apoptotic cells formation. Further examination revealed that physalin B induces expression of the proapoptotic protein NOXA within 2 h and later triggers the expression of Bax and caspase-3 in A375 cells. These results indicate that physalin B can induce apoptosis of melanoma cancer cells via the NOXA, caspase-3, and mitochondria-mediated pathways, but not of human skin fibroblast cells and myoblastic cells. Thus, physalin B has the potential to be developed as an effective chemotherapeutic lead compound for the treatment of malignant melanoma. Copyright © 2011 Elsevier Ltd. All rights reserved.

Free Rhodium (II) citrate and rhodium (II) citrate magnetic carriers as potential strategies for breast cancer therapy

PubMed Central

2011-01-01

Background Rhodium (II) citrate (Rh2(H2cit)4) has significant antitumor, cytotoxic, and cytostatic activity on Ehrlich ascite tumor. Although toxic to normal cells, its lower toxicity when compared to carboxylate analogues of rhodium (II) indicates Rh2(H2cit)4 as a promising agent for chemotherapy. Nevertheless, few studies have been performed to explore this potential. Superparamagnetic particles of iron oxide (SPIOs) represent an attractive platform as carriers in drug delivery systems (DDS) because they can present greater specificity to tumor cells than normal cells. Thus, the association between Rh2(H2cit)4 and SPIOs can represent a strategy to enhance the former's therapeutic action. In this work, we report the cytotoxicity of free rhodium (II) citrate (Rh2(H2cit)4) and rhodium (II) citrate-loaded maghemite nanoparticles or magnetoliposomes, used as drug delivery systems, on both normal and carcinoma breast cell cultures. Results Treatment with free Rh2(H2cit)4 induced cytotoxicity that was dependent on dose, time, and cell line. The IC50 values showed that this effect was more intense on breast normal cells (MCF-10A) than on breast carcinoma cells (MCF-7 and 4T1). However, the treatment with 50 μM Rh2(H2cit)4-loaded maghemite nanoparticles (Magh-Rh2(H2cit)4) and Rh2(H2cit)4-loaded magnetoliposomes (Lip-Magh-Rh2(H2cit)4) induced a higher cytotoxicity on MCF-7 and 4T1 than on MCF-10A (p < 0.05). These treatments enhanced cytotoxicity up to 4.6 times. These cytotoxic effects, induced by free Rh2(H2cit)4, were evidenced by morphological alterations such as nuclear fragmentation, membrane blebbing and phosphatidylserine exposure, reduction of actin filaments, mitochondrial condensation and an increase in number of vacuoles, suggesting that Rh2(H2cit)4 induces cell death by apoptosis. Conclusions The treatment with rhodium (II) citrate-loaded maghemite nanoparticles and magnetoliposomes induced more specific cytotoxicity on breast carcinoma cells than on breast normal cells, which is the opposite of the results observed with free Rh2(H2cit)4 treatment. Thus, magnetic nanoparticles represent an attractive platform as carriers in Rh2(H2cit)4 delivery systems, since they can act preferentially in tumor cells. Therefore, these nanopaticulate systems may be explored as a potential tool for chemotherapy drug development. PMID:21443799

Trypanocidal and leishmanicidal activities of flavonoids isolated from Stevia satureiifolia var. satureiifolia.

PubMed

Beer, María Florencia; Frank, Fernanda Maria; Germán Elso, Orlando; Ernesto Bivona, Augusto; Cerny, Natacha; Giberti, Gustavo; Luis Malchiodi, Emilio; Susana Martino, Virginia; Alonso, María Rosario; Patricia Sülsen, Valeria; Cazorla, Silvia Ines

2016-10-01

Context Chagas' disease and leishmaniasis produce significant disability and mortality with great social and economic impact. The genus Stevia (Asteraceae) is a potential source of antiprotozoal compounds. Objective Aerial parts of four Stevia species were screened on Trypanosoma cruzi. Stevia satureiifolia (Lam.) Sch. Bip. var. satureiifolia (Asteraceae) dichloromethane extract was selected for a bioassay-guided fractionation in order to isolate its active compounds. Additionally, the antileishmanial activity and the cytotoxicity of these compounds on mammalian cells were assessed. Materials and methods The dichloromethane extract was fractionated by column chromatography. The isolated compounds were evaluated using concentrations of 0-100 μg/mL on T. cruzi epimastigotes and on Leishmania braziliensis promastigotes for 72 h, on trypomastigotes and amastigotes of T. cruzi for 24 h and 120 h, respectively. The compounds' cytotoxicity (12.5-500 μg/mL) was assessed on Vero cells by the MTT assay. The structure elucidation of each compound was performed by spectroscopic methods and HPLC analysis. Results The dichloromethane extracts of Stevia species showed significant activity on T. cruzi epimastigotes. The flavonoids eupatorin (1.3%), cirsimaritin (1.9%) and 5-desmethylsinensetin (1.5%) were isolated from S. satureiifolia var. satureiifolia extract. Eupatorin and 5-desmethylsinensetin showed IC50 values of 0.2 and 0.4 μg/mL on T. cruzi epimastigotes and 61.8 and 75.1 μg/mL on trypomastigotes, respectively. The flavonoid 5-desmethylsinensetin showed moderate activity against T. cruzi amastigotes (IC50  value = 78.7 μg/mL) and was the most active compound on L. braziliensis promastigotes (IC50  value = 37.0 μg/mL). Neither of the flavonoids showed cytotoxicity on Vero cells, up to a concentration of 500 μg/mL.

In vitro and in vivo anti-malarial activity of plants from the Brazilian Amazon.

PubMed

Lima, Renata B S; Rocha e Silva, Luiz F; Melo, Marcia R S; Costa, Jaqueline S; Picanço, Neila S; Lima, Emerson S; Vasconcellos, Marne C; Boleti, Ana Paula A; Santos, Jakeline M P; Amorim, Rodrigo C N; Chaves, Francisco C M; Coutinho, Julia P; Tadei, Wanderli P; Krettli, Antoniana U; Pohlit, Adrian M

2015-12-18

The anti-malarials quinine and artemisinin were isolated from traditionally used plants (Cinchona spp. and Artemisia annua, respectively). The synthetic quinoline anti-malarials (e.g. chloroquine) and semi-synthetic artemisinin derivatives (e.g. artesunate) were developed based on these natural products. Malaria is endemic to the Amazon region where Plasmodium falciparum and Plasmodium vivax drug-resistance is of concern. There is an urgent need for new anti-malarials. Traditionally used Amazonian plants may provide new treatments for drug-resistant P. vivax and P. falciparum. Herein, the in vitro and in vivo antiplasmodial activity and cytotoxicity of medicinal plant extracts were investigated. Sixty-nine extracts from 11 plant species were prepared and screened for in vitro activity against P. falciparum K1 strain and for cytotoxicity against human fibroblasts and two melanoma cell lines. Median inhibitory concentrations (IC50) were established against chloroquine-resistant P. falciparum W2 clone using monoclonal anti-HRPII (histidine-rich protein II) antibodies in an enzyme-linked immunosorbent assay. Extracts were evaluated for toxicity against murine macrophages (IC50) and selectivity indices (SI) were determined. Three extracts were also evaluated orally in Plasmodium berghei-infected mice. High in vitro antiplasmodial activity (IC50 = 6.4-9.9 µg/mL) was observed for Andropogon leucostachyus aerial part methanol extracts, Croton cajucara red variety leaf chloroform extracts, Miconia nervosa leaf methanol extracts, and Xylopia amazonica leaf chloroform and branch ethanol extracts. Paullinia cupana branch chloroform extracts and Croton cajucara red variety leaf ethanol extracts were toxic to fibroblasts and or melanoma cells. Xylopia amazonica branch ethanol extracts and Zanthoxylum djalma-batistae branch chloroform extracts were toxic to macrophages (IC50 = 6.9 and 24.7 µg/mL, respectively). Andropogon leucostachyus extracts were the most selective (SI >28.2) and the most active in vivo (at doses of 250 mg/kg, 71% suppression of P. berghei parasitaemia versus untreated controls). Ethnobotanical or ethnopharmacological reports describe the anti-malarial use of these plants or the antiplasmodial activity of congeneric species. No antiplasmodial activity has been demonstrated previously for the extracts of these plants. Seven plants exhibit in vivo and or in vitro anti-malarial potential. Future work should aim to discover the anti-malarial substances present.

Amebicidal activity of the essential oils of Lippia spp. (Verbenaceae) against Acanthamoeba polyphaga trophozoites.

PubMed

Santos, Israel Gomes de Amorim; Scher, Ricardo; Rott, Marilise Brittes; Menezes, Leociley Rocha; Costa, Emmanoel Vilaça; Cavalcanti, Sócrates Cabral de Holanda; Blank, Arie Fitzgerald; Aguiar, Jaciana dos Santos; da Silva, Teresinha Gonçalves; Dolabella, Silvio Santana

2016-02-01

Amoebic keratitis and granulomatous amoebic encephalitis are caused by some strains of free-living amoebae of the genus Acanthamoeba. In the case of keratitis, one of the greatest problems is the disease recurrence due to the resistance of parasites, especially the cystic forms, to the drugs that are currently used. Some essential oils of plants have been used as potential active agents against this protist. Thus, the aim of this study was to determine the amebicidal activity of essential oils from plants of the genus Lippia against Acanthamoeba polyphaga trophozoites. To that end, 8 × 10(4) trophozoites were exposed for 24 h to increasing concentrations of essential oils from Lippia sidoides, Lippia gracilis, Lippia alba, and Lippia pedunculosa and to their major compounds rotundifolone, carvone, and carvacrol. Nearly all concentrations of oils and compounds showed amebicidal activity. The IC50 values for L. sidoides, L. gracilis L. alba, and L. pedunculosa were found to be 18.19, 10.08, 31.79, and 71.47 μg/mL, respectively. Rotundifolone, carvacrol, and carvone were determined as the major compounds showing IC50 of 18.98, 24.74, and 43.62 μg/mL, respectively. With the exception of oil from L. alba, the other oils evaluated showed low cytotoxicity in the NCI-H292 cell line. Given these results, the oils investigated here are promising sources of compounds for the development of complementary therapy against amoebic keratitis and granulomatous amoebic encephalitis and can also be incorporated into cleaning solutions to increase their amebicidal efficiency.

Antimalarial evaluation of selected medicinal plant extracts used in Iranian traditional medicine

PubMed Central

Haddad, Mohammad Hossein Feiz; Mahbodfar, Hamidreza; Zamani, Zahra; Ramazani, Ali

2017-01-01

Objective(s): In an attempt to discover new natural active extracts against malaria parasites, the present study evaluated the antiplasmodial properties of selected plants based on Iranian traditional medicine. Materials and Methods: Ten plant species found in Iran were selected and collected based on the available literature about the Iranian traditional medicine. The methanolic extracts of these plants were investigated for in vitro antimalarial properties against chloroquine-sensitive (3D7) and multi-drug resistant (K1) strains of Plasmodium falciparum. Their in vivo activity against Plasmodium berghei infection in mice was also determined. Cytotoxicity tests were carried out using the Raji cells line using the MTT assay. The extracts were phytochemically screened for their active constituents. Results: According to the IC50 and selectivity index (SI) values, of the 10 selected plant species, Citrullus colocynthis, Physalis alkekengi, and Solanum nigrum displayed potent in vitro antimalarial activity against both 3D7 and K1 strains with no toxicity (IC50= 2.01-18.67 µg/ml and SI=3.55 to 19.25). Comparisons between treated and untreated control mice showed that the mentioned plant species reduced parasitemia by 65.08%, 57.97%, and 60.68%, respectively. The existence of antiplasmodial compounds was detected in these plant extracts. Conclusion: This was the first study to highlight the in vitro and in vivo antiplasmodial effects of C. colocynthis, P. alkekengi, and S. nigrum in Iran. Future studies can use these findings to design further biological tests to identify the active constituents of the mentioned plant species and clarify their mechanism of action. PMID:28804611

Interaction effects of enniatin B, deoxinivalenol and alternariol in Caco-2 cells.

PubMed

Fernández-Blanco, Celia; Font, Guillermina; Ruiz, Maria-Jose

2016-01-22

Enniatin B (ENN B), deoxinivalenol (DON) and alternariol (AOH) are secondary metabolites of filamentous fungi. These mycotoxins are contaminants of vegetables and cereals. They are cytotoxic and their effects are enhanced by their mixtures. The objectives of this study were to compare the cytotoxicity of ENN B, DON and AOH alone or in combination in human adenocarcinoma (Caco-2) cells and to evaluate the type of interactions of mycotoxin mixtures by the isobologram analysis. Cells were treated with concentrations ranging from 1.85 to 90μM (AOH) and from 0.312 to 10μM (for ENN B and DON), individually and in combination of two and three mycotoxins (from 1.85 to 30μM for AOH and from 0.312 to 5μM for ENN B and DON). The relation ratios between the mixtures DON+ENN B was 1:1; AOH+DON and ENN B+AOH was 1:6, and for the tertiary combination DON, ENN B and AOH 1:1:6. The IC50 value of ENN B and DON were 3.87 and 5.54μM, respectively. No IC50 values were obtained for the AOH at any time tested in Caco-2 cells. With the isobologram the type of interaction between mycotoxin was evaluated. Synergistic, antagonistic and addictive effect was observed for the combination studied depending on the concentration affected. Mycotoxins combinations reduce cellular viability in the following increasing order: (DON+ENN B)>(ENN B+AOH)>(DON+AOH)>(DON+AOH+ENN B). Copyright © 2015. Published by Elsevier Ireland Ltd.

Neurite outgrowth stimulatory effects of culinary-medicinal mushrooms and their toxicity assessment using differentiating Neuro-2a and embryonic fibroblast BALB/3T3.

PubMed

Phan, Chia-Wei; David, Pamela; Naidu, Murali; Wong, Kah-Hui; Sabaratnam, Vikineswary

2013-10-11

Mushrooms are not only regarded as gourmet cuisine but also as therapeutic agent to promote cognition health. However, little toxicological information is available regarding their safety. Therefore, the aim of this study was to screen selected ethno-pharmacologically important mushrooms for stimulatory effects on neurite outgrowth and to test for any cytotoxicity. The stimulatory effect of mushrooms on neurite outgrowth was assessed in differentiating mouse neuroblastoma (N2a) cells. Neurite length was measured using Image-Pro Insight processor system. Neuritogenesis activity was further validated by fluorescence immunocytochemical staining of neurofilaments. In vitro cytotoxicity was investigated by using mouse embryonic fibroblast (BALB/3T3) and N2a cells for any embryo- and neuro-toxic effects; respectively. Aqueous extracts of Ganoderma lucidum, Lignosus rhinocerotis, Pleurotus giganteus and Grifola frondosa; as well as an ethanol extract of Cordyceps militaris significantly (p < 0.05) promoted the neurite outgrowth in N2a cells by 38.4 ± 4.2%, 38.1 ± 2.6%, 33.4 ± 4.6%, 33.7 ± 1.5%, and 35.8 ± 3.4%; respectively. The IC50 values obtained from tetrazolium (MTT), neutral red uptake (NRU) and lactate dehydrogenase (LDH) release assays showed no toxic effects following 24 h exposure of N2a and 3T3 cells to mushroom extracts. Our results indicate that G. lucidum, L. rhinocerotis, P. giganteus, G. frondosa and C. militaris may be developed as safe and healthy dietary supplements for brain and cognitive health.

Bioactive Compounds from Vitex leptobotrys#

PubMed Central

Pan, Wenhui; Liu, Kanglun; Guan, Yifu; Tan, Ghee Teng; Hung, Nguyen Van; Cuong, Nguyen Manh; Soejarto, D. Doel; Pezzuto, John M.; Fong, Harry H.S.; Zhang, Hongjie

2014-01-01

A new lignan, vitexkarinol (1), as well as a known lignan, neopaulownin (2), a known chalcone, 3-(4-hydroxyphenyl)-1-(2,4,6-trimethoxyphenyl)-2-propen-1-one (3), two known dehydroflavones, tsugafolin (4) and alpinetin (5), two known dipeptides, aurantiamide and aurantiamide acetate, a known sesquiterpene, vemopolyanthofuran, and five known carotenoid metabolites, vomifoliol, dihydrovomifoliol, dehydrovomifoliol, loliolide and isololiolide, were isolated from the leaves and twigs of Vitex leptobotrys through bioassay-guided fractionation. The chalcone (3) was found to inhibit HIV-1 replication by 77% at 15.9 µM, and the two dehydroflavones (4 and 5) showed weak anti-HIV activity with IC50 values of 118 and 130 µM, respectively, while being devoid of cytotoxicity at 150 µM. A chlorophyll-enriched fraction of V. leptobotrys, containing pheophorbide a, was found to inhibit the replication of HIV-1 by 80% at a concentration of 10 µg/mL. Compounds 1 and 3 were further selected to be evaluated against 21 viral targets available at NIAID (National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD). PMID:24404757

A modified spontaneous emulsification solvent diffusion method for the preparation of curcumin-loaded PLGA nanoparticles with enhanced in vitro anti-tumor activity

NASA Astrophysics Data System (ADS)

Chen, Cen; Yang, Wei; Wang, Dan-Tong; Chen, Chao-Long; Zhuang, Qing-Ye; Kong, Xiang-Dong

2014-12-01

To improve the anti-tumor activity of hydrophobic drug curcumin, we prepared curcumin-loaded PLGA nanoparticles (PLGA-Cur NPs) through a modified spontaneous emulsification solvent diffusion (modified-SESD) method. The influence of main preparation parameters was investigated, such as the volume ratio of binary organic solvents and the concentration of surfactant. Results indicated that the synthesized regular spherical PLGA NPs with the average diameter of 189.7 nm exhibited relatively higher yield (58.9%), drug loading (11.0% (w/w)) and encapsulation efficiency (33.5%), and also a controllable drug release profile. In order to evaluate the in vitro cytotoxicity of the prepared NPs, MTT assay was conducted, and results showed that the NPs could effectively inhibit HL60 and HepG2 cells with lower IC50 values compared with free curcumin. Furthermore, confocal microscopy together with flow cytometry analysis proved the enhanced apoptosis-inducing ability of PLGA-Cur NPs. Polymeric NP formulations are potential to be used for hydrophobic drug delivery systems in cancer therapy.

Elaeodendron orientale as a source of cytotoxic cardenolides.

PubMed

Osorio, Alex A; López, Manuel R; Jiménez, Ignacio A; Moujir, Laila M; Rodríguez, Matías L; Bazzocchi, Isabel L

2014-09-01

In the present study, we report six cardiac glycosides (1-6) along with four known ones (7-10) isolated from the leaves and fruits of Elaeodendron orientale. Their stereostructures were elucidated on the basis of spectroscopic analysis, including 1D and 2D NMR, and the absolute configuration of 1 was determined by X-ray diffraction analysis. The compounds were evaluated for growth inhibitory activity against a panel of human cancer cell lines, HeLa, A-549, MCF-7 and HL-60, and normal Vero cells. Four compounds from this series (5 and 7-9, IC50 values ranging from 0.01 to 0.07μM) exhibited cytotoxicity against three of the cancer cell lines assayed that was similar to or higher than the well-known therapies digoxin and digitoxigenin. Taking into account the narrow safety range of cardiac glycosides used in clinic, this series shows a selectivity index higher than 3 for three of the cancer cell lines assayed, increasing their interest for further study. Copyright © 2014 Elsevier Ltd. All rights reserved.

Three new phenylpropanoids from Lavandula angustifolia and their bioactivities.

PubMed

Tang, Shiyun; Shi, Jianlian; Liu, Chunbo; Jiang, Rui; Zhao, Wei; Liu, Xin; Xiang, Nengjun; Chen, Yongkuan; Shen, Qinpeng; Miao, Mingming; Liu, Zhihua; Yang, Guangyu

2017-06-01

Three new phenylpropanoids, 3-(3,4-dimethoxy-5-methylphenyl)-3-oxopropyl acetate (1), 3-hydroxy-1-(3,4-dimethoxy-5-methylphenyl)propan-1-one (2), and 3-hydroxy-1-(4-methylbenzo[d][1,3]dioxol-6-yl) propan-1-one (3), together with three known phenylpropanoids (4-6) were isolated from the whole plant of Lavandula angustifolia. Their structures were determined by means of HRESIMS and extensive 1D and 2D NMR spectroscopic studies. Compounds 1-6 were tested for their anti-tobacoo mosaic virus (TMV) activities and cytotoxicity activities. The results revealed that compounds 1-3 showed high anti-TMV activity with inhibition rate of 35.2, 38.4 and 33.9%. These rates are higher than that of positive control. The other compounds also showed potential anti-TMV activities with inhibition rates in the range of 26.8-28.9%, respectively. Compounds 1-6 also showed weak inhibitory activities against some tested human tumour cell lines with IC50 values in the range of 3.8-8.8 μM.

Antitumor activity of four macrocyclic ellagitannins from Cuphea hyssopifolia.

PubMed

Wang, C C; Chen, L G; Yang, L L

1999-06-01

We evaluated the antitumor activities of four macrocyclic hydrolyzable tannin dimers, cuphiin D1, cuphiin D2, oenothein B and woodfordin C isolated from Cuphea hyssopifolia (Lythraceae). All significantly inhibited the growth of the human carcinoma cell lines KB, HeLa, DU-145, Hep 3B, and the leukemia cell line HL-60, and showed less cytotoxicity than adriamycin against a normal cell line (WISH). All four compounds inhibited the viability of S-180 tumor cells in an in vitro assay and an in vivo S-180 tumor-bearing ICR mice model. Oenothein B demonstrated the greatest cytotoxicity (IC50 = 11.4 microg/ml) against S-180 tumor cells in culture, while cuphiin D1 resulted in the greatest increase in survival on S-180 tumor-bearing mice (%ILS = 84.1%). Our findings suggest that the antitumor effects of these compounds are not only related to their cytotoxicity on carcinoma cell lines, but also depended on a host-mediated mechanism; they may therefore have potential for antitumor applications.

Synthesis, fluorescence properties and the promising cytotoxicity of pyrene–derived aminophosphonates

PubMed Central

Rodriguez Moya, Maria; Wrona-Piotrowicz, Anna; Gajek, Gabriela

2016-01-01

Summary A large series of variously substituted amino(pyren-1-yl)methylphosphonic acid derivatives was synthesized using a modified aza-Pudovik reaction in 20–97% yields. The fluorescence properties of the obtained compounds were investigated revealing that N-alkylamino(pyren-1-yl)methylphosphonic derivatives are stronger emissive compounds than the corresponding N-aryl derivatives. N-Benzylamino(pyren-1-yl)methylphosphonic acid displayed strong fluorescence (ΦF = 0.68) in phosphate-buffered saline (PBS). The influence of a series of derivatives on two colon cancer cell lines HT29 and HCT116 was also investigated. The most promising results were obtained for N-(4-methoxyphenyl)amino(pyren-1-yl)methylphosphonate, which was found to be cytotoxic for the HCT116 cancer cell line (IC50 = 20.8 μM), simultaneously showing weak toxicity towards normal lymphocytes (IC50 = 230.8 µM). PMID:27559373

Interrogating alkyl and arylalkylpolyamino (bis)urea and (bis)thiourea isosteres as potent antimalarial chemotypes against multiple lifecycle forms of Plasmodium falciparum parasites.

PubMed

Verlinden, Bianca K; de Beer, Marna; Pachaiyappan, Boobalan; Besaans, Ethan; Andayi, Warren A; Reader, Janette; Niemand, Jandeli; van Biljon, Riette; Guy, Kiplin; Egan, Timothy; Woster, Patrick M; Birkholtz, Lyn-Marie

2015-08-15

A new series of potent potent aryl/alkylated (bis)urea- and (bis)thiourea polyamine analogues were synthesized and evaluated in vitro for their antiplasmodial activity. Altering the carbon backbone and terminal substituents increased the potency of analogues in the compound library 3-fold, with the most active compounds, 15 and 16, showing half-maximal inhibitory concentrations (IC50 values) of 28 and 30 nM, respectively, against various Plasmodium falciparum parasite strains without any cross-resistance. In vitro evaluation of the cytotoxicity of these analogues revealed marked selectivity towards targeting malaria parasites compared to mammalian HepG2 cells (>5000-fold lower IC50 against the parasite). Preliminary biological evaluation of the polyamine analogue antiplasmodial phenotype revealed that (bis)urea compounds target parasite asexual proliferation, whereas (bis)thiourea compounds of the same series have the unique ability to block transmissible gametocyte forms of the parasite, indicating pluripharmacology against proliferative and non-proliferative forms of the parasite. In this manuscript, we describe these results and postulate a refined structure-activity relationship (SAR) model for antiplasmodial polyamine analogues. The terminally aryl/alkylated (bis)urea- and (bis)thiourea-polyamine analogues featuring a 3-5-3 or 3-6-3 carbon backbone represent a structurally novel and distinct class of potential antiplasmodials with activities in the low nanomolar range, and high selectivity against various lifecycle forms of P. falciparum parasites. Copyright © 2015 Elsevier Ltd. All rights reserved.

Intrinsic anticarcinogenic effects of Piper sarmentosum ethanolic extract on a human hepatoma cell line

PubMed Central

Zainal Ariffin, Shahrul Hisham; Wan Omar, Wan Haifa Haryani; Zainal Ariffin, Zaidah; Safian, Muhd Fauzi; Senafi, Sahidan; Megat Abdul Wahab, Rohaya

2009-01-01

Background Piper sarmentosum, locally known as kaduk is belonging to the family of Piperaceae. It is our interest to evaluate their effect on human hepatoma cell line (HepG2) for the potential of anticarcinogenic activity. Results The anticarcinogenic activity of an ethanolic extract from Piper sarmentosum in HepG2 and non-malignant Chang's liver cell lines has been previously determined using (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide) (MTT) assays, where the IC50 value was used as a parameter for cytotoxicity. The ethanolic extract that showed anticarcinogenic properties in HepG2 cells had an IC50 of 12.5 μg mL-1, while IC50 values in the non-malignant Chang's liver cell line were greater than 30 μg mL-1. Apoptotic morphological changes in HepG2 cells were observed using an inverted microscope and showed chromatin condensation, cell shrinkage and apoptotic bodies following May-Grunwald-Giemsa's staining. The percentage of apoptotic cells in the overall population (apoptotic index) showed a continuously significant increase (p < 0.05) in 12.5 μg mL-1 ethanolic extract-treated cells at 24, 48 and 72 hours compared to controls (untreated cells). Following acridine orange and ethidium bromide staining, treatment with 10, 12 and 14 μg mL-1 of ethanolic extracts caused typical apoptotic morphological changes in HepG2 cells. Molecular analysis of DNA fragmentation was used to examine intrinsic apoptosis induced by the ethanolic extracts. These results showed a typical intrinsic apoptotic characterisation, which included fragmentation of nuclear DNA in ethanolic extract-treated HepG2 cells. However, the non-malignant Chang's liver cell line produced no DNA fragmentation. In addition, the DNA genome was similarly intact for both the untreated non-malignant Chang's liver and HepG2 cell lines. Conclusion Therefore, our results suggest that the ethanolic extract from P. sarmentosum induced anticarcinogenic activity through an intrinsic apoptosis pathway in HepG2 cells in vitro. PMID:19257877

Synthesis and bioevaluation of substituted chalcones, coumaranones and other flavonoids as anti-HIV agents.

PubMed

Cole, Amy L; Hossain, Sandra; Cole, Alex M; Phanstiel, Otto

2016-06-15

A series of chalcone, flavone, coumaranone and other flavonoid compounds were screened for their anti HIV-1 activity in two cell culture models using TZM-bl and PM1 cells. Within the systems evaluated, the most promising compounds contained either an α- or β-hydroxy-carbonyl motif within their structure (e.g., 8 and 9). Efficacious substituents were identified and used to design new HIV inhibitors with increased potency and lower cytotoxicity. Of the scaffolds evaluated, specific chalcones were found to provide the best balance between anti-HIV potency and low host cell toxicity. Chalcone 8l was shown to inhibit different clinical isolates of HIV in a dose-dependent manner (e.g., IC50 typically⩽5μM). Inhibition of HIV infection experiments using TZM-bl cells demonstrated that chalcone 8l and flavonol 9c had IC50 values of 4.7μM and 10.4μM, respectively. These insights were used to design new chalcones 8o and 8p. Rewardingly, chalcones 8o and 8p (at 10μM) each gave >92% inhibition of viral propagation without impacting PM1 host cell viability. Inhibition of viral propagation significantly increased (60-90%) when PM1 cells were pre-incubated with chalcone 8o, but not with the related flavonol 9c. These results suggested that chalcone 8o may be of value as both a HIV prophylactic and therapy. In summary, O-benzyl-substituted chalcones were identified as promising anti-HIV agents for future investigation. Copyright © 2016 Elsevier Ltd. All rights reserved.

Antitumour properties of the leaf essential oil of Xylopia frutescens Aubl. (Annonaceae).

PubMed

Ferraz, Rosana P C; Cardoso, Gabriella M B; da Silva, Thanany B; Fontes, José Eraldo do N; Prata, Ana Paula do N; Carvalho, Adriana A; Moraes, Manoel O; Pessoa, Claudia; Costa, Emmanoel V; Bezerra, Daniel P

2013-11-01

The aim of this study was to investigate the chemical composition and anticancer effect of the leaf essential oil of Xylopia frutescens in experimental models. The chemical composition of the essential oil was analysed by GC/FID and GC/MS. In vitro cytotoxic activity of the essential oil was determined on cultured tumour cells. In vivo antitumour activity was assessed in Sarcoma 180-bearing mice. The major compounds identified were (E)-caryophyllene (31.48%), bicyclogermacrene (15.13%), germacrene D (9.66%), δ-cadinene (5.44%), viridiflorene (5.09%) and α-copaene (4.35%). In vitro study of the essential oil displayed cytotoxicity on tumour cell lines and showed IC50 values ranging from 24.6 to 40.0 μg/ml for the NCI-H358M and PC-3M cell lines, respectively. In the in vivo antitumour study, tumour growth inhibition rates were 31.0-37.5%. In summary, the essential oil was dominated by sesquiterpene constituents and has some interesting anticancer activity. Copyright © 2013 Elsevier Ltd. All rights reserved.

Boehmenan, a lignan from Hibiscus ficulneus, showed Wnt signal inhibitory activity.

PubMed

Shono, Takumi; Ishikawa, Naoki; Toume, Kazufumi; Arai, Midori A; Ahmed, Firoj; Sadhu, Samir K; Ishibashi, Masami

2015-07-15

The Wnt signal pathway modulates numerous biological processes, and its aberrant activation is related to various diseases. Therefore, inhibition of the Wnt signal may provide an effective (or efficient) strategy for these diseases. Cell-based luciferase assay targeting the Wnt signal (TOP assay) revealed that Hibiscus ficulneus extract inhibited the Wnt signal. The activity-guided isolation of the MeOH extract of H. ficulneus stems yielded four known (1-4) lignans along with myriceric acid (5). Compounds 1-4 potently inhibited the Wnt signal with TOPflash IC50 values of 1.0, 4.5, 6.3, and 1.9 μM, respectively. Compound 1 exhibited cytotoxicity against both Wnt-dependent (HCT116) and Wnt-independent (RKO) cells. Western blot analysis showed that 1 decreased the expression of full, cytosolic and nuclear β-catenin along with c-myc in STF/293 cells. Our results suggested that 1 may have inhibited the Wnt signal by decreasing β-catenin levels. Copyright © 2015 Elsevier Ltd. All rights reserved.

Novel Trisubstituted Benzimidazoles, Targeting Mtb FtsZ, As A New Class of Antitubercular Agents

PubMed Central

Kumar, Kunal; Awasthi, Divya; Lee, Seung-Yub; Zanardi, Ilaria; Ruzsicska, Bela; Knudson, Susan; Tonge, Peter J.; Slayden, Richard A.; Ojima, Iwao

2010-01-01

Libraries of novel trisubstituted benzimidazoles were created through rational drug design. A good number of these benzimidazoles exhibited promising MIC values in the range of 0.5-6 μg/mL (2-15 μM) for their antibacterial activity against Mtb H37Rv strain. Moreover, five of the lead compounds also exhibited excellent activity against clinical Mtb strains with different drug-resistance profiles. All lead compounds do not show appreciable cytotoxicity (IC50 >200 μM) against Vero cells, which inhibit Mtb FtsZ assembly in a dose dependent manner. The two lead compounds unexpectedly showed enhancement of the GTPase activity of Mtb FtsZ. The result strongly suggests that the increased GTPase activity destabilizes FtsZ assembly leading to efficient inhibition of FtsZ polymerization and filament formation. The TEM and SEM analyses of Mtb FtsZ and Mtb cells, respectively, treated with a lead compound strongly suggest that lead benzimidazoles have a novel mechanism of action on the inhibition of Mtb FtsZ assembly and Z-ring formation. PMID:21126020

Bioactive oleanane-type saponins from the rhizomes of Anemone taipaiensis.

PubMed

Wang, Xiao-Yang; Gao, Hui; Zhang, Wei; Li, Yuan; Cheng, Guang; Sun, Xiao-Li; Tang, Hai-Feng

2013-10-15

Investigation of the n-BuOH extract of the rhizomes of Anemone taipaiensis led to the isolation of five new oleanane-type triterpenoid saponins (1-5), together with seven known saponins (6-12). Their structures were determined by the extensive use of (1)D and (2)D NMR experiments along with ESIMS analyses and acid hydrolysis. The aglycone of 1, 2 and 4 was determined as siaresinolic acid, which was reported in this genus for the first time. The cytotoxicities of the saponins 1-12, prosapogenins 4a, 5a, 10a-12a and sapogenins siaresinolic acid (SA), oleanolic acid (OA), hederagenin (HE) were evaluated against five human cancer cell lines, including HepG2, HL-60, A549, HeLa and U87MG. The monodesmosidic saponins 6-8, 5a, 10a-12a and sapogenins SA, OA, HE exhibited cytotoxic activity toward all cancer cell lines, with IC50 values ranging from 2.25 to 57.28 μM. Remarkably, the bisdesmosidic saponins 1-4 and 9 showed selective cytotoxicity against the U87MG cells. Copyright © 2013 Elsevier Ltd. All rights reserved.

Physico-chemical properties and cytotoxic potential of Cordyceps sinensis metabolites.

PubMed

Lee, Eun-Jeong; Jang, Ka-Hee; Im, Seon-Young; Lee, Yoon-Kyung; Farooq, Muhammad; Farhoudi, Rozbeh; Lee, Dong-Jin

2015-01-01

This study was conducted to estimate the antioxidant activities, biochemical properties and biological activities of one of the entomopathogenic fungi, Cordyceps sinensis. Analysis of fungal metabolites indicated that the most abundant free sugar was glucose; the highest component of organic acids was citric acid from 10-day culture medium and the glutamate was the predominant amino acid observed from 3-day culture medium. Maximum total polyphenols and flavonoids were detected in the 15-day culture medium. For cytotoxicity test, three cancer cell lines, HepG2 (liver), MCF-7 (breast) and A549 (lung) were used. The IC50 values of the highest toxicity of HepG2 cell lines were observed from 10-day cultured medium, whereas the highest toxicity of MCF-7 and A549 was observed on 5-day cultured medium. This is the first study reporting on the strong antioxidant and cytotoxic potential of C. sinensis. Culture medium of C. sinensis may thus be used as an effective antioxidant and anticancer treatment of natural origin.

In-vitro and in-vivo antitumour activity of physalins B and D from Physalis angulata.

PubMed

Magalhães, Hemerson Iury Ferreira; Veras, Maria Leopoldina; Torres, Márcia Rocha; Alves, Ana Paula Negreiros Nunes; Pessoa, Otília Deusdênia Loiola; Silveira, Edilberto Rocha; Costa-Lotufo, Letícia Veras; de Moraes, Manoel Odorico; Pessoa, Cláudia

2006-02-01

We have evaluated the in-vitro and in-vivo antitumour activity of physalin B and physalin D isolated from the aerial parts of Physalis angulata. In-vitro, both compounds displayed considerable cytotoxicity against several cancer cell lines, showing IC50 values in the range of 0.58 to 15.18 microg mL(-1) for physalin B, and 0.28 to 2.43 microg mL(-1) for physalin D. The antitumour activity of both compounds was confirmed in-vivo using mice bearing sarcoma 180 tumour cells. The in-vivo antitumour activity was related to the inhibition of tumour proliferation, as observed by the reduction of Ki67 staining in tumours of treated animals. Histopathological examination of the kidney and liver showed that both organs were affected by physalin treatment, but in a reversible manner. These compounds were probably responsible for the previously described antitumour activity of ethanol extracts of P. angulata, and their identification and characterization presented here could explain the ethnopharmacological use of this species in the treatment of cancer.

Biomolecule-loaded chitosan nanoparticles induce apoptosis and molecular changes in cancer cell line (SiHa).

PubMed

Sujima Anbu, Anbu; Velmurugan, Palanivel; Lee, Jeong-Ho; Oh, Byung-Taek; Venkatachalam, Perumal

2016-07-01

The present study reports on the synthesis of chitosan nanoparticles (CNPs) using methanol extracts of Gymnema sylvestre (GS) leaves and Cinnamomum zeylanicum (CZ) bark. Biomolecule-loaded nanoparticles induced apoptosis in a human cervical cancer (SiHa) cell line, and experiments were carried out to elucidate the underlying molecular mechanisms. FT-IR and XRD showed possible functional groups of the biomolecules and the crystalline nature of CNPs, respectively. Transmission electron microscopy images revealed that synthesized GSCNPs and CZCNPs had a smooth spherical shape with average sizes of about 58-80 and 60-120nm, respectively. Dynamic light scattering studies indicated that both GSCNPs and CZCNs were structurally stable with homogenous and heterogeneous natures, respectively. Furthermore, synthesized GSCNPs and CZCNPs exhibited dose-dependent cytotoxicity against the SiHa cancer cell line, with inhibitory concentration (IC50) values of 102.17μg/ml, 87.75μg/ml, 132.74μg/ml and 90.35μg/ml for GS leaf extract, GSCNPs, CZBE and CZCNPs, respectively. Copyright © 2016 Elsevier B.V. All rights reserved.

Comparative assessment of three in vitro exposure methods for combustion toxicity.

PubMed

Lestari, Fatma; Markovic, Boban; Green, Anthony R; Chattopadhyay, Gautam; Hayes, Amanda J

2006-01-01

A comparative assessment of three approaches for the use of human cells in vitro to investigate combustion toxicity was conducted. These included one indirect and two direct (passive and dynamic) exposure methods. The indirect method used an impinger system in which culture medium was used to trap the toxicants, whilst the direct exposure involved the use of a Horizontal Harvard Navicyte Chamber at the air/liquid interface. The cytotoxic effects of thermal decomposition products were assessed using the MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) assay (Promega) on a selection of human cells including: HepG2, A549 and skin fibroblasts. A small scale laboratory fire test using a vertical tube furnace was designed for the generation of combustion products. Polymethyl methacrylate (PMMA) was selected as a model polymer to study the cytotoxic effects of combustion products. NOAEC (no observable adverse effect concentration), IC10 (10% inhibitory concentration), IC50 (50% inhibitory concentration) and TLC (total lethal concentration) values were determined from dose response curves. Assessment using the NRU (neutral red uptake) and ATP (adenosine triphosphate) assays on human lung derived cells (A549) was also undertaken. Comparison between in vitro cytotoxicity results against published toxicity data for PMMA combustion and predicted LC50 (50% lethal concentration) values calculated from identified compounds using GCMS (gas chromatography mass spectrometry) was determined. The results suggested that the indirect exposure method did not appear to simulate closely exposure via inhalation, whilst exposure at the air/liquid interface by using the dynamic method proved to be a more representative method of human inhalation. This exposure method may be a potential system for in vitro cytotoxicity testing in combustion toxicity. Copyright 2005 John Wiley & Sons, Ltd.

Novel Marine Phenazines as Potential Cancer Chemopreventive and Anti-Inflammatory Agents

PubMed Central

Kondratyuk, Tamara P.; Park, Eun-Jung; Yu, Rui; van Breemen, Richard B.; Asolkar, Ratnakar N.; Murphy, Brian T.; Fenical, William; Pezzuto, John M.

2012-01-01

Two new (1 and 2) and one known phenazine derivative (lavanducyanin, 3) were isolated and identified from the fermentation broth of a marine-derived Streptomyces sp. (strain CNS284). In mammalian cell culture studies, compounds 1, 2 and 3 inhibited TNF-α-induced NFκB activity (IC50 values of 4.1, 24.2, and 16.3 μM, respectively) and LPS-induced nitric oxide production (IC50 values of >48.6, 15.1, and 8.0 μM, respectively). PGE2 production was blocked with greater efficacy (IC50 values of 7.5, 0.89, and 0.63 μM, respectively), possibly due to inhibition of cyclooxygenases in addition to the expression of COX-2. Treatment of cultured HL-60 cells led to dose-dependent accumulation in the subG1 compartment of the cell cycle, as a result of apoptosis. These data provide greater insight on the biological potential of phenazine derivatives, and some guidance on how various substituents may alter potential anti-inflammatory and anti-cancer effects. PMID:22412812

Optimization of Cat's Whiskers Tea (Orthosiphon stamineus) Using Supercritical Carbon Dioxide and Selective Chemotherapeutic Potential against Prostate Cancer Cells

PubMed Central

Al-Suede, Fouad Saleih R.; Khadeer Ahamed, Mohamed B.; Abdul Majid, Aman S.; Baharetha, Hussin M.; Hassan, Loiy E. A.; Kadir, Mohd Omar A.; Nassar, Zeyad D.; Abdul Majid, Amin M. S.

2014-01-01

Cat's whiskers (Orthosiphon stamineus) leaves extracts were prepared using supercritical CO2 (SC-CO2) with full factorial design to determine the optimum extraction parameters. Nine extracts were obtained by varying pressure, temperature, and time. The extracts were analysed using FTIR, UV-Vis, and GC-MS. Cytotoxicity of the extracts was evaluated on human (colorectal, breast, and prostate) cancer and normal fibroblast cells. Moderate pressure (31.1 MPa) and temperature (60°C) were recorded as optimum extraction conditions with high yield (1.74%) of the extract (B2) at 60 min extraction time. The optimized extract (B2) displayed selective cytotoxicity against prostate cancer (PC3) cells (IC50 28 µg/mL) and significant antioxidant activity (IC50 42.8 µg/mL). Elevated levels of caspases 3/7 and 9 in B2-treated PC3 cells suggest the induction of apoptosis through nuclear and mitochondrial pathways. Hoechst and rhodamine assays confirmed the nuclear condensation and disruption of mitochondrial membrane potential in the cells. B2 also demonstrated inhibitory effects on motility and colonies of PC3 cells at its subcytotoxic concentrations. It is noteworthy that B2 displayed negligible toxicity against the normal cells. Chemometric analysis revealed high content of essential oils, hydrocarbon, fatty acids, esters, and aromatic sesquiterpenes in B2. This study highlights the therapeutic potentials of SC-CO2 extract of cat's whiskers in targeting prostate carcinoma. PMID:25276215

Synthesis and cytotoxicity of 2,5-dihydroxychalcones and related compounds.

PubMed

Nam, Nguyen-Hai; Hong, Dong-Ho; You, Young-Jae; Kim, Yong; Bang, Seong-Cheol; Kim, Hwan-Mook; Ahn, Byung-Zun

2004-06-01

A series of 2, 5-dihydroxychalcones and related compounds were synthesized, and their cytotoxicities against tumor cell lines and human umbilical venous endothelial cells (HUVEC) evaluated. It was found that chalcones, with electron-withdrawing substituents on an A ring, exhibited significant cytotoxicities. Among the synthesized compounds, 2'-chloro-2, 5-dihydroxychalcone (9) was most potent, with an IC50 value as low as 0.31 microg/mL. This compound also exhibited a significant cytotoxic selectivity toward HUVEC.

Synthesis and in vitro acetylcholinesterase and butyrylcholinesterase inhibitory potential of hydrazide based Schiff bases.

PubMed

Rahim, Fazal; Ullah, Hayat; Taha, Muhammad; Wadood, Abdul; Javed, Muhammad Tariq; Rehman, Wajid; Nawaz, Mohsan; Ashraf, Muhammad; Ali, Muhammad; Sajid, Muhammad; Ali, Farman; Khan, Muhammad Naseem; Khan, Khalid Mohammed

2016-10-01

To discover multifunctional agents for the treatment of Alzheimer's disease, a series of hydrazide based Schiff bases were designed and synthesized based on multitarget-directed strategy. We have synthesized twenty-eight analogs of hydrazide based Schiff bases, characterized by various spectroscopic techniques and evaluated in vitro for acetylcholinesterase and butyrylcholinesterase inhibition. All compounds showed varied degree of acetylcholinesterase and butyrylcholinesterase inhibition when compared with standard Eserine. Among the series, compounds 10, 3 and 24 having IC50 values 4.12±0.01, 8.12±0.01 and 8.41±0.06μM respectively showed potent acetylcholinesterase inhibition when compared with Eserine (IC50=0.85±0.0001μM). Three compounds 13, 24 and 3 having IC50 values 6.51±0.01, 9.22±0.07 and 37.82±0.14μM respectively showed potent butyrylcholinesterase inhibition by comparing with eserine (IC50=0.04±0.0001μM). The remaining compounds also exhibited moderate to weak inhibitory potential. Structure activity relationship has been established. Through molecular docking studies the binding interaction was confirmed. Copyright © 2016 Elsevier Inc. All rights reserved.

Antiviral properties of prodelphinidin B-2 3'-O-gallate from green tea leaf.

PubMed

Cheng, Hua-Yew; Lin, Chun-Ching; Lin, Ta-Chen

2002-07-01

Prodelphinidin B-2 3-O-gallate, a proanthocyanidin gallate isolated from green tea leaf, was investigated for its anti-herpes simplex virus type 2 properties in vitro. Prodelphinidin B-2 3'-O-gallate exhibited antiviral activity with IC50 of 5.0 +/-1.0 microM and 1.6 +/-0.3 pM for XTT and plaque reduction (PRA) assays, respectively. Cytotoxicity assay had shown that prodelphinidin B-2 3'-O-gallate possessed cytotoxic effect toward Vero cell at concentration higher than its IC50. The 50% cytotoxic concentration for cell growth (CC50) was 33.3 +/- 3.7 microM. Thus, the selectivity index (SI) (ratio of IC50 to CC50) for XTT assay and PRA was 6.7 and 20.8, respectively. Prodelphinidin B-2 3'-O-gallate significantly reduced viral infectivity at concentrations 10 microM or more. Result of time-of-addition studies suggested that prodelphinidin B-2 3'-O-gallate affected the late stage of HSV-2 infection. In addition, it was also shown to inhibit the virus from attaching and penetrating into the cell. Thus, prodelphinidin B-2 3'-O-gallate was concluded to possess antiviral activity with mechanism of inhibiting viral attachment and penetration, and disturbing the late stage of viral infection.

Using in situ pore water concentrations to estimate the phytotoxicity of nicosulfuron in soils to corn (Zea mays L.).

PubMed

Liu, Kailin; Cao, Zhengya; Pan, Xiong; Yu, Yunlong

2012-08-01

The phytotoxicity of an herbicide in soil is typically dependent on the soil characteristics. To obtain a comparable value of the concentration that inhibits growth by 50% (IC50), 0.01 M CaCl(2) , excess pore water (EPW) and in situ pore water (IPW) were used to extract the bioavailable fraction of nicosulfuron from five different soils to estimate the nicosulfuron phytotoxicity to corn (Zea mays L.). The results indicated that the phytotoxicity of nicosulfuron in soils to corn depended on the soil type, and the IC50 values calculated based on the amended concentration of nicosulfuron ranged from 0.77 to 9.77 mg/kg among the five tested soils. The range of variation in IC50 values for nicosulfuron was smaller when the concentrations of nicosulfuron extracted with 0.01 M CaCl(2) and EPW were used instead of the amended concentration. No significant difference was observed among the IC50 values calculated from the IPW concentrations of nicosulfuron in the five tested soils, suggesting that the concentration of nicosulfuron in IPW could be used to estimate the phytotoxicity of residual nicosulfuron in soils. Copyright © 2012 SETAC.

Viwithan, a Standardized Withania somnifera Root Extract Induces Apoptosis in Murine Melanoma Cells.

PubMed

Sudeep, H V; Gouthamchandra, K; Venkatesh, B J; Prasad, K Shyam

2018-01-01

Withania somnifera is an Indian medicinal herb known for the multipotential ability to cure various therapeutic ailments as described in the ayurvedic system of medicine. In the present study, we have evaluated the antiproliferative activity of a standardized W. somnifera root extract (Viwithan) against different human and murine cancer cell lines. The cytotoxicity of Viwithan was determined using thiazolyl blue tetrazolium blue assay and crystal violet staining. The apoptotic changes in B16F1 cells following treatment with Viwithan were observed by acridine orange/ethidium bromide (AO/EB) staining and DNA fragmentation assay. The binding affinity of withanolides in Viwithan with antiapoptotic proteins B-cell lymphoma 2, B-cell lymphoma-extra large, and myeloid cell leukemia 1 (MCL-1) were studied using in silico approach. The half maximal inhibitory concentration (IC50) values of Viwithan against liver hepatocellular carcinoma, Henrietta Lacks cervical carcinoma cells, human colorectal carcinoma cell line, and Ehrlich ascites carcinoma cells were 1830, 968, 2715, and 633 μg/ml, respectively. Interestingly, Viwithan was highly effective against B16F1 cells with an IC50 value of 220 μg/ml after 24 h treatment. The morphological alterations of apoptotic cell death were clearly observed in the AO/EB-stained cells after treatment with Viwithan. Viwithan induced late apoptotic changes in treated B16F1 cells as evident by the ladder formation of fragmented DNA in a time-dependent manner. The findings of molecular docking showed that withanolides present in Viwithan have a more binding affinity with the antiapoptotic proteins, particularly MCL-1. We have reported for the first time that Viwithan with 5% withanolides has a potent cytotoxic effect, particularly against B16F1 murine melanoma cells among the different cancer cell lines tested. The present study reports for the first time that Viwithan, a standardized 5% Withania somnifera root extract, has potent cytotoxicity against B16F1 murine melanoma cellsWe have investigated the in vitro cytotoxicity of Viwithan in different human and murine cancer cells. Interestingly, we found that Viwithan was particularly very effective against B16F1 melanoma cells with a half maximal inhibitory concentration value of 220 μg/mlThe microscopic observations following acridine orange/ethidium bromide staining and DNA fragmentation assays clearly indicated that Viwithan might initiate late apoptosis in B16F1 cellsThe binding affinity of withanolides in Viwithan with antiapoptotic proteins of B-cell lymphoma 2 family was predicted using AutoDock tool. The results from in silico studies indicated a plausible synergistic effect of withanolides attributing to the Viwithan-induced apoptosis through suppression of intrinsic pathway for carcinogenesis. Abbreviations used: MTT: Thiazolyl blue tetrazolium blue; DMSO: Dimethyl sulfoxide; BSA: Bovine serum albumin; DMEM: Dulbecco's minimum essential medium; NCCS: National Centre for Cell Science; PBS: Phosphate-Buffered Saline; HepG2: Liver hepatocellular carcinoma; HeLa: Henrietta Lacks cervical carcinoma cells; HCT-116: Human colorectal carcinoma cell line; EAC: Ehrlich ascites carcinoma cells; IC50: Half maximal inhibitory concentration; AO/EB: Acridine orange/Ethidium bromide; BCL-2: B-cell lymphoma 2; BCL-XL: B-cell lymphoma-extra large; MCL-1: Myeloid cell leukemia 1; PDB: Protein Data Bank; ANOVA: Analysis of variance.

Viwithan, a Standardized Withania somnifera Root Extract Induces Apoptosis in Murine Melanoma Cells

PubMed Central

Sudeep, H.V.; Gouthamchandra, K.; Venkatesh, B. J.; Prasad, K. Shyam

2017-01-01

Background: Withania somnifera is an Indian medicinal herb known for the multipotential ability to cure various therapeutic ailments as described in the ayurvedic system of medicine. Objective: In the present study, we have evaluated the antiproliferative activity of a standardized W. somnifera root extract (Viwithan) against different human and murine cancer cell lines. Materials and Methods: The cytotoxicity of Viwithan was determined using thiazolyl blue tetrazolium blue assay and crystal violet staining. The apoptotic changes in B16F1 cells following treatment with Viwithan were observed by acridine orange/ethidium bromide (AO/EB) staining and DNA fragmentation assay. The binding affinity of withanolides in Viwithan with antiapoptotic proteins B-cell lymphoma 2, B-cell lymphoma-extra large, and myeloid cell leukemia 1 (MCL-1) were studied using in silico approach. Results: The half maximal inhibitory concentration (IC50) values of Viwithan against liver hepatocellular carcinoma, Henrietta Lacks cervical carcinoma cells, human colorectal carcinoma cell line, and Ehrlich ascites carcinoma cells were 1830, 968, 2715, and 633 μg/ml, respectively. Interestingly, Viwithan was highly effective against B16F1 cells with an IC50 value of 220 μg/ml after 24 h treatment. The morphological alterations of apoptotic cell death were clearly observed in the AO/EB-stained cells after treatment with Viwithan. Viwithan induced late apoptotic changes in treated B16F1 cells as evident by the ladder formation of fragmented DNA in a time-dependent manner. The findings of molecular docking showed that withanolides present in Viwithan have a more binding affinity with the antiapoptotic proteins, particularly MCL-1. Conclusion: We have reported for the first time that Viwithan with 5% withanolides has a potent cytotoxic effect, particularly against B16F1 murine melanoma cells among the different cancer cell lines tested. SUMMARY The present study reports for the first time that Viwithan, a standardized 5% Withania somnifera root extract, has potent cytotoxicity against B16F1 murine melanoma cellsWe have investigated the in vitro cytotoxicity of Viwithan in different human and murine cancer cells. Interestingly, we found that Viwithan was particularly very effective against B16F1 melanoma cells with a half maximal inhibitory concentration value of 220 μg/mlThe microscopic observations following acridine orange/ethidium bromide staining and DNA fragmentation assays clearly indicated that Viwithan might initiate late apoptosis in B16F1 cellsThe binding affinity of withanolides in Viwithan with antiapoptotic proteins of B-cell lymphoma 2 family was predicted using AutoDock tool. The results from in silico studies indicated a plausible synergistic effect of withanolides attributing to the Viwithan-induced apoptosis through suppression of intrinsic pathway for carcinogenesis. Abbreviations used: MTT: Thiazolyl blue tetrazolium blue; DMSO: Dimethyl sulfoxide; BSA: Bovine serum albumin; DMEM: Dulbecco's minimum essential medium; NCCS: National Centre for Cell Science; PBS: Phosphate-Buffered Saline; HepG2: Liver hepatocellular carcinoma; HeLa: Henrietta Lacks cervical carcinoma cells; HCT-116: Human colorectal carcinoma cell line; EAC: Ehrlich ascites carcinoma cells; IC50: Half maximal inhibitory concentration; AO/EB: Acridine orange/Ethidium bromide; BCL-2: B-cell lymphoma 2; BCL-XL: B-cell lymphoma-extra large; MCL-1: Myeloid cell leukemia 1; PDB: Protein Data Bank; ANOVA: Analysis of variance. PMID:29491636

Identification and isolation of the cyclooxygenase-2 inhibitory principle in Isatis tinctoria.

PubMed

Danz, H; Stoyanova, S; Wippich, P; Brattström, A; Hamburger, M

2001-07-01

Various extracts prepared from the traditional dye and medicinal plant Isatis tinctoria L. were submitted to a broad in vitro screening against 16 anti-inflammatory targets. Dichloromethane (DCM) extracts from dried leaves showed a marked cyclooxygenase (COX) inhibitory activity with a preferential effect on COX-2 catalysed prostaglandin synthesis. A supercritical fluid extraction (SFE) procedure employing CO2-modifier mixtures was developed by which the bioactivity profile and chromatographic fingerprint of the DCM extract could be reproduced. High-resolution activity directed on-line identification of the COX-2 inhibitory principle, using a combination of LC-DAD-MS with a microtitre-based bioassay, led to the identification of tryptanthrin (1) as the constituent responsible for essentially all COX-2 inhibitory activity in the crude extract. Following on-line identification, 1 was isolated at preparative scale and its structure confirmed by comparison with synthetic tryptanthrin. In an assay with lipopolysaccharide stimulated Mono Mac 6 cells, tryptanthrin (1) was of comparable potency (IC50 = 64 nM) than the preferential COX-2 inhibitors nimesulide (IC50 = 39 nM) and NS 398 (IC50 = 2 nM). The SFE extract and 1 showed no cytotoxicity in Mono Mac 6 and RAW 264.7 cells when tested at 100 microg/ml and 10 microM, respectively.

Synthesis and biological evaluation of novel thiadiazole amides as potent Cdc25B and PTP1B inhibitors.

PubMed

Li, Yingjun; Yu, Yang; Jin, Kun; Gao, Lixin; Luo, Tongchuan; Sheng, Li; Shao, Xin; Li, Jia

2014-09-01

A series of novel thiadiazole amide derivatives have been synthesized and evaluated for inhibitory activities against Cdc25B and PTP1B. Most of them showed inhibitory activities against Cdc25B (IC50=1.18-8.01 μg/mL) and PTP1B (IC50=0.85-8.75 μg/mL), respectively. Moreover, compounds 5b and 4l were most potent with IC50 values of 1.18 and 0.85 μg/mL for Cdc25B and PTP1B, respectively, compared with reference drugs Na3VO4 (IC50=0.93 μg/mL) and oleanolic acid (IC50=0.85 μg/mL). The results of selectivity experiments showed that the target compounds were selective inhibitors against PTP1B and Cdc25B. Enzyme kinetic experiments demonstrated that compound 5k was a specific inhibitor with the typical characteristics of a mixed inhibitor. Copyright © 2014 Elsevier Ltd. All rights reserved.

Anti-Inflammatory Components of the Starfish Astropecten polyacanthus

PubMed Central

Thao, Nguyen Phuong; Cuong, Nguyen Xuan; Luyen, Bui Thi Thuy; Quang, Tran Hong; Hanh, Tran Thi Hong; Kim, Sohyun; Koh, Young-Sang; Nam, Nguyen Hoai; Kiem, Phan Van; Minh, Chau Van; Kim, Young Ho

2013-01-01

Inflammation is important in biomedical research, because it plays a key role in inflammatory diseases including rheumatoid arthritis and other forms of arthritis, diabetes, heart disease, irritable bowel syndrome, Alzheimer’s disease, Parkinson’s disease, allergies, asthma, and even cancer. In the present study, we describe the inhibitory effect of crude extracts and steroids isolated from the starfish Astropecten polyacanthus on pro-inflammatory cytokine (Interleukin-12 (IL-12) p40, interleukin-6 (IL-6), and tumor necrosis factor α (TNF-α)) production in lipopolysaccharide (LPS)-stimulated bone marrow-derived dendritic cells (BMDCs). Among those tested, compounds 5 and 7 showed potent inhibitory effects on the production of all three pro-inflammatory cytokines with IC50 values ranging from 1.82 ± 0.11 to 7.00 ± 0.16 μM. Potent inhibitory activities were also observed for compound 1 on the production of IL-12 p40 and IL-6 with values of 3.96 ± 0.12 and 4.07 ± 0.13 μM, respectively, and for compounds 3 and 4 on the production of IL-12 p40 with values of 6.55 ± 0.18 and 5.06 ± 0.16 μM, respectively. Moreover, compounds 2 (IC50 = 34.86 ± 0.31 μM) and 6 (IC50 = 79.05 ± 2.05 μM) exhibited moderate inhibitory effects on the production of IL-12 p40, whereas compounds 3 (IC50 = 22.80 ± 0.21 μM) and 4 (IC50 = 16.73 ± 0.25 μM) moderately inhibited the production of TNF-α and IL-6, respectively. PMID:23945602

Evaluation of in vitro anti-Leishmanial activity of some brown, green and red algae from the Persian Gulf.

PubMed

Fouladvand, M; Barazesh, A; Farokhzad, F; Malekizadeh, H; Sartavi, K

2011-06-01

Leishmaniasis is a protozoan parasitic disease which is transmitted by the female Phlebotomus sand fly and is prevalent in four continents.The first-choice treatment for the leishmaniasis is pentavalent antimonials, which are potentially toxic and often ineffective and use of them exhibit therapeutic failure. These pharmaceutical problems point towards the need to develop novel chemotherapeutic agents. Seaweeds are considered as source of bioactive metabolites characterized by a broad spectrum of biological activities. In this experimental study, cold and hot water crude extracts of four species of green, brown and red marine algae "Caulerpa sertularioides, Gracilaria corticata, Gracillaria salicornia and Sargassum oligocystum" collected along the Bushehr coast of the Persian Gulf (southwest of Iran), prepared and their in vitro activities against Leishmania major promastigote were evaluated by using the MTT assay test. The cold and hot water crude extracts of four algae species exhibited different anti-Leishmanial activities. The minimum inhibitory concentration of hot water extracts calculated as IC50 was as follows: Caulerpa sertularioides (IC50 < or =85 microg/ml), Gracilaria corticata (IC50 < or =38 microg/ml), Gracillaria salicornia (IC50 < or =46 microg/ml) and Sargassum oligocystum (IC(50)9 < or =78 microg/ml, while these values for cold water extracts were (IC50 >125 microg/ml) for Caulerpa Sertularioides (IC50 >65 microg/ml) for Gracilaria corticata (IC50 >74 microg/ml) for Gracilaria salicornia and (IC50 >105 microg/ml) for Sargassum oligocystum, IC50 values for reference drug (Amphotericin B) was (0.16-0.2 microg/ml). According to the results, inhibitory effects of the crude extracts from these four species algae specially hot water crude extracts from "Gracilaria corticata, Gracillaria salicornia and Sargassum oligocystum" are significant and in accordance with other studies that has been done on different algae species. So these results are sufficiently promising to be followed with further studies on isolation and characterization of pure compounds from these algae species as well as in vivo experiments, a work that is already under way in our laboratory.

Shape and surface chemistry effects on the cytotoxicity and cellular uptake of metallic nanorods and nanospheres.

PubMed

Favi, Pelagie Marlene; Valencia, Mariana Morales; Elliott, Paul Robert; Restrepo, Alejandro; Gao, Ming; Huang, Hanchen; Pavon, Juan Jose; Webster, Thomas Jay

2015-12-01

Metallic nanoparticles (such as gold and silver) have been intensely studied for wound healing applications due to their ability to be easily functionalized, possess antibacterial properties, and their strong potential for targeted drug release. In this study, rod-shaped silver nanorods (AgNRs) and gold nanorods (AuNRs) were fabricated by electron beam physical vapor deposition (EBPVD), and their cytotoxicity toward human skin fibroblasts were assessed and compared to sphere-shaped silver nanospheres (AgNSs) and gold nanospheres (AuNSs). Results showed that the 39.94 nm AgNSs showed the greatest toxicity with fibroblast cells followed by the 61.06 nm AuNSs, ∼556 nm × 47 nm (11.8:1 aspect ratio) AgNRs, and the ∼534 nm × 65 nm (8.2:1 aspect ratio) AuNRs demonstrated the least amount of toxicity. The calculated IC50 (50% inhibitory concentration) value for the AgNRs exposed to fibroblasts was greater after 4 days of exposure (387.3 μg mL(-1)) compared to the AgNSs and AuNSs (4.3 and 23.4 μg mL(-1), respectively), indicating that these spherical metallic nanoparticles displayed a greater toxicity to fibroblast cells. The IC50 value could not be measured for the AuNRs due to an incomplete dose response curve. The reduced cell toxicity with the presently developed rod-shaped nanoparticles suggests that they may be promising materials for use in numerous biomedical applications. © 2015 Wiley Periodicals, Inc.

Substituted thieno[2,3-b]thiophenes and related congeners: Synthesis, β-glucuronidase inhibition activity, crystal structure, and POM analyses.

PubMed

Mabkhot, Yahia Nasser; Barakat, Assem; Yousuf, Sammer; Choudhary, M Iqbal; Frey, Wolfgang; Ben Hadda, Taibi; Mubarak, Mohammad S

2014-12-01

A series of 15 novel compounds incorporating the thieno[2,3-b]thiophene moiety were synthesized. The chemical structures of these compounds were deduced from elemental analyses, (1)H NMR, (13)C NMR, and ESI-mass spectral data. The enzyme inhibition potential of these compounds was evaluated, in vitro, against β-glucuronidase, xanthine oxidase, and α-chymotrypsin enzymes. The cytotoxicity was evaluated by a cell viability assay utilizing the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) dye. Among the compounds tested, compound 3 was the most potent β-glucuronidase inhibitor with an IC50 value of 0.9 ± 0.0138 μM; it was much more active than the standard, d-saccharic acid 1,4-lactone (IC50=45.75 ± 2.16 μM). Compound 12, on the other hand, was the most potent as a xanthine oxidase inhibitor with an IC50 of 14.4 ± 1.2 μM. With the characterization of their mechanism of action and with further testing, these compounds could be useful candidates as anticancer drugs. In addition, the newly synthesized compounds were subjected to POM analyses to get insights about their degree of their toxicity. Copyright © 2014 Elsevier Ltd. All rights reserved.

Synthesis of 4-thiazolidinone analogs as potent in vitro anti-urease agents.

PubMed

Rahim, Fazal; Zaman, Khalid; Ullah, Hayat; Taha, Muhammad; Wadood, Abdul; Javed, Muhammad Tariq; Rehman, Wajid; Ashraf, Muhammad; Uddin, Reaz; Uddin, Imad; Asghar, Humna; Khan, Aftab Ahmad; Khan, Khalid M

2015-12-01

4-Thiazolidinone analogs 1-20 were synthesized, characterized by (1)H NMR and EI-MS and investigated for urease inhibitory activity. All twenty (20) analogs exhibited varied degree of urease inhibitory potential with IC50 values 1.73-69.65μM, if compared with standard thiourea having IC50 value of 21.25±0.15μM. Among the series, eight derivatives 3, 6, 8, 10, 15, 17, 19, and 20 showed outstanding urease inhibitory potential with IC50 values of 9.34±0.02, 14.62±0.03, 8.43±0.01, 7.3±0.04, 2.31±0.002, 5.75±0.003, 8.81±0.005, and 1.73±0.001μM, respectively, which is better than the standard thiourea. The remaining analogs showed good to excellent urease inhibition. The binding interactions of these compounds were confirmed through molecular docking studies. Copyright © 2015 Elsevier Inc. All rights reserved.

Neopetrosiquinones A and B, Sesquiterpene Benzoquinones Isolated from the Deep-water Sponge Neopetrosia cf. proxima

PubMed Central

Winder, Priscilla L.; Baker, Heather L.; Linley, Patricia; Guzmán, Esther; Pomponi, Shirley A.; Diaz, M. Cristina; Reed, John K.; Wright, Amy E.

2011-01-01

Two new marine-derived sesquiterpene benzoquinones which we designate as neopetrosiquinone A (1) and B (2), have been isolated from a deep-water sponge of the family Petrosiidae. The structures were elucidated on the basis of their spectroscopic data. Compounds 1 and 2 inhibit the in vitro proliferation of the DLD-1 human colorectal adenocarcinoma cell line with IC50 values of 3.7 and 9.8 μM, respectively, and the PANC-1 human pancreatic carcinoma cell line with IC50 values of 6.1 and 13.8 μM, respectively. Neopetrosiquinone A (1) also inhibited the in vitro proliferation of the AsPC-1 human pancreatic carcinoma cell line with an IC50 value of 6.1 μM. The compounds are structurally related to alisiaquinone A, cyclozonarone and xestoquinone. PMID:22014756

Synthesis and anti-tumor evaluation of panaxadiol halogen-derivatives.

PubMed

Xiao, Shengnan; Chen, Shuai; Sun, Yuanyuan; Zhou, Wuxi; Piao, Huri; Zhao, Yuqing

2017-09-01

In the current work, 13 novel panaxadiol (PD) derivatives were synthesized by reacting with chloroacetyl chloride and bromoacetyl bromide. Their in vitro antitumor activities were evaluated on three human tumor cell lines (HCT-116, BGC-823, SW-480) and three normal cells (human gastric epithelial cell line-GES-1, hair follicle dermal papilla cell line-HHDPC and rat myocardial cell line-H9C2) by MTT assay. Compared with PD, the results demonstrated that compound 1e, 2d, 2e showed significant anti-tumor activity against three tumor cell lines, the IC50 value of compound 2d against HCT-116 was the lowest (3.836μM). The anti-tumor activity of open-ring compounds are significantly better than the compounds of C-25 cyclization. Compound 1f, 2f, 2g showed the strong anti-tumor activity. The IC50 value of compound 2g against BGC-823 and SW-480 were the lowest (0.6μM and 0.1μM, respectively). Combined with cytotoxicity test, the IC50 value of compound 1e, 2d, 2e are greater than 100. the open-ring compounds (1f, 2f, 2g) showed a strong toxicity. The toxicity of 1f is lower than 2f and 2g. These compounds may be useful for the development of novel antiproliferative agents. Copyright © 2017. Published by Elsevier Ltd.

Aluminum doping tunes band gap energy level as well as oxidative stress-mediated cytotoxicity of ZnO nanoparticles in MCF-7 cells

NASA Astrophysics Data System (ADS)

Akhtar, Mohd Javed; Alhadlaq, Hisham A.; Alshamsan, Aws; Majeed Khan, M. A.; Ahamed, Maqusood

2015-09-01

We investigated whether Aluminum (Al) doping tunes band gap energy level as well as selective cytotoxicity of ZnO nanoparticles in human breast cancer cells (MCF-7). Pure and Al-doped ZnO nanoparticles were prepared by a simple sol-gel method. Characterization study confirmed the formation of single phase of AlxZn1-xO nanocrystals with the size range of 33-55 nm. Al-doping increased the band gap energy of ZnO nanoparticles (from 3.51 eV for pure to 3.87 eV for Al-doped ZnO). Al-doping also enhanced the cytotoxicity and oxidative stress response of ZnO nanoparticles in MCF-7 cells. The IC50 for undoped ZnO nanoparticles was 44 μg/ml while for the Al-doped ZnO counterparts was 31 μg/ml. Up-regulation of apoptotic genes (e.g. p53, bax/bcl2 ratio, caspase-3 & caspase-9) along with loss of mitochondrial membrane potential suggested that Al-doped ZnO nanoparticles induced apoptosis in MCF-7 cells through mitochondrial pathway. Importantly, Al-doping did not change the benign nature of ZnO nanoparticles towards normal cells suggesting that Al-doping improves the selective cytotoxicity of ZnO nanoparticles toward MCF-7 cells without affecting the normal cells. Our results indicated a novel approach through which the inherent selective cytotoxicity of ZnO nanoparticles against cancer cells can be further improved.

Design, synthesis and cytotoxicity of pyrano[4,3-b]indol-1(5H)-ones: A hybrid pharmacophore approach via gold catalyzed cyclization.

PubMed

Praveen, Chandrasekar; Ananth, D Babu

2016-05-15

Reported herein is the gold(III)-catalyzed 6-endo-dig cycloisomerization of 2-alkynyl-indole-3-carboxylic acids to form pyrano[4,3-b]indol-1(5H)-ones, which are pharmaceutically important structural motifs. The hitherto unknown substrates required for this methodology were conveniently synthesized in five steps with good overall yields. The utility of this new cycloisomerization is demonstrated by the excellent regioselectivity obtained using a range of substrates. The mildness of the method allowed functional group compatibility towards hydroxyl tether, displaying exquisite chemoselectivity. All the synthesized compounds were screened for their tumor cell growth inhibitory activity against human cervix adenocarcinoma (HeLa). Compound 7d emerged as the most active (IC50=0.69μM) among the tested series compared to the standard cis-platin (IC50=0.08μM). Copyright © 2016 Elsevier Ltd. All rights reserved.

Aluminum doping tunes band gap energy level as well as oxidative stress-mediated cytotoxicity of ZnO nanoparticles in MCF-7 cells.

PubMed

Akhtar, Mohd Javed; Alhadlaq, Hisham A; Alshamsan, Aws; Majeed Khan, M A; Ahamed, Maqusood

2015-09-08

We investigated whether Aluminum (Al) doping tunes band gap energy level as well as selective cytotoxicity of ZnO nanoparticles in human breast cancer cells (MCF-7). Pure and Al-doped ZnO nanoparticles were prepared by a simple sol-gel method. Characterization study confirmed the formation of single phase of Al(x)Zn(1-x)O nanocrystals with the size range of 33-55 nm. Al-doping increased the band gap energy of ZnO nanoparticles (from 3.51 eV for pure to 3.87 eV for Al-doped ZnO). Al-doping also enhanced the cytotoxicity and oxidative stress response of ZnO nanoparticles in MCF-7 cells. The IC50 for undoped ZnO nanoparticles was 44 μg/ml while for the Al-doped ZnO counterparts was 31 μg/ml. Up-regulation of apoptotic genes (e.g. p53, bax/bcl2 ratio, caspase-3 &caspase-9) along with loss of mitochondrial membrane potential suggested that Al-doped ZnO nanoparticles induced apoptosis in MCF-7 cells through mitochondrial pathway. Importantly, Al-doping did not change the benign nature of ZnO nanoparticles towards normal cells suggesting that Al-doping improves the selective cytotoxicity of ZnO nanoparticles toward MCF-7 cells without affecting the normal cells. Our results indicated a novel approach through which the inherent selective cytotoxicity of ZnO nanoparticles against cancer cells can be further improved.

Aluminum doping tunes band gap energy level as well as oxidative stress-mediated cytotoxicity of ZnO nanoparticles in MCF-7 cells

PubMed Central

Akhtar, Mohd Javed; Alhadlaq, Hisham A.; Alshamsan, Aws; Majeed Khan, M.A.; Ahamed, Maqusood

2015-01-01

We investigated whether Aluminum (Al) doping tunes band gap energy level as well as selective cytotoxicity of ZnO nanoparticles in human breast cancer cells (MCF-7). Pure and Al-doped ZnO nanoparticles were prepared by a simple sol-gel method. Characterization study confirmed the formation of single phase of AlxZn1-xO nanocrystals with the size range of 33–55 nm. Al-doping increased the band gap energy of ZnO nanoparticles (from 3.51 eV for pure to 3.87 eV for Al-doped ZnO). Al-doping also enhanced the cytotoxicity and oxidative stress response of ZnO nanoparticles in MCF-7 cells. The IC50 for undoped ZnO nanoparticles was 44 μg/ml while for the Al-doped ZnO counterparts was 31 μg/ml. Up-regulation of apoptotic genes (e.g. p53, bax/bcl2 ratio, caspase-3 & caspase-9) along with loss of mitochondrial membrane potential suggested that Al-doped ZnO nanoparticles induced apoptosis in MCF-7 cells through mitochondrial pathway. Importantly, Al-doping did not change the benign nature of ZnO nanoparticles towards normal cells suggesting that Al-doping improves the selective cytotoxicity of ZnO nanoparticles toward MCF-7 cells without affecting the normal cells. Our results indicated a novel approach through which the inherent selective cytotoxicity of ZnO nanoparticles against cancer cells can be further improved. PMID:26347142

Evaluation of In Vitro Cytotoxic and Antioxidant Activity of Datura metel Linn. and Cynodon dactylon Linn. Extracts.

PubMed

Roy, Soumen; Pawar, Sandip; Chowdhary, Abhay

2016-01-01

To evaluate in vitro cytotoxicity and antioxidant activity of Datura metel L. and Cynodon dactylon L. extracts. The extraction of plants parts (datura seed and fruit pulp) and areal parts of durva was carried out using soxhlet and cold extraction method using solvents namely methanol and distilled water. The total phenolic content (TPC) and total flavonoid content (TFC) was determined by established methods. The in vitro cytotoxicity assay was performed in vero cell line by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay method. In vitro antioxidant activity of the extract was performed by 2, 2-diphenyl-1-picrylhydrazyl radical scavenging method. We found that the highest amount of TPC and TFC in methanolic extracts of seed (268.6 μg of gallic acid equivalence/mg of dry plant material) and fruit pulp (8.84 μg of quercetin equivalence/mg dry plant material) of D. metel, respectively prepared by Soxhlet method. The methanolic extract of C. dactylon prepared using soxhlation has shown potent free radical scavenging activity with 50% inhibitory concentration (IC50) value of 100 μg/ml. The IC50 of a methanolic cold extract of datura fruit was found to be 3 mg/ml against vero cell line. We observed that plant parts of C. dactylon and D. metel have a high antioxidant activity. Further research is needed to explore the therapeutic potential of these plant extracts. In the present study we observed a positive correlation was between the phenolic and flavanoid content of the Datura metel and cynodon doctylon (durva) extracts with the free radical scavenging activities. Both were found to have a high antioxidant activity. Abbreviations used: BHA: Butylated hydroxyanisole, BHT: Butylated hydroxytoluene, CC50: 50% cell cytotoxic concentration, CNS: Central nervous system, DPPH: 2, 2-diphenyl-1-picrylhydrazyl, IC50: 50% inhibitory concentration, MTT: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide), TFC: Total flavonoid content, TPC: Total phenolic content.

Isometachromin, a new cytotoxic sesquiterpenoid from a deep water sponge of the family Spongiidae.

PubMed

McConnell, O J; Longley, R; Gunasekera, M

1992-09-15

Isometachromin (1), a new sesquiterpene-quinone that is related structurally to metachromin C (2), and the known compounds ilimaquinone (3) and 5-epi-ilimaquinone (4), were isolated from a deep water sponge in the family Spongiidae; the structure of isometachromin was elucidated by spectral methods. Isometachromin exhibits in vitro cytotoxicity against the human lung cancer cell line A549 (IC50 = 2.6 micrograms/ml), but not against P388 murine leukemia (IC 50 > or equal to 10 micrograms/ml) and also exhibits antimicrobial activity.

Evaluation of In Vitro Cytotoxic and Antioxidant Activity of Datura metel Linn. and Cynodon dactylon Linn. Extracts

PubMed Central

Roy, Soumen; Pawar, Sandip; Chowdhary, Abhay

2016-01-01

Aim: To evaluate in vitro cytotoxicity and antioxidant activity of Datura metel L. and Cynodon dactylon L. extracts. Materials and Methods: The extraction of plants parts (datura seed and fruit pulp) and areal parts of durva was carried out using soxhlet and cold extraction method using solvents namely methanol and distilled water. The total phenolic content (TPC) and total flavonoid content (TFC) was determined by established methods. The in vitro cytotoxicity assay was performed in vero cell line by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay method. In vitro antioxidant activity of the extract was performed by 2, 2-diphenyl-1-picrylhydrazyl radical scavenging method. Results: We found that the highest amount of TPC and TFC in methanolic extracts of seed (268.6 μg of gallic acid equivalence/mg of dry plant material) and fruit pulp (8.84 μg of quercetin equivalence/mg dry plant material) of D. metel, respectively prepared by Soxhlet method. The methanolic extract of C. dactylon prepared using soxhlation has shown potent free radical scavenging activity with 50% inhibitory concentration (IC50) value of 100 μg/ml. The IC50 of a methanolic cold extract of datura fruit was found to be 3 mg/ml against vero cell line. Conclusion: We observed that plant parts of C. dactylon and D. metel have a high antioxidant activity. Further research is needed to explore the therapeutic potential of these plant extracts. SUMMARY In the present study we observed a positive correlation was between the phenolic and flavanoid content of the Datura metel and cynodon doctylon (durva) extracts with the free radical scavenging activities. Both were found to have a high antioxidant activity. Abbreviations used: BHA: Butylated hydroxyanisole, BHT: Butylated hydroxytoluene, CC50: 50% cell cytotoxic concentration, CNS: Central nervous system, DPPH: 2, 2-diphenyl-1-picrylhydrazyl, IC50: 50% inhibitory concentration, MTT: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide), TFC: Total flavonoid content, TPC: Total phenolic content. PMID:27034603

Schedule-Dependent Antiangiogenic and Cytotoxic Effects of Chemotherapy on Vascular Endothelial and Retinoblastoma Cells.

PubMed

Winter, Ursula; Mena, Hebe A; Negrotto, Soledad; Arana, Eloisa; Pascual-Pasto, Guillem; Laurent, Viviana; Suñol, Mariona; Chantada, Guillermo L; Carcaboso, Angel M; Schaiquevich, Paula

2016-01-01

Current treatment of retinoblastoma involves using the maximum dose of chemotherapy that induces tumor control and is tolerated by patients. The impact of dose and schedule on the cytotoxicity of chemotherapy has not been studied. Our aim was to gain insight into the cytotoxic and antiangiogenic effect of the treatment scheme of chemotherapy used in retinoblastoma by means of different in vitro models and to evaluate potential effects on multi-drug resistance proteins. Two commercial and two patient-derived retinoblastoma cell types and two human vascular endothelial cell types were exposed to increasing concentrations of melphalan or topotecan in a conventional (single exposure) or metronomic (7-day continuous exposure) treatment scheme. The concentration of chemotherapy causing a 50% decrease in cell proliferation (IC50) was determined by MTT and induction of apoptosis was evaluated by flow cytometry. Expression of ABCB1, ABCG2 and ABCC1 after conventional or metronomic treatments was assessed by RT-qPCR. We also evaluated the in vivo response to conventional (0.6 mg/kg once a week for 2 weeks) and metronomic (5 days a week for 2 weeks) topotecan in a retinoblastoma xenograft model. Melphalan and topotecan were cytotoxic to both retinoblastoma and endothelial cells after conventional and metronomic treatments. A significant decrease in the IC50 (median, 13-fold; range: 3-23) was observed following metronomic chemotherapy treatment in retinoblastoma and endothelial cell types compared to conventional treatment (p<0.05). Metronomic topotecan or melphalan significantly inhibited in vitro tube formation in HUVEC and EPC compared to vehicle-treated cells (p<0.05). Both treatment schemes induced apoptosis and/or necrosis in all cell models. No significant difference was observed in the expression of ABCB1, ABCC1 or ABCG2 when comparing cells treated with melphalan or topotecan between treatment schedules at the IC50 or with control cells (p>0.05). In mice, continuous topotecan lead to significantly lower tumor volumes compared to conventional treatment after 14 days of treatment (p<0.05). Continuous exposure to melphalan or topotecan increased the chemosensitivity of retinoblastoma and endothelial cells to both chemotherapy agents with lower IC50 values compared to short-term treatment. These findings were validated in an in vivo model. None of the dosing modalities induced multidrug resistance mechanisms while apoptosis was the mechanism of cell death after both treatment schedules. Metronomic chemotherapy may be a valid option for retinoblastoma treatment allowing reductions of the daily dose.

Selectivity of Pinus sylvestris extract and essential oil to estrogen-insensitive breast cancer cells Pinus sylvestris against cancer cells.

PubMed

Hoai, Nguyen Thi; Duc, Ho Viet; Thao, Do Thi; Orav, Anne; Raal, Ain

2015-10-01

So far, the anticancer action of pine tree extracts has mainly been shown for the species distributed widely around the Asian countries. Therefore, this study was performed to examine the potential cytotoxicity of Scots pine (Pinus sylvestris L.) native also to the European region and growing widely in Estonia. The cytotoxic activity of methanol extract and essential oil of Scots pine needles was determined by sulforhodamine B assay in different human cancer cell lines. This needle extract was found to suppress the viability of several human cancer cell lines showing some selectivity to estrogen receptor negative breast cancer cells, MDA-MB-231(half maximal inhibitory concentration [IC50] 35 μg/ml) in comparison with estrogen receptor-positive breast cancer cells, MCF-7 (IC50 86 μg/ml). It is the strongest cytotoxic effect at all measured, thus far for the needles and leaves extracts derived from various pine species, and is also the first study comparing the anticancer effects of pine tree extracts on molecularly different human breast cancer cells. The essential oil showed the stronger cytotoxic effect to both negative and positive breast cancer cell lines (both IC50 29 μg/ml) than pine extract (IC50 42 and 80 μg/ml, respectively). The data from this report indicate that Scots pine needles extract and essential oil exhibits some potential as chemopreventive or chemotherapeutic agent for mammary tumors unresponsive to endocrine treatment.

New Anti-Inflammatory Cembranes from the Cultured Soft Coral Nephthea columnaris

PubMed Central

Hsiao, Ting-Hsi; Sung, Chun-Sung; Lan, Yu-Hsuan; Wang, Yi-Chen; Lu, Mei-Chin; Wen, Zhi-Hong; Wu, Yang-Chang; Sung, Ping-Jyun

2015-01-01

Two new cembranes, columnariols A (1) and B (2), were isolated from the cultured soft coral Nephthea columnaris. The structures of cembranes 1 and 2 were elucidated by spectroscopic methods. In the anti-inflammatory effects test, cembranes 1 and 2 were found to significantly inhibit the accumulation of the pro-inflammatory iNOS and COX-2 protein of the lipopolysaccharide (LPS)-stimulated RAW264.7 macrophage cells. Compound 1 exhibited moderate cytotoxicity toward LNCaP cells with an IC50 value of 9.80 μg/mL. PMID:26035022

Potent cytotoxic effects of Calomeria amaranthoides on ovarian cancers

PubMed Central

2011-01-01

Background Ovarian cancer remains the leading cause of death from gynaecological malignancy. More than 60% of the patients are presenting the disease in stage III or IV. In spite of combination of chemotherapy and surgery the prognosis stays poor for therapy regimen. Methods The leaves of a plant endemic to Australia, Calomeria amaranthoides, were extracted and then fractionated by column chromatography. In vitro cytotoxicity tests were performed with fractions of the plant extract and later with an isolated compound on ovarian cancer cell lines, as well as normal fibroblasts at concentrations of 1-100 μg/mL (crude extract) and 1-10 μg/mL (compound). Cytotoxicity was measured after 24, 48 and 72 hours by using a non-fluorescent substrate, Alamar blue. In vivo cytotoxicity was tested on ascites, developed in the abdomen of nude mice after inoculation with human OVCAR3 cells intraperitoneally. The rate of change in abdomen size for the mice was determined by linear regression and statistically evaluated for significance by the unpaired t test. Results Two compounds were isolated by chromatographic fractionation and identified by 1H-NMR, 13C-NMR and mass spectrometry analyses, EPD, an α-methylene sesquiterpene lactone of the eremophilanolide subtype, and EPA, an α-methylene carboxylic acid. Cytotoxicity of EPD for normal fibroblasts at all time points IC50 was greater than 10 μg/mL, whereas, for OVCAR3 cells at 48 hours IC50 was 5.3 μg/mL (95% confidence interval 4.3 to 6.5 μg/mL). Both, the crude plant extract as well as EPD killed the cancer cells at a final concentration of 10 μg/mL and 5 μg/mL respectively, while in normal cells only 20% cell killing effect was observed. EPA had no cytotoxic effects. Changes in abdomen size for control versus Cisplatin treated mice were significantly different, P = 0.023, as were control versus EPD treated mice, P = 0.025, whereas, EPD versus Cisplatin treated mice were not significantly different, P = 0.13. Conclusions For the first time both crude plant extract from Calomeria amaranthoides and EPD have been shown to have potent anti-cancer effects against ovarian cancer. PMID:21401934

Reversal of in vitro cellular MRP1 and MRP2 mediated vincristine resistance by the flavonoid myricetin.

PubMed

van Zanden, Jelmer J; de Mul, Anika; Wortelboer, Heleen M; Usta, Mustafa; van Bladeren, Peter J; Rietjens, Ivonne M C M; Cnubben, Nicole H P

2005-06-01

In the present study, the effects of myricetin on either MRP1 or MRP2 mediated vincristine resistance in transfected MDCKII cells were examined. The results obtained show that myricetin can inhibit both MRP1 and MRP2 mediated vincristine efflux in a concentration dependent manner. The IC50 values for cellular vincristine transport inhibition by myricetin were 30.5+/-1.7 microM for MRP1 and 24.6+/-1.3 microM for MRP2 containing MDCKII cells. Cell proliferation analysis showed that the MDCKII control cells are very sensitive towards vincristine toxicity with an IC50 value of 1.1+/-0.1 microM. The MDCKII MRP1 and MRP2 cells are less sensitive towards vincristine toxicity with IC50 values of 33.1+/-1.9 and 22.2+/-1.4 microM, respectively. In both the MRP1 and MRP2 cells, exposure to 25 microM myricetin enhances the sensitivity of the cells towards vincristine toxicity to IC50 values of 7.6+/-0.5 and 5.8+/-0.5 microM, respectively. The increase of sensitivity represents a reversal of the resistance towards vincristine as a result of MRP1 and MRP2 inhibition. Thus, the present study demonstrates the ability of the flavonoid myricetin to modulate MRP1 and MRP2 mediated resistance to the anticancer drug vincristine in transfected cells, indicating that flavonoids might be a valuable adjunct to chemotherapy to block MRP mediated resistance.

Urease inhibitory profile of extracts and chemical constituents of Pistacia atlantica ssp. cabulica Stocks.

PubMed

Uddin, Ghias; Ismail; Rauf, Abdur; Raza, Muslim; Khan, Haroon; Nasruddin; Khan, Majid; Farooq, Umar; Khan, Ajmal; Arifullah

2016-06-01

The current study was designed to evaluate the urease inhibitory profile of extract and fractions of Pistacia atlantica ssp. cabulica Stocks followed by bioactivity-guided isolated compounds. The crude extract was found significantly active with urease inhibitor (95.40% at 0.2 mg/mL) with IC50 values of 32.0 ± 0.28 μg/mL. Upon fractionation, ethyl acetate fraction displayed 100% urease inhibition with IC50 values of 19.9 ± 0.51 μg/mL at 0.2 mg/mL. However, n-hexane and chloroform fractions exhibited insignificant urease inhibition. Similarly, the isolated compound, transilitin (1) and dihydro luteolin (2) demonstrated marked urease attenuation with 95 and 98% respectively, at 0.15 mg/mL. Both the isolated compounds showed marked potency with IC50 values of 8.54 ± 0.54 and 9.58 ± 2.22 μg/mL, respectively. In short, both the extract and fractions and isolated compounds showed marked urease inhibition and thus a useful natural source of urease inhibition.

Unsaponifiable matter from oil of green coffee beans: cosmetic properties and safety evaluation.

PubMed

Wagemaker, Tais A L; Campos, Patrícia M B G Maia; Fernandes, Ana Sofia; Rijo, Patrícia; Nicolai, Marisa; Roberto, Amílcar; Rosado, Catarina; Reis, Catarina; Rodrigues, Luis M; Carvalho, Cássia Regina Limonta; Maia, Nilson Borlina; Guerreiro Filho, Oliveiro

2016-10-01

Unsaponifiable matter (UM), a fraction of green coffee oil (GCO) contains functional compounds responsible for desirable cosmetic properties such as UV-B absorption. To evaluate oil content and sun protection factor (SPF) variability of the two most important species of coffee and, the toxic and cytotoxic effects, as well as cosmetic properties, including antioxidant and antimicrobial activities of UM obtained from green Coffea arabica seed oil. The safety and potential cosmetic properties of UM extracted from green coffee oil (GCO) were evaluated by the brine shrimp viability and the MTT cytotoxicity assays. The SPF and antioxidant activity were evaluated using in vitro methods. Relevant cytotoxicity was found against keratinocytes for concentrations ≥25 µg/mL and in the brine shrimp assay (LC50 24 µg/mL). Antimicrobial and antioxidant activities (IC50 1448 µg/mL) were low in UM but SPF was 10 times higher than in GCO. UM is a novel potential UV-B absorbent but its use as a cosmetic ingredient should be better considered due to the considerable cytotoxicity shown in the experimental conditions described.

A new protoberberine alkaloid from Meconopsis simplicifolia (D. Don) Walpers with potent antimalarial activity against a multidrug resistant Plasmodium falciparum strain.

PubMed

Wangchuk, Phurpa; Phurpa, Wangchuk; Keller, Paul A; Pyne, Stephen G; Lie, Wilford; Willis, Anthony C; Rattanajak, Roonglawan; Kamchonwongpaisan, Sumalee

2013-12-12

The aerial components of Meconopsis simplicifolia (D. Don) Walpers are indicated in Bhutanese traditional medicine for treating malaria, coughs and colds, and the infections of the liver, lung and blood. This study is to validate the ethnopharmacological uses of this plant and also identify potent antimalarial drug leads through bioassays of its crude extracts and phytochemical constituents. Meconopsis simplicifolia (D. Don) Walpers was collected from Bhutan and its crude MeOH extract was subjected to acid-base fractionation. Through repeated extractions, separations and spectroscopic analysis, the alkaloids obtained were identified and tested for their antimalarial and cytotoxicity activities. Phytochemical studies resulted in the isolation of one new protoberberine type alkaloid which we named as simplicifolianine and five known alkaloids: protopine, norsanguinarine, dihydrosanguinarine, 6-methoxydihydrosanguinarine and oxysanguinarine. Among the five of the alkaloids tested, simplicifolianine showed the most potent antiplasmodial activities against the Plasmodium falciparum strains, TM4/8.2 (chloroquine-antifolate sensitive strain) and K1CB1 (multidrug resistant strain) with IC50 values of 0.78 μg/mL and 1.29 μg/mL, respectively. The compounds tested did not show any significant cytotoxicity activities against human oral carcinoma KB cells and normal Vero cells of African kidney epithelial cells. This study validated the traditional uses of the plant for the treatment of malaria and identified a new alkaloid, simplicifolianine as a potential antimalarial drug lead. © 2013 Published by Elsevier Ireland Ltd.

Biological evaluation and molecular docking of baicalin and scutellarin as Helicobacter pylori urease inhibitors.

PubMed

Yu, Xiao-Dan; Zheng, Rong-Bo; Xie, Jian-Hui; Su, Ji-Yan; Huang, Xiao-Qi; Wang, Yong-Hong; Zheng, Yi-Feng; Mo, Zhi-Zhun; Wu, Xiao-Li; Wu, Dian-Wei; Liang, Ye-er; Zeng, Hui-Fang; Su, Zi-Ren; Huang, Ping

2015-03-13

Baicalin and scutellarin are the principal bioactive components of Scutellaria baicalensis Georgi which has extensively been incorporated into heat-clearing and detoxification formulas for the treatment of Helicobacter pylori-related gastrointestinal disorders in traditional Chinese medicine. However, the mechanism of action remained to be defined. To explore the inhibitory effect, kinetics and mechanism of Helicobacter pylori urease (the vital pathogenetic factor for Helicobacter pylori infection) inhibition by baicalin and scutellarin, for their therapeutic potential. The ammonia formations, indicator of urease activity, were examined using modified spectrophotometric Berthelot (phenol-hypochlorite) method. The inhibitory effect of baicalin and scutellarin was characterized with IC50 values, compared to acetohydroxamic acid (AHA), a well known Helicobacter pylori urease inhibitor. Lineweaver-Burk and Dixon plots for the Helicobacter pylori urease inhibition of baicalin and scutellarin was constructed from the kinetic data. SH-blocking reagents and competitive active site Ni(2+) binding inhibitors were employed for mechanism study. Molecular docking technique was used to provide some information on binding conformations as well as confirm the inhibition mode. Moreover, cytotoxicity experiment using Gastric Epithelial Cells (GES-1) was evaluated. Baicalin and scutellarin effectively suppressed Helicobacter pylori urease in dose-dependent and time-independent manner with IC50 of 0.82±0.07 mM and 0.47±0.04 mM, respectively, compared to AHA (IC50=0.14±0.05 mM). Structure-activity relationship disclosed 4'-hydroxyl gave flavones an advantage to binding with Helicobacter pylori urease. Kinetic analysis revealed that the types of inhibition were non-competitive and reversible with inhibition constant Ki of 0.14±0.01 mM and 0.18±0.02 mM for baicalin and scutellarin, respectively. The mechanism of urease inhibition was considered to be blockage of the SH groups of Helicobacter pylori urease, since thiol reagents (L,D-dithiothreitol, L-cysteine and glutathione) abolished the inhibitory action and competitive active site Ni(2+) binding inhibitors (boric acid and sodium fluoride) carried invalid effect. Molecular docking study further supported the structure-activity analysis and indicated that baicalin and scutellarin interacted with the key residues Cys321 located on the mobile flap through S-H·π interaction, but did not interact with active site Ni(2+). Moreover, Baicalin (at 0.59-1.05 mM concentrations) and scutellarin (at 0.23-0.71 mM concentrations) did not exhibit significant cytotoxicity to GES-1. Baicalin and scutellarin were non-competitive inhibitors targeting sulfhydryl groups especially Cys321 around the active site of Helicobacter pylori urease, representing potential to be good candidate for future research as urease inhibitor for treatment of Helicobacter pylori infection. Furthermore, our work gave additional scientific support to the use of Scutellaria baicalensis in traditional Chinese medicine (TCM) to treat gastrointestinal disorders. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Unambiguous Identification of β-Tubulin as the Direct Cellular Target Responsible for the Cytotoxicity of Chalcone by Photoaffinity Labeling.

PubMed

Zhou, Bo; Yu, Xingxin; Zhuang, Chunlin; Villalta, Peter; Lin, Yong; Lu, Junxuan; Xing, Chengguo

2016-07-05

Chalcone is a simple and potentially privileged structure in medicinal chemistry with a diverse repertoire of biological activities, among which cytotoxicity is of particular interest. The sharp structure-activity relationship (SAR) for chalcone's cytotoxicity suggests structure-specific target interactions. Despite the numerous putative targets proposed, evidence for direct target interactions in cells is unavailable. In this study, guided by the sharp cytotoxic SAR, we developed a cytotoxic chalcone-based photoaffinity labeling (PAL) probe, (E)-3-(3-azidophenyl)-1-[3,5-dimethoxy-4-(prop-2-yn-1-yloxy)phenyl]-2-methylprop-2-en-1-one (C95; IC50 : 0.38±0.01 μm), along with two structurally similar non-cytotoxic probes. These probes were used to search for the direct cellular target responsible for chalcone's cytotoxicity through intact cell-based PAL experiments, in which β-tubulin was identified to specifically interact with the cytotoxic probe (i.e., C95) but not the non-cytotoxic probes. A set of phenotypical and biochemical assays further reinforced β-tubulin as the cytotoxic target of chalcones. Peptide mass quantitation by mass spectrometric analysis revealed one peptide potentially labeled by C95, providing information on chalcone's binding site on β-tubulin. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Quantum Dot Nanotoxicity Investigations Using Human Lung Cells and TOXOR Electrochemical Enzyme Assay Methodology.

PubMed

O'Hara, Tony; Seddon, Brian; O'Connor, Andrew; McClean, Siobhán; Singh, Baljit; Iwuoha, Emmanuel; Fuku, Xolile; Dempsey, Eithne

2017-01-27

Recent studies have suggested that certain nanomaterials can interfere with optically based cytotoxicity assays resulting in underestimations of nanomaterial toxicity. As a result there has been growing interest in the use of whole cell electrochemical biosensors for nanotoxicity applications. Herein we report application of an electrochemical cytotoxicity assay developed in house (TOXOR) in the evaluation of toxic effects of mercaptosuccinic acid capped cadmium telluride quantum dots (MSA capped CdTe QDs), toward mammalian cells. MSA capped CdTe QDs were synthesized, characterized, and their cytotoxicity toward A549 human lung epithelial cells investigated. The internalization of QDs within cells was scrutinized via confocal microscopy. The cytotoxicity assay is based on the measurement of changes in cellular enzyme acid phosphatase upon 24 h exposure to QDs. Acid phosphatase catalyzes dephosphorylation of 2-naphthyl phosphate to 2-naphthol (determined by chronocoulometry) and is indicative of metabolic activity in cells. The 24 h IC50 (concentration resulting in 50% reduction in acid phosphatase activity) value for MSA capped CdTe QDs was found to be 118 ± 49 μg/mL using the TOXOR assay and was in agreement with the MTT assay (157 ± 31 μg/mL). Potential uses of this electrochemical assay include the screening of nanomaterials, environmental toxins, in addition to applications in the pharmaceutical, food, and health sectors.

Design, Synthesis and Biological Evaluation of4-(Imidazolylmethyl)-2-(4-methylsulfonyl phenyl)-Quinoline Derivatives as Selective COX-2 Inhibitors and In-vitro Anti-breast Cancer Agents

PubMed Central

Ghodsi, Razieh; Azizi, Ebrahim; Zarghi, Afshin

2016-01-01

A new group of 4-(Imidazolylmethyl)quinoline derivatives possessing a methylsulfonyl COX-2 pharmacophore at the para position of the C-2 phenyl ring were designed and synthesized as selective COX-2 inhibitors and in-vitroanti breast cancer agents. In-vitro COX-1 and COX-2 inhibition studies showed that all the compounds were potent and selective inhibitors of the COX-2 isozyme with IC50 values in the potent range 0.063-0.090 µM, and COX-2 selectivity indexes in the 179.9 to 547.6 range. Molecular modeling studies indicated that the methylsulfonyl substituent can be inserted into the secondary pocket of COX-2 active site for interactions with Arg513. Cytotoxicity of quinolines 9a-e against human breast cancer MCF-7 and T47D cell lines were also evaluated. All the compounds 9a-e were more cytotoxic against MCF-7 cells in comparison with those of T47D which express aromatase mRNA less than MCF-7 cells.The data showed that the increase of lipophilic properties of substituents on the C-7 and C-8 quinoline ring increased their cytotoxicity on MCF-7cells andCOX-2 inhibitory activity. Among the quinolines 9a-e, 4-((1H-Imidazol-1-yl)methyl) 7,8,9,10-tetrahydro-2-(4-methylsulfonylphenyl)-benzo[h]quinoline (9d)was identified as the most potent andselective COX-2inhibitor as well as the most cytotoxic agent against MCF-7 cells. PMID:27610157

Biosynthesis of Silver Nanoparticles from Protium serratum and Investigation of their Potential Impacts on Food Safety and Control

PubMed Central

Mohanta, Yugal K.; Panda, Sujogya K.; Bastia, Akshaya K.; Mohanta, Tapan K.

2017-01-01

Silver nanoparticles play an integral part in the evolution of new antimicrobials against the broad ranges of pathogenic microorganisms. Recently, biological synthesis of metal nanoparticles using plant extracts has been successfully consummated. In the present study, the biosynthesis of silver nanoparticles (AgNPs) was conducted using the leaf extract of plant Protium serratum, having novel ethnomedicinal. The synthesized AgNPs were characterized using UV-Visible spectroscopy, dynamic light scattering spectroscopy (DLS), Fourier transform infrared spectroscopy (FTIR), and scanning electron microscopy. The DLS study revealed the surface charge of the resulted nanoparticles that was highly negative, i.e., −25.0 ± 7.84 mV and the size was 74.56 ± 0.46 nm. The phytochemical and FTIR analysis confirmed the role of water-soluble phyto-compounds for the reduction of silver ions to silver nanoparticles. The potential antibacterial activity of AgNPs was studied against the food borne pathogens viz. Pseudomonas aeruginosa (IC50 = 74.26 ± 0.14 μg/ml), Escherichia coli (IC50 = 84.28 ± 0.36 μg/ml), Bacillus subtilis (IC50 = 94.43 ± 0.4236 μg/ml). The in vitro antioxidant potential of AgNPs was evaluated using 1, 1-diphenyl-2-picryl-hydrazil (IC50 = 6.78 ± 0.15 μg/ml) and hydroxyl radical assay (IC50 = 89.58 ± 1.15 μg/ml). In addition, the cytotoxicity of AgNPs was performed against fibroblast cell line L-929 to evaluate their biocompatibility. The overall results of the present investigation displayed the potential use of P. serratum leaf extract as a good bio-resource for the biosynthesis of AgNPs and their implementation in diverse applications, specifically as antibacterial agent in food packaging and preservation to combat against various food borne pathogenic bacteria along with its pharmaceutical and biomedical applications. PMID:28458659

Biological Evaluation of Azomethine-dihydroquinazolinone Conjugates as Cancer and Cholinesterase Inhibitors.

PubMed

Iqbal, Jamshed; Saeed, Aamer; Shah, Syed J A; al-Rashida, Mariya; Shams-ul Mahmood

2016-01-01

In an attempt to discover novel anti-cancer agents and potent cholinesterase inhibitors, 11 azomethine-dihydroquinazolinone conjugates were evaluated against lung carcinoma cells and cholinesterases. Most of the compounds exhibited significant cytotoxicity at low micromolar concentrations and were less toxic to normal cells. After 24 h incubation period, 2i showed maximum cytotoxicity. The 4-bromine substituted compounds showed higher acetylcholinesterase (AChE) inhibitory activity than other screened compounds. The most active compound 2c, among the series, had an IC50 value 209.8 µM against AChE. The tested compounds showed less inhibition against butyrylcholinesterase. Molecular docking studies were performed in order to investigate the plausible binding modes of synthesized compounds. The compounds can be further optimized to treat cancer and Alzheimer's disease. These derivatives may open new pathways for introducing new therapies for curing cancer and senile dementia.

In vitro ovicidal and larvicidal activities of some saponins and flavonoids against parasitic nematodes of goats.

PubMed

Santos, Acidália Carine Vieira; Santos, Francianne Oliveira; Lima, Hélimar Gonçalves; Silva, Gisele Dias Da; Uzêda, Rosangela Soares; Dias, Êuder Reis; Branco, Alexsandro; Cardoso, Klauber Viana; David, Jorge Mauricio; Botura, Mariana Borges; Costa, Silvia Lima; Batatinha, Maria José Moreira

2018-05-21

This study assessed the anthelmintic activity of plant-derived compounds against gastrointestinal nematodes of goats using the egg hatch and larval motility assays. The compounds tested were saponins (digitonin and aescin) and their respective sapogenins (aglycones), hecogenin acetate and flavonoids (catechin, hesperidin, isocordoin and a mixture of isocordoin and cordoin). Additionally, cytotoxicity of active substances was analysed on Vero cell through 3-4,5-dimethylthiazol-2-yl,2,5diphenyltetrazolium bromide (MTT) and propidium iodide (PI) tests. Significant reduction on the egg hatching (P 90%). Nevertheless, higher cytotoxicity was observed in the MTT assay, with IC50 of 0.20 mg mL-1 (aescin) and 0.0074 mg mL-1 (digitonin). Aescin and digitonin have a pronounced in vitro anthelmintic effect and the glycone portion of these saponins plays an important role in this activity.

Cytotoxic and antimicrobial activity of selected Cameroonian edible plants

PubMed Central

2013-01-01

Background In Cameroon, the use of edible plants is an integral part of dietary behavior. However, evidence of the antimicrobial as well as the cytotoxic effects of many of them has not been investigated. In the present study, aqueous and methanol extracts from barks, seeds, leaves and roots of three Cameroonian edible plants namely Garcina lucida, Fagara heitzii and Hymenocardia lyrata were evaluated for their cytotoxic and antimicrobial activities. Methods Antibacterial and antifungal activities were assessed by the broth micro-dilution method meanwhile the cytotoxicity was performed using sulphorhodamine B assay (SRB) against the human leukemia THP-1, the alveolar epithelial A549, prostate cancer PC-3, breast adenocarcinoma MCF-7 and cervical cancer HeLa cell lines. Results The minimum inhibitory concentration (MIC) values of the seven tested extracts ranged from 62.5 μg/ml to 1000 μg/ml. The methanol (MeOH) extract from the roots of H. lyrata showed the highest antibacterial activity against Gram-positive bacteria S. aureus and S. epidermitis. The best antifungal activity was obtained with the MeOH extract from the leaves of G. lucida against C. tropicalis (MIC value of 62.5 μg/ml). The in vitro antiproliferative activity revealed that, extract from the bark of F. heitzii and extract from H. lyrata roots had significant cytotoxic activity on THP-1 (IC50 8.4 μg/ml) and PC-3 (IC50 9.5 μg/ml) respectively. Conclusion Our findings suggest that Cameroonian spices herein studied could be potentially useful for the development of therapeutic agents against bacterial infections as well as for prostate and leukemia cancer. PMID:23565827

Selectivity of Pinus sylvestris extract and essential oil to estrogen-insensitive breast cancer cells Pinus sylvestris against cancer cells

PubMed Central

Hoai, Nguyen Thi; Duc, Ho Viet; Thao, Do Thi; Orav, Anne; Raal, Ain

2015-01-01

Background: So far, the anticancer action of pine tree extracts has mainly been shown for the species distributed widely around the Asian countries. Objective: Therefore, this study was performed to examine the potential cytotoxicity of Scots pine (Pinus sylvestris L.) native also to the European region and growing widely in Estonia. Materials and Methods: The cytotoxic activity of methanol extract and essential oil of Scots pine needles was determined by sulforhodamine B assay in different human cancer cell lines. Results: This needle extract was found to suppress the viability of several human cancer cell lines showing some selectivity to estrogen receptor negative breast cancer cells, MDA-MB-231(half maximal inhibitory concentration [IC50] 35 μg/ml) in comparison with estrogen receptor-positive breast cancer cells, MCF-7 (IC50 86 μg/ml). It is the strongest cytotoxic effect at all measured, thus far for the needles and leaves extracts derived from various pine species, and is also the first study comparing the anticancer effects of pine tree extracts on molecularly different human breast cancer cells. The essential oil showed the stronger cytotoxic effect to both negative and positive breast cancer cell lines (both IC50 29 μg/ml) than pine extract (IC50 42 and 80 μg/ml, respectively). Conclusion: The data from this report indicate that Scots pine needles extract and essential oil exhibits some potential as chemopreventive or chemotherapeutic agent for mammary tumors unresponsive to endocrine treatment. PMID:26664017

Anti-proliferative effect of the essential oil of Cymbopogon citratus (DC) Stapf (lemongrass) on intracellular amastigotes, bloodstream trypomastigotes and culture epimastigotes of Trypanosoma cruzi (Protozoa: Kinetoplastida).

PubMed

Santoro, G F; Cardoso, M G; Guimarães, L G L; Freire, J M; Soares, M J

2007-10-01

This study analyses the anti-proliferative effect of lemongrass essential oil and its main constituent (citral) on all 3 evolutive forms of Trypanosoma cruzi. Steam distillation was used to obtain lemongrass essential oil, with chemical composition determined by gas chromatography (GC) and GC coupled to mass spectrometry (GC-MS). The IC50/24 h (concentration that reduced the parasite population by 50%) of the oil and of citral upon T. cruzi was determined by cell counting in a Neubauer chamber, while morphological alterations were visualized by scanning and transmission electron microscopy. Treatment with the essential oil resulted in epimastigote growth inhibition with IC50=126.5 microg/ml, while the IC50 for trypomastigote lysis was 15.5 microg/ml. The IC50/48 h for the Association Index (% macrophage infection x number of amastigotes per cell) was 5.1 microg/ml, with a strong inhibition of intracellular amastigote proliferation. Ultrastructural analysis demonstrated cytoplasmic and nuclear extraction, while the plasma membrane remained morphologically preserved. Our data show that lemongrass essential oil is effective against T. cruzi trypomastigotes and amastigotes, and that its main component, citral, is responsible for the trypanocidal activity. These results indicate that essential oils can be promising anti-parasitic agents, opening perspectives to the discovery of more effective drugs of vegetal origin for treatment of parasitic diseases. However, additional cytotoxicity experiments on different cell lines and tests in a T. cruzi-mouse model are needed to support these data.

Design and evaluation of clickable gelatin-oleic nanoparticles using fattigation-platform for cancer therapy.

PubMed

Meghani, Nilesh M; Amin, Hardik H; Park, Chulhun; Park, Jun-Bom; Cui, Jing-Hao; Cao, Qing-Ri; Lee, Beom-Jin

2018-07-10

The principles of bioorthogonal click chemistry and metabolic glycoengineering were applied to produce targeted anti-cancer drug delivery via fattigation-platform-based gelatin-oleic nanoparticles. A sialic acid precursor (Ac 4 ManNAz) was introduced to the cell surface. Gelatin and oleic acid were conjugated by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride/N-hydroxysuccinimide (EDC/NHS) chemistry with the subsequent covalent attachment of dibenzocyclooctyne (DBCO) in a click reaction on the cell surface. The physicochemical properties, drug release, in vitro cytotoxicity, and cellular uptake of DBCO-conjugated gelatin oleic nanoparticles (GON-DBCO; particle size, ∼240 nm; zeta potential, 6 mV) were evaluated. Doxorubicin (DOX) was used as a model drug and compared with the reference product, Caelyx®. A549 and MCF-7 cell lines were used for the in vitro studies. GON-DBCO showed high DOX loading and encapsulation efficiencies. In A549 cells, the IC50 value for GON-DBCO-DOX (1.29 µg/ml) was six times lower than that of Caelyx® (10.54 µg/ml); in MCF-7 cells, the IC50 values were 1.78 µg/ml and 2.84 µg/ml, respectively. Confocal microscopy confirmed the click reaction between GON-DBCO and Ac4ManNAz on the cell surface. Flow cytometry data revealed that the intracellular uptake of GON-DBCO-DOX was approximately two times greater than that of GON-DOX and Caelyx®. Thus, the newly designed GON-DBCO-DOX provided a safe and efficient drug delivery system to actively target the anticancer agents. Copyright © 2018 Elsevier B.V. All rights reserved.

3-Coumaranone derivatives as inhibitors of monoamine oxidase

PubMed Central

Van Dyk, Adriaan S; Petzer, Jacobus P; Petzer, Anél; Legoabe, Lesetja J

2015-01-01

The present study examines the monoamine oxidase (MAO) inhibitory properties of a series of 20 3-coumaranone [benzofuran-3(2H)-one] derivatives. The 3-coumaranone derivatives are structurally related to series of α-tetralone and 1-indanone derivatives, which have recently been shown to potently inhibit MAO, with selectivity for MAO-B (in preference to the MAO-A isoform). 3-Coumaranones are similarly found to selectively inhibit human MAO-B with half-maximal inhibitory concentration (IC50) values of 0.004–1.05 µM. Nine compounds exhibited IC50<0.05 µM for the inhibition of MAO-B. For the inhibition of human MAO-A, IC50 values ranged from 0.586 to >100 µM, with only one compound possessing an IC50<1 µM. For selected 3-coumaranone derivatives, it is established that MAO-A and MAO-B inhibition are reversible since dialysis of enzyme–inhibitor mixtures almost completely restores enzyme activity. On the basis of the selectivity profiles and potent action, it may be concluded that the 3-coumaranone derivatives are suitable leads for the development of selective MAO-B inhibitors as potential treatment for disorders such as Parkinson’s disease and Alzheimer’s disease. PMID:26491258

New efficient artemisinin derived agents against human leukemia cells, human cytomegalovirus and Plasmodium falciparum: 2nd generation 1,2,4-trioxane-ferrocene hybrids.

PubMed

Reiter, Christoph; Fröhlich, Tony; Zeino, Maen; Marschall, Manfred; Bahsi, Hanife; Leidenberger, Maria; Friedrich, Oliver; Kappes, Barbara; Hampel, Frank; Efferth, Thomas; Tsogoeva, Svetlana B

2015-06-05

In our ongoing search for highly active hybrid molecules exceeding their parent compounds in anticancer, antimalaria as well as antiviral activity and being an alternative to the standard drugs, we present the synthesis and biological investigations of 2nd generation 1,2,4-trioxane-ferrocene hybrids. In vitro tests against the CCRF-CEM leukemia cell line revealed di-1,2,4-trioxane-ferrocene hybrid 7 as the most active compound (IC50 of 0.01 μM). Regarding the activity against the multidrug resistant subline CEM/ADR5000, 1,2,4-trioxane-ferrocene hybrid 5 showed a remarkable activity (IC50 of 0.53 μM). Contrary to the antimalaria activity of hybrids 4-8 against Plasmodium falciparum 3D7 strain with slightly higher IC50 values (between 7.2 and 30.2 nM) than that of their parent compound DHA, hybrids 5-7 possessed very promising activity (IC50 values lower than 0.5 μM) against human cytomegalovirus (HCMV). The application of 1,2,4-trioxane-ferrocene hybrids against HCMV is unprecedented and demonstrated here for the first time. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

A new report of Nocardiopsis valliformis strain OT1 from alkaline Lonar crater of India and its use in synthesis of silver nanoparticles with special reference to evaluation of antibacterial activity and cytotoxicity.

PubMed

Rathod, Dnyaneshwar; Golinska, Patrycja; Wypij, Magdalena; Dahm, Hanna; Rai, Mahendra

2016-10-01

The authors report the biological synthesis of silver nanoparticles (AgNPs) by alkaliphilic actinobacterium Nocardiopsis valliformis OT1 strain isolated for the first time from Lonar crater, India. The primary detection of silver NPs formation was made by colour change from colourless to dark brown and confirmed by UV-Vis spectrum of AgNPs at 423 nm, specific for AgNPs. Further, AgNPs were characterized by nanoparticle tracking analysis, Zeta sizer, Fourier transform infrared spectroscopy (FTIR) and transmission electron microscopy (TEM) analyses. FTIR analysis showed the presence of proteins as capping agent. TEM analysis revealed the formation of spherical and polydispersed AgNPs within the size range of 5-50 nm. The antimicrobial activity of silver nanoparticles against Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Staphylococcus aureus and Bacillus subtilis was evaluated. The AgNPs showed the maximum antibacterial activity against B. subtilis (Gram positive) and the minimum against E. coli (Gram negative). The minimal inhibitory concentration values of AgNPs for the tested bacteria were found to be in the range of 30-80 µg/mL. The AgNPs demonstrated higher antibacterial activity against all the bacteria tested as compared with the commercially available antibiotics. The cytotoxicity of biosynthesized AgNPs against in vitro human cervical cancer cell line (HeLa) demonstrated a dose-response activity. The IC50 value was found to be 100 µg/mL of AgNPs against cancer HeLa cell line.

Synthesis and cytotoxic activities of novel 4-methoxy-substituted and 5-methyl-substituted (3′S,4′S)-(−)-cis-khellactone derivatives that induce apoptosis via the intrinsic pathway

PubMed Central

Chen, Jingrun; Liu, Junjie; Cui, Dongxiao; Yan, Chaoqun; Meng, Liqiang; Sun, Liqian; Ban, Shurong; Ge, Rui; Liang, Taigang; Li, Qingshan

2017-01-01

This study deals with the design and synthesis of a series of novel 4-methoxy-substituted and 5-methyl-substituted (3′S,4′S)-(−)-cis-khellactones. The newly synthesized compounds were characterized by 1H nuclear magnetic resonance (NMR), 13C-NMR, mass spectrometry, and elemental analysis. All the derivatives were subjected to in vitro cytotoxicity screening against HEPG-2 (human liver carcinoma), SGC-7901 (human gastric carcinoma), and LS174T (human colon carcinoma), by using the MTT assay. The results revealed that several of the 4-methoxy-substituted compounds exhibited potent cytotoxicity. Among these, compound 12e showed the highest activity against cancer cells which 50% inhibitory concentration (IC50) values were in the range of 6.1–9.2 μM with low toxicity on normal human hepatocyte. Preliminary investigation of possible mechanisms of action of compound 12e against HEPG-2 cells indicated possible induction of apoptosis, as determined by morphological observations and Annexin V/propidium iodide (PI) double staining, in addition to apparent dissipation of mitochondrial membrane potential (MMP), as measured by 5,5′,6,6′-tetrachloro-1,1′,3,3′-tetraethyl-imidacarbocyanine iodide (JC-1) staining in combination with the activation of caspase-9 and caspase-3 by Western blot analysis. Overall, the data suggest that compound 12e may be a promising potential anti-cancer agent that could act primarily by inducing apoptosis through the mitochondria-mediated intrinsic pathway in human hepatoma cells. PMID:28694689

Neurite outgrowth stimulatory effects of culinary-medicinal mushrooms and their toxicity assessment using differentiating Neuro-2a and embryonic fibroblast BALB/3T3

PubMed Central

2013-01-01

Background Mushrooms are not only regarded as gourmet cuisine but also as therapeutic agent to promote cognition health. However, little toxicological information is available regarding their safety. Therefore, the aim of this study was to screen selected ethno-pharmacologically important mushrooms for stimulatory effects on neurite outgrowth and to test for any cytotoxicity. Methods The stimulatory effect of mushrooms on neurite outgrowth was assessed in differentiating mouse neuroblastoma (N2a) cells. Neurite length was measured using Image-Pro Insight processor system. Neuritogenesis activity was further validated by fluorescence immunocytochemical staining of neurofilaments. In vitro cytotoxicity was investigated by using mouse embryonic fibroblast (BALB/3T3) and N2a cells for any embryo- and neuro-toxic effects; respectively. Results Aqueous extracts of Ganoderma lucidum, Lignosus rhinocerotis, Pleurotus giganteus and Grifola frondosa; as well as an ethanol extract of Cordyceps militaris significantly (p < 0.05) promoted the neurite outgrowth in N2a cells by 38.4 ± 4.2%, 38.1 ± 2.6%, 33.4 ± 4.6%, 33.7 ± 1.5%, and 35.8 ± 3.4%; respectively. The IC50 values obtained from tetrazolium (MTT), neutral red uptake (NRU) and lactate dehydrogenase (LDH) release assays showed no toxic effects following 24 h exposure of N2a and 3T3 cells to mushroom extracts. Conclusion Our results indicate that G. lucidum, L. rhinocerotis, P. giganteus, G. frondosa and C. militaris may be developed as safe and healthy dietary supplements for brain and cognitive health. PMID:24119256

In vitro and in vivo characterization of the anticancer activity of Thai stingless bee (Tetragonula laeviceps) cerumen

PubMed Central

Nugitrangson, Pongvit; Puthong, Songchan; Iempridee, Tawin; Pimtong, Wittaya; Chanchao, Chanpen

2015-01-01

Tetragonula laeviceps cerumen was sequentially extracted with 80% (v/v) methanol, dichloromethane, and hexane and also in the reverse order. By the MTT assay and the respective 50% inhibition concentration value, the most active fraction was further purified to apparent homogeneity by bioassay-guided silica gel column chromatography. α-Mangostin was identified by high-resolution electrospray ionization mass spectrometry and nuclear magnetic resonance analyses. It had a potent cytotoxicity against the BT474, Chago, Hep-G2, KATO-III, and SW620 cell lines (IC50 values of 1.22 ± 0.03, 2.25 ± 0.20, 0.94 ± 0.01, 0.88 ± 0.16, and 1.50 ± 0.39 µmol/L, respectively). The in vitro cytotoxicity of α-mangostin against the five human cancer cell lines and primary fibroblasts was further characterized by real-time impedance-based analysis. Interestingly, α-mangostin was more cytotoxic against the cancer-derived cell lines than against the primary fibroblasts. Later, the migration assay was performed by continuously measuring the attachment of cells to the plate electrodes at the bottom of the transwell membrane. The combined caspase-3 and -7 activities were assayed by the Caspase-Glo® 3/7 kit. It showed that the cytotoxic mechanism involved caspase-independent apoptosis, while at low (non-toxic) concentrations α-mangostin did not significantly alter cell migration. Furthermore, the in vivo cytotoxicity and angiogenesis were determined by alkaline phosphatase staining in zebrafish embryos along with monitoring changes in the transcript expression level of two genes involved in angiogenesis (vegfaa and vegfr2) by quantitative real-time reverse transcriptase- polymerase chain reaction. It was found that the in vivo cytotoxicity of α-mangostin against zebrafish embryos had a 50% lethal concentration of 9.4 µM, but no anti-angiogenic properties were observed in zebrafish embryos at 9 and 12 µM even though it downregulated the expression of vegfaa and vegfr2 transcripts. Thus, α-mangostin is a major active compound with a potential anticancer activity in T. laeviceps cerumen in Thailand. PMID:26290139

Inhibition of the recombinant cattle tick Rhipicephalus (Boophilus) annulatus glutathione S-transferase.

PubMed

Guneidy, Rasha A; Shahein, Yasser E; Abouelella, Amira M K; Zaki, Eman R; Hamed, Ragaa R

2014-09-01

Rhipicephalus (Boophilus) annulatus is a bloodsucking ectoparasite that causes severe production losses in the cattle industry. This study aims to evaluate the in vitro effects of tannic acid, hematin (GST inhibitors) and different plant extracts (rich in tannic acid) on the activity of the recombinant glutathione S-transferase enzyme of the Egyptian cattle tick R. annulatus (rRaGST), in order to confirm their ability to inhibit the parasitic essential detoxification enzyme glutathione S-transferase. Extraction with 70% ethanol of Hibiscus cannabinus (kenaf flowers), Punica granatum (red and white pomegranate peel), Musa acuminata (banana peel) (Musaceae), Medicago sativa (alfalfa seeds), Tamarindus indicus (seed) and Cuminum cyminum (cumin seed) were used to assess: (i) inhibitory capacities of rRaGST and (ii) their phenolic and flavonoid contents. Ethanol extraction of red pomegranate peel contained the highest content of phenolic compounds (29.95mg gallic acid/g dry tissue) compared to the other studied plant extracts. The highest inhibition activities of rRaGST were obtained with kenaf and red pomegranate peel (P. granatum) extracts with IC50 values of 0.123 and 0.136mg dry tissue/ml, respectively. Tannic acid was the more effective inhibitor of rRaGST with an IC50 value equal to 4.57μM compared to delphinidine-HCl (IC50=14.9±3.1μM). Gossypol had a weak inhibitory effect (IC50=43.7μM), and caffeic acid had almost no effect on tick GST activity. The IC50 values qualify ethacrynic acid as a potent inhibitor of rRaGST activity (IC50=0.034μM). Cibacron blue and hematin showed a considerable inhibition effect on rRaGST activity, and their IC50 values were 0.13μM and 7.5μM, respectively. The activity of rRaGST was highest for CDNB (30.2μmol/min/mg protein). The enzyme had also a peroxidatic activity (the specific activity equals 26.5μmol/min/mg protein). Both tannic acid and hematin inhibited rRaGST activity non-competitively with respect to GSH and competitively with respect to CDNB. While red pomegranate extracts inhibited rRaGST activity competitively with respect to GSH, uncompetitive inhibition was observed with respect to CDNB. Copyright © 2014 Elsevier GmbH. All rights reserved.

In vitro anti-influenza viral activities of constituents from Caesalpinia sappan.

PubMed

Liu, Ai-Lin; Shu, Shi-Hui; Qin, Hai-Lin; Lee, Simon Ming Yuen; Wang, Yi-Tao; Du, Guan-Hua

2009-03-01

Six constituents with neuraminidase (NA) inhibitory activity, namely brazilein, brazilin, protosappanin A, 3-deoxysappanchalcone, sappanchalcone and rhamnetin, were isolated from the hearthwood of Caesalpinia sappan (Leguminosae). Their in vitro anti-influenza virus activities were evaluated with the cytopathic effect (CPE) reduction method. The results showed that 3-deoxysappanchalcone and sappanchalcone exhibited the highest activity against influenza virus (H3N2) with IC50 values of 1.06 and 2.06 microg/mL, respectively, in comparison to the positive control oseltamivir acid and ribavirin with IC50 values of 0.065 and 9.17 microg/mL, respectively.

Improved Photodynamic Efficacy of Zn(II) Phthalocyanines via Glycerol Substitution

PubMed Central

Chin, Yunni; Lim, Siang Hui; Zorlu, Yunus; Ahsen, Vefa; Kiew, Lik Voon; Chung, Lip Yong; Dumoulin, Fabienne; Lee, Hong Boon

2014-01-01

Phthalocyanines are excellent photosensitizers for photodynamic therapy as they have strong absorbance in the near infra-red region which is most relevant for in vivo activation in deeper tissular regions. However, most phthalocyanines present two major challenges, ie, a strong tendency to aggregate and low water-solubility, limiting their effective usage clinically. In the present study, we evaluated the potential enhancement capability of glycerol substitution on the photodynamic properties of zinc (II) phthalocyanines (ZnPc). Three glycerol substituted ZnPc, 1–3, (tetra peripherally, tetra non-peripherally and mono iodinated tri non-peripherally respectively) were evaluated in terms of their spectroscopic properties, rate of singlet oxygen generation, partition coefficient (log P), intracellular uptake, photo-induced cytotoxicity and vascular occlusion efficiency. Tetrasulfonated ZnPc (ZnPcS4) was included as a reference compound. Here, we showed that 1–3 exhibited 10–100 nm red-shifted absorption peaks with higher molar absorptivity, and at least two-fold greater singlet oxygen generation rates compared to ZnPcS4. Meanwhile, phthalocyanines 1 and 2 showed more hydrophilic log P values than 3 consistent with the number of glycerol attachments but 3 was most readily taken up by cells compared to the rest. Both phthalocyanines 2 and 3 exhibited potent phototoxicity against MCF-7, HCT-116 and HSC-2 cancer cell-lines with IC50 ranging 2.8–3.2 µM and 0.04–0.06 µM respectively, while 1 and ZnPcS4 (up to 100 µM) failed to yield determinable IC50 values. In terms of vascular occlusion efficiency, phthalocyanine 3 showed better effects than 2 by causing total occlusion of vessels with diameter <70 µm of the chorioallantoic membrane. Meanwhile, no detectable vascular occlusion was observed for ZnPcS4 with treatment under similar experimental conditions. These findings provide evidence that glycerol substitution, in particular in structures 2 and 3, is able to improve the photodynamic properties of ZnPc. PMID:24840576

The dual effect of curcumin nanoparticles encapsulated by 1-3/1-6 β-glucan from medicinal mushrooms Hericium erinaceus and Ganoderma lucidum

NASA Astrophysics Data System (ADS)

Huong Le, Mai; Doan Do, Hai; Tran Thi, Hong Ha; Dung, Le Vu; Nguyen, Hoai Nam; Nhu Tran Thi, Hang; Dinh Nguyen, Luyen; Hoang, Chi Kim; Le, Huu Cuong; Huong Le Thi, Thu; Trinh, Hoang Trung; Thu Ha, Phuong

2016-12-01

Curcumin is a polyphenol from turmeric Curcuma longa L that has been proved to possess numerous biological and pharmaceutical activities, including anti-cancer properties. However, curcumin has only limited clinical applications due to the aqueous insolubility characteristic that reduces its biological availability. On the other hand, using nanoparticles as drug delivery system has potential as it increases solubility of hydrophobic substances such as curcumin. Furthermore, nanoparticles can protect and control release of drug. Therefore, the objective of this project is to prepare nanoparticles by polymeric encapsulating curcumin by 1-3/1-6 β-glucan extracted from Vietnamese mushrooms to increase drug delivery efficiency and biological effect. Method of the preparation is nano-precipitation. The produced curcumin-β-glucan-nanoparticles (NanoGluCur) takes spherical shape with 60-70 nm in diameter. As expected, water solubility of curcumin increases about 180 times, from 0.6 μg ml-1 to 0.11 mg ml-1. Loading capacity of NanoGluCur is 18.16%. In vitro cytotoxicity and anti-tumor promoting effects of NanoGluCur were also investigated. Results revealed that NanoGluCur is able to inhibit the growth of two human cancer cell lines Hep-G2 and LU-1 with IC50 values of 6.82 and 15.53 mg ml-1, respectively, while free curcumin expresses the activity with IC50 values of 7.41 and 18.82 mg ml-1. At the concentration of 40 mg ml-1, NanoGluCur showed anti-tumor promoting effects in reducing tumor size by 59.93% and tumor density by 40.52%, while the percentages caused by pristine curcumin were 41.36% and 29.14%, respectively. These results demonstrated dual effect of 1-3/1-6 β-glucan encapsulated curcumin nanoparticles: higher water solubility and better in vitro anti-cancer effects compared to free curcumin and 1-3/1-6 β-glucan, expectedly. This observation can potentially open a new approach in research and manufacture of functional foods from medicinal mushrooms.

In vitro and in vivo characterization of the anticancer activity of Thai stingless bee (Tetragonula laeviceps) cerumen.

PubMed

Nugitrangson, Pongvit; Puthong, Songchan; Iempridee, Tawin; Pimtong, Wittaya; Pornpakakul, Surachai; Chanchao, Chanpen

2016-01-01

Tetragonula laeviceps cerumen was sequentially extracted with 80% (v/v) methanol, dichloromethane, and hexane and also in the reverse order. By the MTT assay and the respective 50% inhibition concentration value, the most active fraction was further purified to apparent homogeneity by bioassay-guided silica gel column chromatography. α-Mangostin was identified by high-resolution electrospray ionization mass spectrometry and nuclear magnetic resonance analyses. It had a potent cytotoxicity against the BT474, Chago, Hep-G2, KATO-III, and SW620 cell lines (IC50 values of 1.22 ± 0.03, 2.25 ± 0.20, 0.94 ± 0.01, 0.88 ± 0.16, and 1.50 ± 0.39 µmol/L, respectively). The in vitro cytotoxicity of α-mangostin against the five human cancer cell lines and primary fibroblasts was further characterized by real-time impedance-based analysis. Interestingly, α-mangostin was more cytotoxic against the cancer-derived cell lines than against the primary fibroblasts. Later, the migration assay was performed by continuously measuring the attachment of cells to the plate electrodes at the bottom of the transwell membrane. The combined caspase-3 and -7 activities were assayed by the Caspase-Glo® 3/7 kit. It showed that the cytotoxic mechanism involved caspase-independent apoptosis, while at low (non-toxic) concentrations α-mangostin did not significantly alter cell migration. Furthermore, the in vivo cytotoxicity and angiogenesis were determined by alkaline phosphatase staining in zebrafish embryos along with monitoring changes in the transcript expression level of two genes involved in angiogenesis (vegfaa and vegfr2) by quantitative real-time reverse transcriptase- polymerase chain reaction. It was found that the in vivo cytotoxicity of α-mangostin against zebrafish embryos had a 50% lethal concentration of 9.4 µM, but no anti-angiogenic properties were observed in zebrafish embryos at 9 and 12 µM even though it downregulated the expression of vegfaa and vegfr2 transcripts. Thus, α-mangostin is a major active compound with a potential anticancer activity in T. laeviceps cerumen in Thailand. © 2015 by the Society for Experimental Biology and Medicine.

Dihydropyrimidine based hydrazine dihydrochloride derivatives as potent urease inhibitors.

PubMed

Khan, Ajmal; Hashim, Jamshed; Arshad, Nuzhat; Khan, Ijaz; Siddiqui, Naureen; Wadood, Abdul; Ali, Muzaffar; Arshad, Fiza; Khan, Khalid Mohammed; Choudhary, M Iqbal

2016-02-01

Four series of heterocyclic compounds 4-dihydropyrimidine-2-thiones 7-12 (series A), N,S-dimethyl-dihydropyrimidines 13-18 (series B), hydrazine derivatives of dihydropyrimidine 19-24 (series C), and tetrazolo dihydropyrimidine derivatives 25-30 (series D), were synthesized and evaluated for in vitro urease inhibitory activity. The series B-D were first time examined for urease inhibition. Series A and C were found to be significantly active with IC50 values between 34.7-42.9 and 15.0-26.0 μM, respectively. The structure-activity relationship showed that the free S atom and hydrazine moiety are the key pharmacophores against urease enzyme. The kinetic studies of the active series A (7-12) and C (19-24) were carried out to determine their modes of inhibition and dissociation constants Ki. Compounds of series A (7-12) and series C (19-24) showed a mixed-type of inhibition with Ki values ranging between 15.76-25.66 and 14.63-29.42 μM, respectively. The molecular docking results showed that all the active compounds of both series have significant binding interactions with the active sites specially Ni-ion of the urease enzyme. Cytotoxicity of all series A-D was also evaluated against mammalian mouse fibroblast 3T3 cell lines, and no toxicity was observed in cellular model. Copyright © 2016 Elsevier Inc. All rights reserved.

Inhibitory effects of psychotropic drugs on the acetylcholine receptor-operated potassium current (IK.ACh) in guinea-pig atrial myocytes.

PubMed

Okada, Muneyoshi; Watanabe, Shinya; Matada, Takashi; Asao, Yoko; Hamatani, Ramu; Yamawaki, Hideyuki; Hara, Yukio

2013-01-01

Influences of psychotropic drugs, six antipsychotics and three antidepressants, on acetylcholine receptor-operated potassium current (IK.ACh) were examined by a whole-cell patch clamp method in freshly isolated guinea-pig atrial myocyte. IK.ACh was induced by a superfusion of carbachol (CCh) or by an intracellular application of guanosine 5'-[thio] triphosphate (GTPγS). To elucidate mechanism for anticholinergic action, IC50 ratio, the ratio of IC50 for GTPγS-activated IK.ACh to CCh-induced IK.ACh, was calculated. Antipsychotics and antidepressants inhibited CCh-induced IK.ACh in a concentration-dependent manner. The IC50 values were as follows; chlorpromazine 0.53 μM, clozapine 0.06 μM, fluphenazine 2.69 μM, haloperidol 2.66 μM, sulpiride 42.3 μM, thioridazine 0.07 μM, amitriptyline 0.03 μM, imipramine 0.22 μM and maprotiline 1.81 μM. The drugs, except for sulpiride, inhibited GTPγS-activated IK.ACh with following IC50 values; chlorpromazine 1.71 μM, clozapine 14.9 μM, fluphenazine 3.55 μM, haloperidol 2.73 μM, thioridazine 1.90 μM, amitriptyline 7.55 μM, imipramine 7.09 μM and maprotiline 5.93 μM. The IC50 ratio for fluphenazine and haloperidol was close to unity. The IC50 ratio for chlorpromazine, clozapine, thioridazine, amitriptyline, imipramine and maprotiline was much higher than unity. The present findings suggest that the psychotropics studied suppress IK.ACh. Chlorpromazine, clozapine, thioridazine, amitriptyline, imipramine, maprotiline and sulpiride are preferentially acting on muscarinic receptor. Fluphenazine and haloperidol may act on G protein and/or potassium channel.

3-Coumaranone derivatives as inhibitors of monoamine oxidase.

PubMed

Van Dyk, Adriaan S; Petzer, Jacobus P; Petzer, Anél; Legoabe, Lesetja J

2015-01-01

The present study examines the monoamine oxidase (MAO) inhibitory properties of a series of 20 3-coumaranone [benzofuran-3(2H)-one] derivatives. The 3-coumaranone derivatives are structurally related to series of α-tetralone and 1-indanone derivatives, which have recently been shown to potently inhibit MAO, with selectivity for MAO-B (in preference to the MAO-A isoform). 3-Coumaranones are similarly found to selectively inhibit human MAO-B with half-maximal inhibitory concentration (IC50) values of 0.004-1.05 µM. Nine compounds exhibited IC50<0.05 µM for the inhibition of MAO-B. For the inhibition of human MAO-A, IC50 values ranged from 0.586 to >100 µM, with only one compound possessing an IC50<1 µM. For selected 3-coumaranone derivatives, it is established that MAO-A and MAO-B inhibition are reversible since dialysis of enzyme-inhibitor mixtures almost completely restores enzyme activity. On the basis of the selectivity profiles and potent action, it may be concluded that the 3-coumaranone derivatives are suitable leads for the development of selective MAO-B inhibitors as potential treatment for disorders such as Parkinson's disease and Alzheimer's disease.

In Vitro and In Vivo Toxicity Profiling of Ammonium-Based Deep Eutectic Solvents

PubMed Central

Hayyan, Maan; Looi, Chung Yeng; Hayyan, Adeeb; Wong, Won Fen; Hashim, Mohd Ali

2015-01-01

The cytotoxic potential of ammonium-based deep eutectic solvents (DESs) with four hydrogen bond donors, namely glycerine (Gl), ethylene glycol (EG), triethylene glycol (TEG) and urea (U) were investigated. The toxicity of DESs was examined using In Vitro cell lines and In Vivo animal model. IC50 and selectivity index were determined for the DESs, their individual components and their combinations as aqueous solutions for comparison purposes. The cytotoxicity effect of DESs varied depending on cell lines. The IC50 for the GlDES, EGDES, UDES and TEGDES followed the sequence of TEGDES< GlDES< EGDES< UDES for OKF6, MCF-7, A375, HT29 and H413, respectively. GlDES was selective against MCF-7 and A375, EGDES was selective against MCF-7, PC3, HepG2 and HT29, UDES was selective against MCF-7, PC3, HepG2 and HT29, and TEGDES was selective against MCF-7 and A375. However, acute toxicity studies using ICR mice showed that these DESs were relatively toxic in comparison to their individual components. DES did not cause DNA damage, but it could enhance ROS production and induce apoptosis in treated cancer cells as evidenced by marked LDH release. Furthermore, the examined DESs showed less cytotoxicity compared with ionic liquids. To the best of our knowledge, this is the first time that combined In Vitro and In Vivo toxicity profiles of DESs were being demonstrated, raising the toxicity issue of these neoteric mixtures and their potential applicability to be used for therapeutic purposes. PMID:25679975

O-naphthoquinone isolated from Capraria biflora L. induces selective cytotoxicity in tumor cell lines.

PubMed

de S Wisintainer, G G N; Scola, G; Moura, S; Lemos, T L G; Pessoa, C; de Moraes, M O; Souza, L G S; Roesch-Ely, M; Henriques, J A P

2015-12-21

Biflorin is an o-naphthoquinone isolated from the roots of the plant Capraria biflora L. (Scrophulariaceae). In this study, the cytotoxic effects of biflorin were verified, and late apoptosis was detected in various cancer cell lines by in situ analysis. The cytotoxicity was further evaluated exclusively for 48 h of treatment in different tumor and non-tumor cell lines (Hep-2, HeLa, HT-29, A-375, and A-549, and HEK-293, respectively). The results indicated that biflorin induced selective cytotoxicity in tumor cells. HeLa cells were more susceptible to biflorin, followed by HT-29, A-549, A-375, and Hep-2 at all concentrations (range 5-50 μg/mL), and the highest half-maximal inhibitory concentration IC50 (56.01 ± 1.17 μg/mL) was observed in HEK-293 cells. Late apoptotic/necrotic events, observed by in situ immunostaining with Annexin V, varied with each cell line; an increase in late apoptotic events was observed corresponding to the increase in biflorin dosage. Hep-2 cells showed a greater percentage of late apoptotic events among the tumor cell lines when treated with higher concentrations of biflorin (69.63 ± 2.28%). The non-tumor HEK-293 line showed greater resistance to late apoptotic events, as well as a lower level of cytotoxicity (77.69 ± 6.68%) than the tested tumor lines. The data presented indicate that biflorin showed an important, possibly selective, cytotoxicity against tumor cell lines, thereby revealing a promising novel substance with potential anticancer activity for tumor therapy.

Chemistry and biological activity of coumarins at molecular level.

PubMed

Garro, Hugo A; García, Celina; Martín, Víctor S; Tonn, Carlos E; Pungitore, Carlos R

2014-08-01

Synthetic coumarins were prepared in high yields using ionic liquids as an environmental friendly alternative. 3,4-Dimethyl-7-hydroxycoumarin (3ab) and 3-isopropyl-4-methyl-5,7-dihydroxycoumarin (3bc) showed interesting activity against Taq DNA polymerase with IC50 values of 115.7 microM and 82.2 microM, respectively. Also, 4-methyl-7-hydroxycoumarin (3aa) and 4-methyl-5,7-dihydroxycoumarin (3ba) exhibited inhibitory activity against MMLV-RT with IC50 values of 23.5 microM and 18.3 microM, respectively. These inhibitors could have importance as antiretroviral chemotherapeutic agents and also for the development of antitumor drugs.

In vitro effect of important herbal active constituents on human cytochrome P450 1A2 (CYP1A2) activity.

PubMed

Pan, Yan; Tiong, Kai Hung; Abd-Rashid, Badrul Amini; Ismail, Zakiah; Ismail, Rusli; Mak, Joon Wah; Ong, Chin Eng

2014-10-15

This study was designed to investigate eight herbal active constituents (andrographolide, asiaticoside, asiatic acid, madecassic acid, eupatorin, sinensetin, caffeic acid, and rosmarinic acid) on their potential inhibitory effects on human cytochrome P450 1A2 (CYP1A2) activity. A fluorescence-based enzyme assay was performed by co-incubating human cDNA-expressed CYP1A2 with its selective probe substrate, 3-cyano-7-ethoxycoumarin (CEC), in the absence or presence of various concentrations of herbal active constituents. The metabolite (cyano-hydroxycoumarin) formed was subsequently measured in order to obtain IC50 values. The results indicated that only eupatorin and sinensetin moderately inhibited CYP1A2 with IC50 values of 50.8 and 40.2 μM, while the other active compounds did not significantly affect CYP1A2 activity with IC50 values more than 100 μM. Ki values further determined for eupatorin and sinensetin were 46.4 and 35.2 μM, respectively. Our data indicated that most of the investigated herbal constituents have negligible CYP1A2 inhibitory effect. In vivo studies however may be warranted to ascertain the inhibitory effect of eupatorin and sinensetin on CYP1A2 activity in clinical situations. Copyright © 2014 Elsevier GmbH. All rights reserved.

Enhancing the efficiency of bortezomib conjugated to pegylated gold nanoparticles: an in vitro study on human pancreatic cancer cells and adenocarcinoma human lung alveolar basal epithelial cells.

PubMed

Coelho, Sílvia Castro; Almeida, Gabriela M; Santos-Silva, Filipe; Pereira, Maria Carmo; Coelho, Manuel A N

2016-08-01

Gold nanoparticles have become promising vectors for cancer diagnosis and treatment. The present study investigates the effect of bortezomib (BTZ), a proteasome inhibitor, conjugated with pegylated gold nanoparticles (PEGAuNPs) in pancreatic and lung cancer cells. Synthesized gold nanoparticles (PEGAuNPs) were conjugated with bortezomib antitumor drug. We investigated the cytotoxicity induced by BTZ conjugated with functionalized gold nanoparticles in vitro, in the human pancreatic (S2-013) and lung (A549) cancer cell lines. We found an efficient of conjugation of BTZ with PEGAuNPs. In vitro assays showed that after 72 h' incubation with PEGAuNPs-BTZ cancer cells revealed alterations in morphology; also for S2-013 and A549 cancer cells, the IC50 value of free BTZ is respectively 1.5 and 4.3 times higher than the IC50 value of PEGAuNPs-BTZ. Furthermore, for TERT-HPNE, the IC50 value is around 63 times lower for free BTZ than the conjugated nanovehicle. Cell growth inhibition results showed a remarkable enhancement in the effect of BTZ when conjugated with AuNPs. Our findings showed that conjugation with PEGAuNPs enhance the BTZ growth-inhibition effect on human cancer cells (S2-013 and A549) and decreases its toxicity against normal cells (TERT-HPNE).

Design, Synthesis and Biological Evaluation of (E)-N-Aryl-2-arylethene-sulfonamide Analogues as Potent and Orally Bioavailable Microtubule-targeted Anticancer Agents

PubMed Central

Ramana Reddy, M. V.; Mallireddigari, Muralidhar R.; Pallela, Venkat R.; Cosenza, Stephen C.; Billa, Vinay K.; Akula, Balaiah; Venkata Subbaiah, D. R. C.; Bharathi, E. Vijaya; Padgaonkar, Amol; Lv, Hua; Gallo, James M.; Reddy, E. Premkumar

2013-01-01

A series of novel (E)-N-aryl-2-arylethenesulfonamides (6) were synthesized and evaluated for their anticancer activity. Some of the compounds in this series showed potent cytotoxicity against a wide spectrum of cancer cell-lines (IC50 values ranging from 5 to 10 nM) including all drug resistant cell-lines. Nude mice xenograft assays with compound (E)-N-(3-Amino-4-methoxyphenyl)-2-(2′,4′,6′-trimethoxyphenyl)ethenesulfonamide (6t) showed dramatic reduction in tumor size indicating their in vivo potential as anticancer agents. A preliminary drug development study with compound 6t is predicted to have increased blood-brain barrier permeability relative to many clinically used anti-mitotic agents. Mechanistic studies indicate that 6t and some other analogs disrupted microtubule formation, formation of mitotic spindles and arrest of cells in mitotic phase. Compound 6t inhibited purified tubulin polymerization in vitro and in vivo and circumvented drug resistance mediated by P-glycoprotein. Compound 6t specifically competed with colchicine binding to tubulin and with similar avidity as podophylltoxin indicating its binding site on tubulin. PMID:23750455

In Vitro Evaluations and In Vivo Toxicity and Efficacy Studies of MFM501 against MRSA

PubMed Central

Mohtar, Mastura; Syed Mohamad, Sharifah Aminah; Mohammat, Mohd Fazli; Sahdan, Rohana; Mohamed, Azman; Mohamad Ridhwan, Mohamad Jemain

2017-01-01

Previously we have discovered a synthetically derived pyrrolidone alkaloid, MFM501, exhibiting good inhibitory activity against 53 MRSA and MSSA isolates with low cytotoxicity against three normal cell-lines with IC50 values at >625 µg/ml. Time-kill assay, scanning electron microscopy (SEM) analysis, in vivo oral acute toxicity test, and mice peritonitis model were carried out in this study. In the time-kill study, MFM501 showed a less than 3 log10 decrease in bacterial colony concentration value (CFU/ml) which represented a bacteriostatic action while displaying a time-dependent inhibitory mechanism. Following that, SEM analysis suggested that MFM501 may exert its inhibitory activity via cytoplasmic membrane disruption. Moreover, MFM501 showed no toxicity effect on treated mice at an estimated median acute lethal dose (LD50) value of more than 300 mg/kg and less than 2000 mg/kg. For the efficacy test, a mean effective dose (ED50) of 87.16 mg/kg was obtained via a single dose oral administration. Our data demonstrated that MFM501 has the potential to be developed further as a new, safe, and effective oral-delivered antibacterial agent against MRSA isolates. PMID:28536702

A mononuclear Cu(II) complex with 5,6-diphenyl-3-(2-pyridyl)-1,2,4-triazine: Synthesis, crystal structure, DNA- and BSA-binding, molecular modeling, and anticancer activity against MCF-7, A-549, and HT-29 cell lines.

PubMed

Anjomshoa, Marzieh; Hadadzadeh, Hassan; Torkzadeh-Mahani, Masoud; Fatemi, Seyed Jamilaldin; Adeli-Sardou, Mahboubeh; Rudbari, Hadi Amiri; Nardo, Viviana Mollica

2015-01-01

The copper(II) complex of 1,2,4-triazine derivatives, [Cu(dppt)2(H2O)](PF6)2(dppt is 5,6-diphenyl-3-(2-pyridyl)-1,2,4-triazine), has been synthesized and fully characterized by spectroscopic methods and single crystal X-ray diffraction. The in vitro DNA-binding studies of the complex have been investigated by several methods. The results showed that the complex intercalates into the base pairs of DNA. The complex also indicated good binding propensity to BSA. The results of molecular docking and molecular dynamic simulation methods confirm the experimental results. Finally, the in vitro cytotoxicity indicate that the complex has excellent anticancer activity against the three human carcinoma cell lines, MCF-7, A-549, and HT-29, with IC50 values of 9.8, 7.80, and 4.50 μM, respectively. The microscopic analyses of the cancer cells demonstrate that the Cu(II) complex apparently induced apoptosis. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Biochemical effects and growth inhibition in MCF-7 cells caused by novel sulphonamido oxa-polyamine derivatives.

PubMed

Pavlov, V; Lin, P Kong Thoo; Rodilla, V

2002-04-01

The novel polyamine derivatives sulphonamido oxa-spermine (oxa-Spm) and sulphonamido oxa-spermidine (oxa-Spd) exhibited rapid cytotoxic action towards MCF-7 human breast cancer cells with IC50 values of 4.35 and 6.47 pM, respectively, after 24-h drug exposure. Neither compound is a substrate of serum amine oxidase. Both oxa-Spm and oxa-Spd caused cell shrinkage, as determined by phase-contrast microscopy. After incubation with 10 microM of either compound for 8 h, the cells underwent chromatin condensation and nuclear fragmentation. However, no clear DNA ladder was obtained by electrophoresis. The sulphonamido oxa-polyamine derivatives and especially oxa-Spd enhanced the activity of polyamine oxidase (PAO), an enzyme capable of oxidising N1-acetylated spermine and spermidine to spermidine and putrescine, respectively, generating cytotoxic H2O2 and 3-acetamidopropanal as by-products. The intracellular polyamine content was only marginally reduced in response to drug treatment. In conclusion, our data show that these novel sulphonamido oxa-polyamine derivatives possess high cytotoxic activity against MCF-7 cells and indicate that induction of PAO may mediate their cytotoxicity via apoptosis.

Antitumor potential of crown ethers: structure-activity relationships, cell cycle disturbances, and cell death studies of a series of ionophores.

PubMed

Marjanović, Marko; Kralj, Marijeta; Supek, Fran; Frkanec, Leo; Piantanida, Ivo; Smuc, Tomislav; Tusek-Bozić, Ljerka

2007-03-08

The present paper demonstrates the antiproliferative ability and structure-activity relationships (SAR) of 14 crown and aza-crown ether analogues on five tumor-cell types. The most active compounds were di-tert-butyldicyclohexano-18-crown-6 (3), which exhibited cytotoxicity in the submicromolar range, and di-tert-butyldibenzo-18-crown-6 (5) (IC50 values of approximately 2 microM). Also, 3 and 5 induced marked influence on the cell cycle phase distribution--strong G1 arrest, followed by the induction of apoptosis. A computational SAR modeling effort offers insight into possible mechanisms of crown ether biological activity, presumably involving penetration into cell membranes, and points out structural features of molecules important for this activity. The results reveal that crown ethers possess marked tumor-cell growth inhibitory activity, the extent of which depends on the characteristics of the hydrophilic macrocylic cavity and the surrounding hydrophobic ring. Our work supports the hypothesis that crown ether compounds inhibit tumor-cell growth by disrupting potassium ion homeostasis, which in turn leads to cell cycle perturbations and apoptosis.

Chondroitin sulfate-capped super-paramagnetic iron oxide nanoparticles as potential carriers of doxorubicin hydrochloride.

PubMed

Mallick, Neha; Anwar, Mohammed; Asfer, Mohammed; Mehdi, Syed Hassan; Rizvi, Mohammed Moshahid Alam; Panda, Amulya Kumar; Talegaonkar, Sushama; Ahmad, Farhan Jalees

2016-10-20

Chondroitin-4-sulfate (CS), a glycosaminoglycan, was used to prepare CS-capped super-paramagnetic iron oxide nanoparticles, which were further employed for loading a water-soluble chemotherapeutic agent (doxorubicin hydrochloride, DOX). CS-capped SPIONs have potential biomedical application in cancer targeting. The optimized formulation had a hydrodynamic size of 91.2±0.8nm (PDI; 0.228±0.004) and zeta potential of -49.1±1.66mV. DOX was loaded onto the formulation up to 2% (w/w) by physical interaction with CS. TEM showed nano-sized particles having a core-shell structure. XRD confirmed crystal phase of iron oxide. FT-IR conceived the interaction of iron oxide with CS as bidentate chelation and also confirmed DOX loading. Vibration sample magnetometry confirmed super-paramagnetic nature of nanoparticles, with saturation magnetization of 0.238emug(-1). In vitro release profile at pH 7.4 showed that 96.67% of DOX was released within 24h (first order kinetics). MTT assay in MCF7 cells showed significantly higher (p<0.0001) cytotoxicity for DOX in SPIONs than DOX solution (IC50 values 6.294±0.4169 and 11.316±0.1102μgmL(-1), respectively). Copyright © 2016 Elsevier Ltd. All rights reserved.

Flavonolignans and other constituents from Lepidium meyenii with activities in anti-inflammation and human cancer cell lines.

PubMed

Bai, Naisheng; He, Kan; Roller, Marc; Lai, Ching-Shu; Bai, Lu; Pan, Min-Hsiung

2015-03-11

From the roots of Lepidium meyenii Walpers (Brassicaceae) have been isolated and identified 2 flavonolignans, tricin 4'-O-[threo-β-guaiacyl-(7″-O-methyl)-glyceryl] ether (1) and tricin 4'-O-(erythro-β-guaiacyl-glyceryl) ether (2), along with 11 other known compounds, tricin (3), pinoresinol (4), 4-hydroxycinnamic acid (5), guanosine (6), glucotropaeolin (7), desulfoglucotropaeolin (8), 3-hydroxybenzylisothiocyanate (9), malic acid benzoate (10), 5-(hydroxymethyl)-2-furfural (11), d-phenylalanine (12), and vanillic acid 4-O-β-d-glucoside (13). Structures were elucidated on the basis of NMR and MS data. Some isolates and previously isolated lepidiline B (14) were tested for cytotoxicity in a small panel of human cancer cell lines (Hep G2, COLO 205, and HL-60) and for anti-inflammatory activities in LPS-treated RAW 264.7 macrophage. Among them, compounds 1 and 14 were modestly active for inhibiting nitrite production in macrophage. Compounds 1, 14, and 3 were demonstrated to be selectively active against HL-60 cells with IC50 values of 40.4, 52.0, and 52.1 μM, respectively.

Modulation of Induced Cytotoxicity of Doxorubicin by Using Apoferritin and Liposomal Cages

PubMed Central

Gumulec, Jaromir; Fojtu, Michaela; Raudenska, Martina; Sztalmachova, Marketa; Skotakova, Anna; Vlachova, Jana; Skalickova, Sylvie; Nejdl, Lukas; Kopel, Pavel; Knopfova, Lucia; Adam, Vojtech; Kizek, Rene; Stiborova, Marie; Babula, Petr; Masarik, Michal

2014-01-01

Doxorubicin is an effective chemotherapeutic drug, however, its toxicity is a significant limitation in therapy. Encapsulation of doxorubicin inside liposomes or ferritin cages decreases cardiotoxicity while maintaining anticancer potency. We synthesized novel apoferritin- and liposome-encapsulated forms of doxorubicin (“Apodox” and “lip-8-dox”) and compared its toxicity with doxorubicin and Myocet on prostate cell lines. Three different prostatic cell lines PNT1A, 22Rv1, and LNCaP were chosen. The toxicity of the modified doxorubicin forms was compared to conventional doxorubicin using the MTT assay, real-time cell impedance-based cell growth method (RTCA), and flow cytometry. The efficiency of doxorubicin entrapment was 56% in apoferritin cages and 42% in the liposome carrier. The accuracy of the RTCA system was verified by flow-cytometric analysis of cell viability. The doxorubicin half maximal inhibition concentrations (IC50) were determined as 170.5, 234.0, and 169.0 nM for PNT1A, 22Rv1, and LNCaP, respectively by RTCA. Lip8-dox is less toxic on the non-tumor cell line PNT1A compared to doxorubicin, while still maintaining the toxicity to tumorous cell lines similar to doxorubicin or epirubicin (IC50 = 2076.7 nM for PNT1A vs. 935.3 and 729.0 nM for 22Rv1 and LNCaP). Apodox IC50 was determined as follows: 603.1, 1344.2, and 931.2 nM for PNT1A, 22Rv1, and LNCaP. PMID:25514405

Bioactive compounds from Stuhlmannia moavi from the Madagascar dry forest.

PubMed

Liu, Yixi; Harinantenaina, Liva; Brodie, Peggy J; Bowman, Jessica D; Cassera, Maria B; Slebodnick, Carla; Callmander, Martin W; Randrianaivo, Richard; Rakotobe, Etienne; Rasamison, Vincent E; Applequist, Wendy; Birkinshaw, Chris; Lewis, Gwilym P; Kingston, David G I

2013-12-15

Bioassay-directed fractionation of the leaf and root extracts of the antiproliferative Madagascar plant Stuhlmannia moavi afforded 6-acetyl-5,8-dihydroxy-2-methoxy-7-methyl-1,4-naphthoquinone (stuhlmoavin, 1) as the most active compound, with an IC50 value of 8.1 μM against the A2780 human ovarian cancer cell line, as well as the known homoisoflavonoid bonducellin (2) and the stilbenoids 3,4,5'-trihydroxy-3'-methoxy-trans-stilbene (3), piceatannol (4), resveratrol (5), rhapontigenin (6), and isorhapontigenin (7). The structure elucidation of all compounds was based on NMR and mass spectroscopic data, and the structure of 1 was confirmed by a single crystal X-ray analysis. Compounds 2-5 showed weak A2780 activities, with IC50 values of 10.6, 54.0, 41.0, and 74.0 μM, respectively. Compounds 1-3 also showed weak antimalarial activity against Plasmodium falciparum with IC50 values of 23, 26, and 27 μM, respectively. Copyright © 2013 Elsevier Ltd. All rights reserved.

Structure-based design, synthesis and biological evaluation of β-glucuronidase inhibitors.

PubMed

Khan, Khalid M; Ambreen, Nida; Taha, Muhammad; Halim, Sobia A; Zaheer-ul-Haq; Naureen, Shagufta; Rasheed, Saima; Perveen, Shahnaz; Ali, Sajjad; Choudhary, Mohammad Iqbal

2014-05-01

Using structure-based virtual screening approach, a coumarin derivative (1) was identified as β-glucuronidase inhibitor. A focused library of coumarin derivatives was synthesized by eco-benign version of chemical reaction, and all synthetic compounds were characterized by using spectroscopy. These compounds were found to be inhibitor of β-glucuronidase with IC50 values in a micromolar range. All synthetic compounds exhibited interesting inhibitory activity against β-glucuronidase, however, their potency varied substantially from IC50 = 9.9-352.6 µM. Of twenty-one compounds, four exhibited a better inhibitory profile than the initial hit 1. Interestingly, compounds 1e, 1k, 1n and 1p exhibited more potency than the standard inhibitor with IC50 values 34.2, 21.4, 11.7, and 9.9 µM, respectively. We further studied their dose responses and also checked our results by using detergent Triton ×-100. We found that our results are true and not affected by detergent.

Effects of Fungicides on Rat's Neurosteroid Synthetic Enzymes

PubMed Central

Shen, Xiuwei; Chen, Fan; Chen, Lanlan; Su, Ying; Huang, Ping

2017-01-01

Exposure to environmental endocrine disruptors may interfere with nervous system's activity. Fungicides such as tebuconazole, triadimefon, and vinclozolin have antifungal activities and are used to prevent fungal infections in agricultural plants. In the present study, we studied effects of tebuconazole, triadimefon, and vinclozolin on rat's neurosteroidogenic 5α-reductase 1 (5α-Red1), 3α-hydroxysteroid dehydrogenase (3α-HSD), and retinol dehydrogenase 2 (RDH2). Rat's 5α-Red1, 3α-HSD, and RDH2 were cloned and expressed in COS-1 cells, and effects of these fungicides on them were measured. Tebuconazole and triadimefon competitively inhibited 5α-Red1, with IC50 values of 8.670 ± 0.771 × 10−6 M and 17.390 ± 0.079 × 10−6 M, respectively, while vinclozolin did not inhibit the enzyme at 100 × 10−6 M. Triadimefon competitively inhibited 3α-HSD, with IC50 value of 26.493 ± 0.076 × 10−6 M. Tebuconazole and vinclozolin weakly inhibited 3α-HSD, with IC50 values about 100 × 10−6 M, while vinclozolin did not inhibit the enzyme even at 100 × 10−6 M. Tebuconazole and triadimefon weakly inhibited RDH2 with IC50 values over 100 × 10−6 M and vinclozolin did not inhibit this enzyme at 100 × 10−6 M. Docking study showed that tebuconazole, triadimefon, and vinclozolin bound to the steroid-binding pocket of 3α-HSD. In conclusion, triadimefon potently inhibited rat's neurosteroidogenic enzymes, 5α-Red1 and 3α-HSD. PMID:28812018

Identification of New Human Malaria Parasite Plasmodium Falciparum Dihydroorotate Dehydrogenase Inhibitors by Pharmacophore and Structure-Based Virtual Screening

PubMed Central

Pavadai, Elumalai; El Mazouni, Farah; Wittlin, Sergio; de Kock, Carmen; Phillips, Margaret A.; Chibale, Kelly

2016-01-01

Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH), a key enzyme in the de novo pyrimidine biosynthesis pathway, which the Plasmodium falciparum relies on exclusively for survival, has emerged as a promising target for antimalarial drugs. In an effort to discover new and potent PfDHODH inhibitors, 3D-QSAR pharmacophore models were developed based on the structures of known PfDHODH inhibitors and the validated Hypo1 model was used as a 3D search query for virtual screening of the National Cancer Institute database. The virtual hit compounds were further filtered based on molecular docking and Molecular Mechanics/Generalized Born Surface Area binding energy calculations. The combination of the pharmacophore and structure-based virtual screening resulted in the identification of nine new compounds that showed >25% inhibition of PfDHODH at a concentration of 10 μM, three of which exhibited IC50 values in the range of 0.38–20 μM. The most active compound, NSC336047, displayed species-selectivity for PfDHODH over human DHODH and inhibited parasite growth with an IC50 of 26 μM. In addition to this, thirteen compounds inhibited parasite growth with IC50 values of ≤ 50 μM, four of which showed IC50 values in the range of 5–12 μM. These compounds could be further explored in the identification and development of more potent PfDHODH and parasite growth inhibitors. PMID:26915022

Prediction of kinase-inhibitor binding affinity using energetic parameters

PubMed Central

Usha, Singaravelu; Selvaraj, Samuel

2016-01-01

The combination of physicochemical properties and energetic parameters derived from protein-ligand complexes play a vital role in determining the biological activity of a molecule. In the present work, protein-ligand interaction energy along with logP values was used to predict the experimental log (IC50) values of 25 different kinase-inhibitors using multiple regressions which gave a correlation coefficient of 0.93. The regression equation obtained was tested on 93 kinase-inhibitor complexes and an average deviation of 0.92 from the experimental log IC50 values was shown. The same set of descriptors was used to predict binding affinities for a test set of five individual kinase families, with correlation values > 0.9. We show that the protein-ligand interaction energies and partition coefficient values form the major deterministic factors for binding affinity of the ligand for its receptor. PMID:28149052

AVP-IC50 Pred: Multiple machine learning techniques-based prediction of peptide antiviral activity in terms of half maximal inhibitory concentration (IC50).

PubMed

Qureshi, Abid; Tandon, Himani; Kumar, Manoj

2015-11-01

Peptide-based antiviral therapeutics has gradually paved their way into mainstream drug discovery research. Experimental determination of peptides' antiviral activity as expressed by their IC50 values involves a lot of effort. Therefore, we have developed "AVP-IC50 Pred," a regression-based algorithm to predict the antiviral activity in terms of IC50 values (μM). A total of 759 non-redundant peptides from AVPdb and HIPdb were divided into a training/test set having 683 peptides (T(683)) and a validation set with 76 independent peptides (V(76)) for evaluation. We utilized important peptide sequence features like amino-acid compositions, binary profile of N8-C8 residues, physicochemical properties and their hybrids. Four different machine learning techniques (MLTs) namely Support vector machine, Random Forest, Instance-based classifier, and K-Star were employed. During 10-fold cross validation, we achieved maximum Pearson correlation coefficients (PCCs) of 0.66, 0.64, 0.56, 0.55, respectively, for the above MLTs using the best combination of feature sets. All the predictive models also performed well on the independent validation dataset and achieved maximum PCCs of 0.74, 0.68, 0.59, 0.57, respectively, on the best combination of feature sets. The AVP-IC50 Pred web server is anticipated to assist the researchers working on antiviral therapeutics by enabling them to computationally screen many compounds and focus experimental validation on the most promising set of peptides, thus reducing cost and time efforts. The server is available at http://crdd.osdd.net/servers/ic50avp. © 2015 Wiley Periodicals, Inc.

Bioactive metabolites from the fungus Nectria galligena, the main apple canker agent in Chile.

PubMed

Gutiérrez, Margarita; Theoduloz, Cristina; Rodríguez, Jaime; Lolas, Mauricio; Schmeda-Hirschmann, Guillermo

2005-10-05

The phytopathogenic fungus Nectria galligena Bres. is the most common canker disease agent of hardwood trees. The terpenoids colletochlorin B, colletorin B, ilicicolin C, E, and F, as well as the phytotoxin alpha,beta-dehydrocurvularin have been isolated from liquid cultures of N. galligena obtained from the xylem of infected apple trees in central Chile. Ilicicolin C and F and alpha,beta-dehydrocurvularin were active against Pseudomonas syringae with IC50 values of 28.5, 28.5, and 14.2 microg/mL, respectively, in the same range as streptomycin and penicillin G (11 and 15 microg/mL, respectively). All of the compounds showed moderate inhibitory activity toward the enzymes acetylcholinesterase (AChE) and beta-glucuronidase. The most active enzyme inhibitors were colletochlorin B and ilicicolin C and E, with IC50 values of 30-36 microg/mL in the AChE assay and 32-43 microg/mL in the beta-glucuronidase test. All of the chlorinated compounds showed some toxicity toward human lung fibroblasts, with IC50 values in the range of 64-120 microg/mL. alpha,beta-Dehydrocurvularin proved to be the most toxic compound, showing IC50 values less than 12 microg/mL. The effect of the isolated compounds on seed germination and radicle and epicotyl growth was assessed in lettuce and millet seeds. At 100 and 200 microg/disk, alpha,beta-dehydrocurvularin significantly reduced radicle length and epicotyl growth in Lactuca sativa. This is the first report on the occurrence of colletochlorin B, colletorin B, ilicicolin C, E, and F, as well as alpha,beta-dehydrocurvularin associated to N. galligena.

Rotenone isolated from Pachyrhizus erosus displays cytotoxicity and genotoxicity in K562 cells.

PubMed

Estrella-Parra, Edgar A; Gomez-Verjan, Juan C; González-Sánchez, Ignacio; Vázquez-Martínez, Edgar Ricardo; Vergara-Castañeda, Edgar; Cerbón, Marco A; Alavez-Solano, Dagoberto; Reyes-Chilpa, Ricardo

2014-01-01

Pachyrhizus erosus (Fabaceae) is a herb commonly known as 'yam bean', which has been cultivated in México since pre-Columbian times for its edible tubers. The seeds are also known for their acaricidal and insecticidal properties due to rotenone and other isoflavonoid contents. Rotenone has exhibited cytotoxic activity against several human tumour cell lines; however, its mechanism of action is still not fully understood. In this study, we determined the cytotoxicity of rotenone isolated from P. erosus seeds on K562 human leukaemia cells. Rotenone exhibited significant cytotoxic activity (IC50 = 13.05 μM), as determined by the MTT assay. Three other isolated isoflavonoids were not cytotoxic. Rotenone genotoxicity was detected using the comet assay. Rotenone induced cell death, and caspase-3 activation as indicated by TUNEL assay, and immunocytofluorescence. Plasmid nicking assay indicated that rotenone does not interact directly with DNA.

Purification, characterization, and biological activities of broccolini lectin.

PubMed

Xu, Pingping; Zhang, Ting; Guo, Xiaolei; Ma, Chungwah; Zhang, Xuewu

2015-01-01

Plant lectins have displayed a variety of biological activities. In this study, for the first time, a 27 kDa arabinose- and mannose-specific lectin from Broccolini (Brassica oleracea Italica × Alboglabra), named as BL (Broccolini lectin), was purified by an activity-driven protocol. Mass spectrometry analysis and database search indicated that no matches with any plant lectin were found, but BL contained some peptide fragments (QQQGQQGQQLQQVISR, QQGQQQGQQGQQLQQVISR and VCNIPQVSVCPF QK). BL exhibited hemagglutinating activity against chicken erythrocytes at 4 µg/mL. BL retained full hemagglutinating activity at pH 7-8 and temperature 30-40°C, and had an optimal activity in Ca(2+) solution. Bioactivity assay revealed that BL exhibited dose-dependent inhibition activity on 5 bacterial species with IC50 values of 143.95-486.33 μg/mL, and on 3 cancer cells with IC50 values of 178.82-350.93 μg/mL. Notably, 5-fold reduction in IC50 values was observed on normal L-O2 vs cancerous HepG-2 cells (924.35 vs. 178.82 μg/mL). This suggests that BL should be promising in food and medicine. © 2015 American Institute of Chemical Engineers.

Protective effect of unsymmetrical dichalcogenide, a novel antioxidant agent, in vitro and an in vivo model of brain oxidative damage.

PubMed

Prigol, Marina; Wilhelm, Ethel A; Schneider, Caroline C; Nogueira, Cristina W

2008-11-25

Unsymmetrical dichalcogenides, a class of organoselenium compounds, were screened for antioxidant activity in rat brain homogenates in vitro. Unsymmetrical dichalcogenides (1-3) were tested against lipid peroxidation induced by sodium nitroprusside (SNP) or malonate, and reactive species (RS) production induced by sodium azide in rat brain homogenates. Compounds 1 (without a substituent at the phenyl group), 2 (chloro substituent at the phenyl group bounded to the sulfur atom) and 3 (chloro substituent at the phenyl group bounded to the selenium atom) protected against lipid peroxidation induced by SNP. The IC50 values followed the order 3<2<1. Lipid peroxidation induced by malonate was also reduced by dichalcogenides 1, 2 and 3. The IC50 values were 3

Anti-inflammatory phenanthrene derivatives from stems of Dendrobium denneanum.

PubMed

Lin, Yuan; Wang, Fei; Yang, Li-Juan; Chun, Ze; Bao, Jin-Ku; Zhang, Guo-Lin

2013-11-01

Cultivated Dendrobium denneanum has been substituted for other endangered Dendrobium species in recent years, but there have been few studies regarding either its chemical constituents or pharmacological effects. In this study, three phenanthrene glycosides, three 9,10-dihydrophenanthrenes, two 9,10-dihydrophenanthrenes glycosides, and four known phenanthrene derivatives, were isolated from the stems of D. denneanum. Their structures were elucidated on the basis of MS and NMR spectroscopic data. Ten compounds were found to inhibit nitric oxide (NO) production in lipopolysaccharide (LPS)-activated mouse macrophage RAW264.7 cells with IC50 values of 0.7-41.5 μM, and exhibited no cytotoxicity in RAW264.7, HeLa, or HepG2 cells. Additionally, it was found that 2,5-dihydroxy-4-methoxy-phenanthrene 2-O-β-d-glucopyranoside, and 5-methoxy-2,4,7,9S-tetrahydroxy-9,10-dihydrophenanthrene suppressed LPS-induced expression of inducible NO synthase (iNOS) inhibited phosphorylation of p38, JNK as well as mitogen-activated protein kinase (MAPK), and inhibitory kappa B-α (IκBα). This indicated that both compounds exert anti-inflammatory effects by inhibiting MAPKs and nuclear factor κB (NF-κB) pathways. Copyright © 2013 Elsevier Ltd. All rights reserved.

The Biological Activity and Composition of the Essential Oil of Sclerorhachis leptoclada (Asteraceae-Anthemideae) from Iran

PubMed Central

Sonboli, Ali; Mirjalili, Mohammad Hossein; Hadian, Javad; Yousefzadi, Morteza

2014-01-01

The biological activity and composition of the essential oil of Sclerorhachis leptoclada Rech. f. an endemic species from northeast of Iran was studied. The essential oil was isolated from the aerial flowering parts of the plant and analyzed by GC and GC-MS. Fifty-four compounds accounting for 95.9% of the total oil were characterized. The main constituents were (E)-nerolidol (14.5%), terpinen-4-ol (13.3%), camphor (6.1%), 1,8-cineole (4.8%) and p-cymene (4.5%). The antimicrobial activity of the essential oil of S. leptoclada was tested against eight microbial strains and a fungi. The results of the bioassays showed that the Gram-positive bacteria, Bacillus subtilis and Staphylococcus epidermidis, were the most sensitive to the oil than others with the MIC value of 1.8 mg/mL. The tested fungi, Saccharomyces cerevisiae was highly inhibited by the oil of S. leptoclada with MIC value of 10 mg/mL. In the case of cytotoxicity, IC50 values estimated to be 312, 1250, 625 and 1250 μg oil/mL respectively, for the Vero, SW480, MCF7, and JET 3 cancer cell lines. PMID:25276213

Synthesis of New Hydrazone Derivatives for MAO Enzymes Inhibitory Activity.

PubMed

Can, Nafiz Öncü; Osmaniye, Derya; Levent, Serkan; Sağlık, Begüm Nurpelin; İnci, Beril; Ilgın, Sinem; Özkay, Yusuf; Kaplancıklı, Zafer Asım

2017-08-20

In the present work, 14 new 1-substituted-2-phenylhydrazone derivatives were synthesized to evaluate their inhibitory activity against hMAO enzymes. The structures of the newly synthesized hydrazones 2a-2n were characterized by IR, 1H-NMR, 13C-NMR, HR-MS spectroscopic methods. The inhibitory activity of compounds 2a-2n against hMAO-A and hMAO-B enzymes was elucidated by using an in-vitro Amplex Red® reagent assay based on fluorometric methods. According to the activity studies, 2a and 2b were found to be the most active compounds against hMAO-A enzyme, with IC50 values of 0.342 µM and 0.028 µM, respectively. The most active compounds 2a-2b were evaluated by means of enzyme kinetics and docking studies. Moreover, these compounds were subjected to cytotoxicity and genotoxicity tests to establish their preliminary toxicological profiles and were found to be non-cytotoxic and non-genotoxic. Consequently, the findings of this study display the biological importance of compounds 2a, 2b as selective, irreversible and competitive inhibitors of hMAO-A. Docking studies revealed that there is a strong interaction between hMAO-A and the most active compound 2b.

Synthesis, pH dependent photometric and electrochemical investigation, redox mechanism and biological applications of novel Schiff base and its metallic derivatives

NASA Astrophysics Data System (ADS)

Rauf, Abdur; Shah, Afzal; Khan, Abdul Aziz; Shah, Aamir Hassan; Abbasi, Rashda; Qureshi, Irfan Zia; Ali, Saqib

2017-04-01

A novel Schiff base, 1-((2, 4-dimethylphenylimino)methyl)naphthalen-2-ol abbreviated as (HL) and its four metallic complexes were synthesized and confirmed by 1H and 13C NMR, FTIR, TGA and UV-Visible spectroscopy. Schiff base was also characterized by X-ray analysis. The photometric and electrochemical responses of all the synthesized compounds were investigated in a wide pH range. Structures of the compounds were optimized computationally for the evaluation of different physico-chemical parameters. On the basis of electrochemical results the redox mechanistic pathways of the compounds were proposed. The cytotoxicity analysis on Hela cells revealed that HL and its complexes inhibit cell growth as revealed from their IC50 values (HL):106.7 μM, (L2VO): 40.66 μM, (L2Sn): 5.92 μM, (L2Zn): 42.82 and (L2Co): 107.68 μM. The compounds were tested for anti-diabetic, triglyceride, cholesterol, anti-microbial, anti-fungal and enzyme inhibition activities. The results revealed that HL and its complexes are promising new therapeutic options as these compounds exhibit strong activity against cancer cells, diabetics, fungal and microbial inhibition.

Penifupyrone, a new cytotoxic funicone derivative from the endophytic fungus Penicillium sp. HSZ-43.

PubMed

Chen, Ming-Jun; Fu, Yang-Wu; Zhou, Qun-Ying

2014-01-01

Penifupyrone (1), a new funicone derivative, has been isolated from the endophytic fungus Penicillium sp. HSZ-43, along with three known analogues, funicone (2), deoxyfunicone (3) and 3-O-methylfunicone (4). These structures were identified by using spectroscopic methods, including UV, MS, 1D and 2D NMR experiments. The structure of 1 was confirmed by single-crystal X-ray diffraction analysis. All the isolated compounds were evaluated for cytotoxicity against human oral epidermoid carcinoma KB cells, and compound 1 exhibited moderate cytotoxic activity with IC50 value of 4.7 μM.

Citrus flavone tangeretin inhibits leukaemic HL-60 cell growth partially through induction of apoptosis with less cytotoxicity on normal lymphocytes.

PubMed

Hirano, T; Abe, K; Gotoh, M; Oka, K

1995-12-01

Certain anti-cancer agents are known to induce apoptosis in human tumour cells. However, these agents are intrinsically cytotoxic against cells of normal tissue origin, including myelocytes and immunocytes. Here we show that a naturally occurring flavone of citrus origin, tangeretin (5,6,7,8,4'-pentamethoxyflavone), induces apoptosis in human promyelocytic leukaemia HL-60 cells, whereas the flavone showed no cytotoxicity against human peripheral blood mononuclear cells (PBMCs). The growth of HL-60 cells in vitro assessed by [3H]thymidine incorporation or tetrazolium crystal formation was strongly suppressed in the presence of tangeretin; the IC50 values range between 0.062 and 0.173 microM. Apoptosis of HL-60 cells, assessed by cell morphology and DNA fragmentation, was demonstrated in the presence of > 2.7 microM tangeretin. Flow cytometric analysis of tangeretin-treated HL-60 cells also demonstrated apoptotic cells with low DNA content and showed a decrease of G1 cells and a concomitant increase of S and/or G2/M cells. Apoptosis was evident after 24 h of incubation with tangeretin, and the tangeretin effect as assessed by DNA fragmentation or growth inhibition was significantly attenuated in the presence of Zn2+, which is known to inhibit Ca(2+)-dependent endonuclease activity. Ca2+ and Mg2+, in contrast, promoted the effect of tangeretin. Cycloheximide significantly decreased the tangeretin effect on HL-60 cell growth, suggesting that protein synthesis is required for flavonoid-induced apoptosis. Tangeretin showed no cytotoxicity against either HL-60 cells or mitogen-activated PBMCs even at high concentration (27 microM) as determined by a dye exclusion test. Moreover, the flavonoid was less effective on growth of human T-lymphocytic leukaemia MOLT-4 cells or on blastogenesis of PBMCs. These results suggest that tangeretin inhibits growth of HL-60 cells in vitro, partially through induction of apoptosis, without causing serious side-effects on immune cells.

Steroidal glycosides from the bulbs of Easter lily (Lilium longiflorum Thunb.) promote dermal fibroblast migration in vitro.

PubMed

Esposito, Debora; Munafo, John P; Lucibello, Teresa; Baldeon, Manuel; Komarnytsky, Slavko; Gianfagna, Thomas J

2013-07-09

Preparations derived from bulbs of various Lilium species have been used to promote the healing of skin abrasions, sores and burns and to aid in healing wounds in Traditional Chinese and Greco-Roman Medicine. To evaluate fractionated Easter lily bulb extracts and their steroidal glycosides (1-5) for the promotion of dermal fibroblast migration in vitro, a model for the early events in wound healing. An activity-guided screening approach was used by coupling sequential solvent extraction, gel permeation chromatography (GPC), and semi-preparative reverse-phase high performance liquid chromatography (RP-HPLC) with an in vitro dermal fibroblast migration assay. Cytotoxicity was evaluated with methyl thiazole tetrazolium (MTT). To gain insight into the mode of action of the steroidal glycosides, nitric oxide (NO) production, and expression of genes for transforming growth factor beta-1 (TGF-β) and its receptors were evaluated. Fractionated bulb extracts and the two isolated steroidal glycoalkaloids (1) and (2) induced NO production and TGF-β receptor I mRNA expression in fibroblast cell culture. In a cytotoxicity assay, steroidal glycosides (1) and (3) had IC50 values of 8.2 and 8.7 µM, but the natural acetylation of the C-6″' hydroxy of the terminal glucose unit in (2) resulted in a 3-fold decrease in cell cytotoxicity when compared with (1). Results from the dermal fibroblast migration assay revealed that the steroidal glycoalkaloids (1) and (2), and the furostanol saponin (3) promoted fibroblast migration from the range of 23.7±5.7 to 37.7±5.1%, as compared with the control. Collectively, our data demonstrate that the steroidal glycosides present in Easter lily bulbs induce, at least in part, the observed dermal fibroblast migration activity of the bulb extracts. This is the first evidence that steroidal glycosides from Lilium longiflorum may potentially play a role in the wound healing process and may provide a scientific basis for the historical use of lily bulbs for this purpose. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Some Strychnos spinosa (Loganiaceae) leaf extracts and fractions have good antimicrobial activities and low cytotoxicities.

PubMed

Isa, Adamu Imam; Awouafack, Maurice Ducret; Dzoyem, Jean Paul; Aliyu, Mohammed; Magaji, Rabiu AbduSsalam; Ayo, Joseph Olusegun; Eloff, Jacobus Nicolaas

2014-11-27

Strychnos spinosa Lam. is a deciduous tree used in traditional medicine to treat infectious diseases. This study is designed to determine the antimicrobial, antioxidant and cytotoxic activities of extracts and fractions from leaves of S. spinosa. Extracts were obtained by maceration with acetone, methanol and dichloromethane/methanol (1/1) while fractions were prepared by liquid-liquid fractionation of the acetone extract. A broth serial microdilution method with tetrazolium violet as growth indicator was used to determine the minimum inhibitory concentration (MIC) against fungi, Gram-positive and Gram-negative bacteria. The antioxidant activity was determined using free-radical-scavenging assays, and the 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide reduction assay was used to determine cytotoxicity. Four extracts and five fractions had good to weak antimicrobial activity with MICs ranging from 0.04 to >1.25 mg/ml against both fungi and bacteria. The chloroform and ethyl acetate fractions had an MIC of 0.08 mg/ml against Aspergillus fumigatus. The n-butanol fraction had an MIC of 0.04 mg/ml against Cryptococcus neoformans. The hexane and chloroform fractions had an MIC of 0.08 mg/ml against Staphylococcus aureus. The antioxidant activities were much lower than that of the positive controls. Except for the alkaloid extract, all the extracts and fractions had free-radical-scavenging activity (IC50 ranging from 33.66 to 314.30 μg/ml). The cytotoxicity on Vero cells was reasonable to low with LC50 values ranging between 30.56 and 689.39 μg/ml. The acetone extract and the chloroform fraction had the highest antibacterial activity. By solvent-solvent fractionation it was possible to increase the activity against A. fumigatus and to decrease the cytotoxicity leading to a potentially useful product to protect animals against aspergillosis. Our results therefore support the use of S. spinosa leaves in traditional medicine to treat infectious diseases.

Role of carbonate in the cytotoxicity of carboplatin.

PubMed

Di Pasqua, Anthony J; Goodisman, Jerry; Kerwood, Deborah J; Toms, Bonnie B; Dubowy, Ronald L; Dabrowiak, James C

2007-06-01

Carboplatin, [Pt(NH3)2(CBDCA-O,O')], 1, where CBDCA is cyclobutane-1,1-dicarboxylate, is used against ovarian, lung, and other types of cancer. We recently showed (Di Pasqua et al. (2006) Chem. Res. Toxicol. 19, 139-149) that carboplatin reacts with carbonate under conditions that simulate therapy to produce carbonato carboplatin, cis-[Pt(NH3)2(O-CBDCA)(CO3)]2-, 2. We use 13C and 1H NMR and UV-visible absorption spectroscopy to show that solutions containing carboplatin that have been aged in carbonate buffer under various conditions contain 1, 2, and other compounds. We then show that aging carboplatin in carbonate produces compounds that are more toxic to human neuroblastoma (SK-N-SH), proximal renal tubule (HK-2) and Namalwa-luc Burkitt's lymphoma (BL) cells than carboplatin alone. Moreover, increasing the aging time increases the cytotoxicity of the platinum solutions as measured by the increase in cell death. Although HK-2 cells experience a large loss in survival upon exposure to carbonato forms of the drug, they have the highest values of IC50 of the three cell lines studied, so that HK-2 cells remain the most resistant to the toxic effects of the carbonato forms in the culture medium. This is consistent with the well-known low renal toxicity observed for carboplatin in therapy. The uptake rates for normal Jurkat cells (NJ) and cisplatin-resistant Jurkat cells (RJ), measured by inductively coupled plasma mass spectrometry (ICP-MS), are 16.6 +/- 4.2 and 12.3 +/- 4.8 amol of Pt h-1 cell-1, respectively, when exposed to carboplatin alone. However, when these cells are exposed to carboplatin that has been aged in carbonate media, normal Jurkat cells strongly bind/take up Pt at a rate of 14.5 +/- 4.1 amol of Pt h-1 cell-1, while resistant cells strongly bind/take up 5.1 +/- 3.3 amol of Pt h-1 cell-1. Collectively, these studies show that carboplatin carbonato species may play a major role in the cytotoxicity and uptake of carboplatin by cells.

Large scale screening of commonly used Iranian traditional medicinal plants against urease activity

PubMed Central

2012-01-01

Background and purpose of the study H. pylori infection is an important etiologic impetus usually leading to gastric disease and urease enzyme is the most crucial role is to protect the bacteria in the acidic environment of the stomach. Then urease inhibitors would increase sensitivity of the bacteria in acidic medium. Methods 137 Iranian traditional medicinal plants were examined against Jack bean urease activity by Berthelot reaction. Each herb was extracted using 50% aqueous methanol. The more effective extracts were further tested and their IC50 values were determined. Results 37 plants out of the 137 crude extracts revealed strong urease inhibitory activity (more than 70% inhibition against urease activity at 10 mg/ml concentration). Nine of the whole studied plants crude extracts were found as the most effective with IC50 values less than 500 μg/ml including; Rheum ribes, Sambucus ebulus, Pistachia lentiscus, Myrtus communis, Areca catechu, Citrus aurantifolia, Myristica fragrans, Cinnamomum zeylanicum and Nicotiana tabacum. Conclusions The most potent urease inhibitory was observed for Sambucus ebulus and Rheum ribes extracts with IC50 values of 57 and 92 μg/ml, respectively. PMID:23351780

Structure-based design, synthesis and biological evaluation of β-glucuronidase inhibitors

NASA Astrophysics Data System (ADS)

Khan, Khalid M.; Ambreen, Nida; Taha, Muhammad; Halim, Sobia A.; Zaheer-ul-Haq; Naureen, Shagufta; Rasheed, Saima; Perveen, Shahnaz; Ali, Sajjad; Choudhary, Mohammad Iqbal

2014-05-01

Using structure-based virtual screening approach, a coumarin derivative ( 1) was identified as β-glucuronidase inhibitor. A focused library of coumarin derivatives was synthesized by eco-benign version of chemical reaction, and all synthetic compounds were characterized by using spectroscopy. These compounds were found to be inhibitor of β-glucuronidase with IC50 values in a micromolar range. All synthetic compounds exhibited interesting inhibitory activity against β-glucuronidase, however, their potency varied substantially from IC50 = 9.9-352.6 µM. Of twenty-one compounds, four exhibited a better inhibitory profile than the initial hit 1. Interestingly, compounds 1e, 1k, 1n and 1p exhibited more potency than the standard inhibitor with IC50 values 34.2, 21.4, 11.7, and 9.9 µM, respectively. We further studied their dose responses and also checked our results by using detergent Triton ×-100. We found that our results are true and not affected by detergent.

Chemical composition and in vitro cytotoxic effects of the essential oil from Nectandra leucantha leaves.

PubMed

Grecco, Simone dos S; Martins, Euder Glendes A; Girola, Natália; de Figueiredo, Carlos R; Matsuo, Alisson L; Soares, Marisi G; Bertoldo, Bruno de C; Sartorelli, Patricia; Lago, João Henrique G

2015-01-01

Nectandra (Lauraceae) species have been used in folk medicine as an antidiarrheal, analgesic, antifungal, etc., and have many pharmacological proprieties. Investigation of the chemical composition and cytotoxicity of essential oil from Nectandra leucantha Nees & Mart. leaves. This is the first study involving N. leucantha reported in the literature. The essential oil of N. leucantha leaves was obtained by hydrodistillation. Its chemical composition was determined using a combination of GC/FID, GC/MS, and determination of Kovats index (KI). In vitro cytotoxic activity was evaluated against six cancer cell lines - murine melanoma (B16F10-Nex2), human glioblastome (U-87), human cervical carcinoma (HeLa), human colon carcinoma (HCT), human breast adenocarcinoma (MCF7), and human cervical tumor (Siha) as well as against one non-tumorigenic cell line - human foreskin fibroblast (HFF). Thirty-three compounds were identified primarily sesquiterpenes (81.41%), the main compounds being bicyclogermacrene (28.44%), germacrene A (7.34%), spathulenol (5.82%), and globulol (5.25%). Furthermore, monoterpenes were also found in the analyzed oil (12.84%), predominantly α- and β-pinenes (6.59 and 4.57%, respectively). The crude essential oil displayed significant cytotoxic activity against B16F10-Nex2 (IC50 33 ± 1 μg/mL) and U87 (IC50 75.95 ± 0.03 μg/mL) and HeLa (IC50 60 ± 12 μg/mL) cell lines. The main identified compound, bicyclogermacrene, displayed IC50 ranging from 3.1 ± 0.2 to 21 ± 6 μg/mL. The results indicate that the crude oils from leaves of N. leucantha displayed cytotoxic activity being bicyclogermacrene, the main compound identified in the crude oil responsible, at least in part, for this potential.

Synthesis and evaluation of the antioxidative potential of minoxidil-polyamine conjugates.

PubMed

Hadjipavlou-Litina, Dimitra; Magoulas, George E; Bariamis, Stavros E; Tsimali, Zinovia; Avgoustakis, Konstantinos; Kontogiorgis, Christos A; Athanassopoulos, Constantinos M; Papaioannou, Dionissios

2013-07-01

A series of conjugates (MNX-CO-PA) of minoxidil (MNX) with the polyamines (PAs) putrescine (PUT), spermidine (SPD) and spermine (SPM) as well as dopamine were produced through activation of MNX with N,N'-carbonyldiimidazole, followed by reaction with dopamine or selectively protected PAs and acid-mediated deprotection. These conjugates together with conjugates of the general type MNX-PA or PA-MNX-PA, readily produced using literature protocols, were tested as antioxidants. The most potent inhibitors of lipid peroxidation were the conjugates MNX-SPM (2, 94%), SPM-MNX-SPM (4, 94%) and MNX-N(4)-SPD (7, 91%) and MNX (91%). The most powerful lipoxygenase (LOX) inhibitors were MNX (IC50 = 20 μM) and the conjugates MNX-N(8)-SPD (9, IC50 = 22.1 μM), MNX-CO-dopamine (11, IC50 = 28 μM) and MNX-N(1)-SPD (8, IC50 = 30 μM). The most interesting conjugates 2, MNX-CO-PUT (5), 8 and 11 as well as MNX were generally found to exhibit weaker (22-36.5%) or no (conjugate 8) anti-inflammatory activity than indomethacin (47%) with the exception of MNX which showed almost equal potency (49%) to indomethacin. The cytocompatibility of conjugates and MNX at the highest concentration of 100 μM showed a survival percentage of 87-107%, with the exception of conjugates with SPM (compound 2) and MNX-CO-SPM (6), which showed considerable cytotoxicity (survival percentage 8-14%). Molecular docking studies were carried on conjugate 9 and the parent compound MNX and were found to be in accordance with our experimental biological results. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

Biochemical, Cellular, and Biophysical Characterization of a Potent Inhibitor of Mutant Isocitrate Dehydrogenase IDH1*

PubMed Central

Davis, Mindy I.; Gross, Stefan; Shen, Min; Straley, Kimberly S.; Pragani, Rajan; Lea, Wendy A.; Popovici-Muller, Janeta; DeLaBarre, Byron; Artin, Erin; Thorne, Natasha; Auld, Douglas S.; Li, Zhuyin; Dang, Lenny; Boxer, Matthew B.; Simeonov, Anton

2014-01-01

Two mutant forms (R132H and R132C) of isocitrate dehydrogenase 1 (IDH1) have been associated with a number of cancers including glioblastoma and acute myeloid leukemia. These mutations confer a neomorphic activity of 2-hydroxyglutarate (2-HG) production, and 2-HG has previously been implicated as an oncometabolite. Inhibitors of mutant IDH1 can potentially be used to treat these diseases. In this study, we investigated the mechanism of action of a newly discovered inhibitor, ML309, using biochemical, cellular, and biophysical approaches. Substrate binding and product inhibition studies helped to further elucidate the IDH1 R132H catalytic cycle. This rapidly equilibrating inhibitor is active in both biochemical and cellular assays. The (+) isomer is active (IC50 = 68 nm), whereas the (−) isomer is over 400-fold less active (IC50 = 29 μm) for IDH1 R132H inhibition. IDH1 R132C was similarly inhibited by (+)-ML309. WT IDH1 was largely unaffected by (+)-ML309 (IC50 >36 μm). Kinetic analyses combined with microscale thermophoresis and surface plasmon resonance indicate that this reversible inhibitor binds to IDH1 R132H competitively with respect to α-ketoglutarate and uncompetitively with respect to NADPH. A reaction scheme for IDH1 R132H inhibition by ML309 is proposed in which ML309 binds to IDH1 R132H after formation of the IDH1 R132H NADPH complex. ML309 was also able to inhibit 2-HG production in a glioblastoma cell line (IC50 = 250 nm) and had minimal cytotoxicity. In the presence of racemic ML309, 2-HG levels drop rapidly. This drop was sustained until 48 h, at which point the compound was washed out and 2-HG levels recovered. PMID:24668804

Classification of drug molecules considering their IC50 values using mixed-integer linear programming based hyper-boxes method.

PubMed

Armutlu, Pelin; Ozdemir, Muhittin E; Uney-Yuksektepe, Fadime; Kavakli, I Halil; Turkay, Metin

2008-10-03

A priori analysis of the activity of drugs on the target protein by computational approaches can be useful in narrowing down drug candidates for further experimental tests. Currently, there are a large number of computational methods that predict the activity of drugs on proteins. In this study, we approach the activity prediction problem as a classification problem and, we aim to improve the classification accuracy by introducing an algorithm that combines partial least squares regression with mixed-integer programming based hyper-boxes classification method, where drug molecules are classified as low active or high active regarding their binding activity (IC50 values) on target proteins. We also aim to determine the most significant molecular descriptors for the drug molecules. We first apply our approach by analyzing the activities of widely known inhibitor datasets including Acetylcholinesterase (ACHE), Benzodiazepine Receptor (BZR), Dihydrofolate Reductase (DHFR), Cyclooxygenase-2 (COX-2) with known IC50 values. The results at this stage proved that our approach consistently gives better classification accuracies compared to 63 other reported classification methods such as SVM, Naïve Bayes, where we were able to predict the experimentally determined IC50 values with a worst case accuracy of 96%. To further test applicability of this approach we first created dataset for Cytochrome P450 C17 inhibitors and then predicted their activities with 100% accuracy. Our results indicate that this approach can be utilized to predict the inhibitory effects of inhibitors based on their molecular descriptors. This approach will not only enhance drug discovery process, but also save time and resources committed.

Cyclopentenone derivatives and polyhydroxylated steroids from the soft coral Sinularia acuta.

PubMed

Zhang, Nai-Xia; Tang, Xu-Li; van Ofwegen, Leen; Xue, Lei; Song, Wen-Juan; Li, Ping-Lin; Li, Guo-Qiang

2015-02-01

Four new polyhydroxylated steroids, 1-4, and the racemic form of cyclopentenone 9, together with four known steroids, 5-8, one known cyclopentenone derivative, 10, and one known butenolide derivative, 11, were isolated from the soft coral Sinularia acuta collected from Weizhou Island of Guangxi Province, P. R. China. Their structures were elucidated on the basis of spectroscopic analyses and by comparison of the corresponding data with those previously reported. The cytotoxicities of the isolates 1-11 in vitro against the selected tumor cell lines HL-60, HeLa, and K562 were evaluated. Compounds 2 and 5 showed potent cytotoxicities against HL-60 cell lines with IC50 values of 7.3 and 9.9 μM, respectively. Compounds 5 and 6 showed moderate activities against K562 cell lines with IC50 values of 10.9 and 11.7 μM, respectively, while compounds 1, 2, and 6 showed weak activities against HeLa cell lines with respective IC50 values of 44.8, 27.1, and 18.2 μM. This is the first report on chemical and bioactivity research of S. acuta. Copyright © 2015 Verlag Helvetica Chimica Acta AG, Zürich.

Synthesis and biological evaluation of a series of dithiocarbamates as new cholinesterase inhibitors.

PubMed

Altıntop, Mehlika D; Gurkan-Alp, A Selen; Ozkay, Yusuf; Kaplancıklı, Zafer A

2013-08-01

In the present paper, a novel series of dithiocarbamates was synthesized via the treatment of 4-(trifluoromethyl)benzyl chloride with appropriate sodium salts of N,N-disubstituted dithiocarbamic acids. The chemical structures of the compounds were elucidated by (1) H NMR, mass spectral data, and elemental analyses. Each derivative was evaluated for its ability to inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) using a modification of Ellman's spectrophotometric method. The most potent AChE inhibitor was found as compound 2g (IC50  = 0.53 ± 0.001 µM) followed by compounds 2f (IC50  = 0.74 ± 0.001 µM) and 2j (IC50  = 0.89 ± 0.002 µM) when compared with donepezil (IC50  = 0.048 ± 0.001 µM). Compounds 2f and 2g were more effective than donepezil (IC50  = 7.88 ± 0.52 µM) on BuChE inhibition. Compounds 2f and 2g exhibited the inhibitory effect on BuChE with IC50 values of 1.39 ± 0.041 and 3.64 ± 0.072 µM, respectively. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Chemical composition, immunostimulatory, cytotoxic and antiparasitic activities of the essential oil from Brazilian red propolis

PubMed Central

das Neves, Raquel Nascimento; de Pinho, Rodrigo Barros; Silva, Mara Thais de Oliveira; Savegnago, Lucielli; Collares, Tiago; Seixas, Fabiana; Begnini, Karine; Henriques, João Antonio Pêgas; Ely, Mariana Roesch; Rufatto, Luciane C.; Moura, Sidnei; Barcellos, Thiago; Padilha, Francine; Dellagostin, Odir; Borsuk, Sibele

2018-01-01

Most studies of Brazilian red propolis have explored the composition and biological properties of its ethanolic extracts. In this work, we chemically extracted and characterized the essential oil of Brazilian red propolis (EOP) and assessed its adjuvant, antiparasitic and cytotoxic activities. The chemical composition of EOP was analyzed using gas chromatography with mass spectrometry (GC-MS). EOP was tested for in vitro activity against Trichomonas vaginalis (ATCC 30236 isolate); trophozoites were treated with different concentrations of EOP (ranging from 25 to 500 μg/mL) in order to establish the MIC and IC50 values. A cytotoxicity assay was performed in CHO-K1 cells submitted to different EOP concentrations. BALB/c mice were used to test the adjuvant effect of EOP. The animals were divided in 3 groups and inoculated as follows: 0.4 ng/kg BW EOP (G1); 50 μg of rCP40 protein (G2); or a combination of 0.4 ng/kg BW EOP and 50 μg of rCP40 (G3). Total IgG, IgG1 and IgG2a levels were assessed by ELISA. The major constituent compounds of EOP were methyl eugenol (13.1%), (E)-β-farnesene (2.50%), and δ-amorphene (2.3%). Exposure to EOP inhibited the growth of T. vaginalis, with an IC50 value of 100 μg/mL of EOP. An EOP concentration of 500 μg/mL was able to kill 100% of the T. vaginalis trophozoites. The EOP kinetic growth curve showed a 36% decrease in trophozoite growth after a 12 h exposure to 500 μg/mL of EOP, while complete parasite death was induced at 24 h. With regard to CHO-K1 cells, the CC50 was 266 μg/mL, and 92% cytotoxicity was observed after exposure to 500 μg/mL of EOP. Otherwise, a concentration of 200 μg/mL of EOP was able to reduce parasite proliferation by 70% and was not cytotoxic to CHO-K1 cells. As an adjuvant, a synergistic effect was observed when EOP was combined with the rCP40 protein (G3) in comparison to the administration of each component alone (G1 and G2), resulting in higher concentrations of IgG, IgG1 and IgG2a. EOP is constituted by biologically active components with promising antiparasitic and immunostimulatory activities and can be investigated for the formulation of new vaccines or trichomonacidal drugs. PMID:29390009

Galactose conjugated platinum(II) complex targeting the Warburg effect for treatment of non-small cell lung cancer and colon cancer.

PubMed

Wu, Meng; Li, Hong; Liu, Ran; Gao, Xiangqian; Zhang, Menghua; Liu, Pengxing; Fu, Zheng; Yang, Jinna; Zhang-Negrerie, Daisy; Gao, Qingzhi

2016-03-03

Malignant neoplasms exhibit a higher rate of glycolysis than normal cells; this is known as the Warburg effect. To target it, a galactose-conjugated (trans-R,R-cyclohexane-1,2-diamine)-2-chloromalonato-platinum(II) complex (Gal-Pt) was designed, synthesized, and evaluated in five human cancer cell lines and against two different xenograft tumour models. Gal-Pt exhibits much higher aqueous solubility (over 25 times) and improved cytotoxicity than oxaliplatin, especially in human colon (HT29) and lung (H460) cancer cell lines. The safety profile of Gal-Pt was investigated in vivo by exploring the maximum tolerated dose (MTD) and animal mortality rate. The ratios of the animal lethal dosage values to the cytotoxicity in HT29 (LD50/IC50) showed that Gal-Pt was associated with an increased therapeutic index by over 30-fold compared to cisplatin and oxaliplatin. We evaluated in vivo antitumor activity by single agent intravenous treatment comparison studies of Gal-Pt (50 mg/kg as 65% MTD) and cisplatin (3 mg/kg, as 80% MTD) in a H460 lung cancer xenograft model, and with oxaliplatin (7 mg/kg, as 90% MTD) in a HT29 colon cancer xenograft model. The results show that Gal-Pt was more efficacious against H460 than cisplatin, and had superior potency in HT29 cells compared to oxaliplatin under nontoxic dosage conditions. The dependency between cytotoxicity of Gal-Pt and glucose transporters (GLUTs) was investigated by using quercetin as an inhibitor of GLUTs in HT29 cells. The cytotoxic potency of Gal-Pt was highly reduced by the inhibitor, suggesting that the uptake of Gal-Pt was regulated by glucose transporters. The GLUT mediated transportability and cellular uptake of Gal-Pt was also demonstrated using a fluorescent glucose bioprobe in HT29 competition assay. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Design and synthesis of potent antileishmanial cycloalkylidene-substituted ether phospholipid derivatives.

PubMed

Calogeropoulou, Theodora; Angelou, Panagiotis; Detsi, Anastasia; Fragiadaki, Irene; Scoulica, Effie

2008-02-28

Two series of novel ether phospholipids (EPs) have been synthesized. The first includes cyclodecylidene- or cyclopentadecylidene-substituted EPs carrying N,N,N-trimethylammonium or N-methylpiperidino or N-methylmorpholino head groups. The second series encompasses more rigid head groups in combination with cycloalkylidene moieties in the lipid portion. In addition, hydrogenated derivatives were obtained. All the new analogues, except 33, were 1.5- to 62-fold more potent than miltefosine against the intracellular L. infantum, and the most active ones were also less cytotoxic against the human monocytic cell line THP1 and less hemolytic than miltefosine. The analogues that combine high potency with low cytotoxicity and hemolytic activity were 19, 37, 21 23, 38, 39, and 40. Cyclopentadecylpentylphosphocholine (38) possesses an IC50 of 0.7 microM against L. infantum amastigotes and is the least cytotoxic analogue, since it does not present toxicity against THP1 macrophages, even at a concentration that is 800-fold the antiparasitic IC50 value, and does not present significant hemolytic activity.

Reactive Oxygen Species (ROS) Inducible DNA Cross-Linking Agents and Their Effect on Cancer Cells and Normal Lymphocytes

PubMed Central

2015-01-01

Reducing host toxicity is one of the main challenges of cancer chemotherapy. Many tumor cells contain high levels of ROS that make them distinctively different from normal cells. We report a series of ROS-activated aromatic nitrogen mustards that selectively kill chronic lymphocytic leukemia (CLL) over normal lymphocytes. These agents showed powerful DNA cross-linking abilities when coupled with H2O2, one of the most common ROS in cancer cells, whereas little DNA cross-linking was detected without H2O2. Consistent with chemistry observation, in vitro cytotoxicity assay demonstrated that these agents induced 40–80% apoptosis in primary leukemic lymphocytes isolated from CLL patients but less than 25% cell death to normal lymphocytes from healthy donors. The IC50 for the most potent compound (2) was ∼5 μM in CLL cells, while the IC50 was not achieved in normal lymphocytes. Collectively, these data provide utility and selectivity of these agents that will inspire further and effective applications. PMID:24801734

Chemical composition, immunostimulatory, cytotoxic and antiparasitic activities of the essential oil from Brazilian red propolis.

PubMed

Sena-Lopes, Ângela; Bezerra, Francisco Silvestre Brilhante; das Neves, Raquel Nascimento; de Pinho, Rodrigo Barros; Silva, Mara Thais de Oliveira; Savegnago, Lucielli; Collares, Tiago; Seixas, Fabiana; Begnini, Karine; Henriques, João Antonio Pêgas; Ely, Mariana Roesch; Rufatto, Luciane C; Moura, Sidnei; Barcellos, Thiago; Padilha, Francine; Dellagostin, Odir; Borsuk, Sibele

2018-01-01

Most studies of Brazilian red propolis have explored the composition and biological properties of its ethanolic extracts. In this work, we chemically extracted and characterized the essential oil of Brazilian red propolis (EOP) and assessed its adjuvant, antiparasitic and cytotoxic activities. The chemical composition of EOP was analyzed using gas chromatography with mass spectrometry (GC-MS). EOP was tested for in vitro activity against Trichomonas vaginalis (ATCC 30236 isolate); trophozoites were treated with different concentrations of EOP (ranging from 25 to 500 μg/mL) in order to establish the MIC and IC50 values. A cytotoxicity assay was performed in CHO-K1 cells submitted to different EOP concentrations. BALB/c mice were used to test the adjuvant effect of EOP. The animals were divided in 3 groups and inoculated as follows: 0.4 ng/kg BW EOP (G1); 50 μg of rCP40 protein (G2); or a combination of 0.4 ng/kg BW EOP and 50 μg of rCP40 (G3). Total IgG, IgG1 and IgG2a levels were assessed by ELISA. The major constituent compounds of EOP were methyl eugenol (13.1%), (E)-β-farnesene (2.50%), and δ-amorphene (2.3%). Exposure to EOP inhibited the growth of T. vaginalis, with an IC50 value of 100 μg/mL of EOP. An EOP concentration of 500 μg/mL was able to kill 100% of the T. vaginalis trophozoites. The EOP kinetic growth curve showed a 36% decrease in trophozoite growth after a 12 h exposure to 500 μg/mL of EOP, while complete parasite death was induced at 24 h. With regard to CHO-K1 cells, the CC50 was 266 μg/mL, and 92% cytotoxicity was observed after exposure to 500 μg/mL of EOP. Otherwise, a concentration of 200 μg/mL of EOP was able to reduce parasite proliferation by 70% and was not cytotoxic to CHO-K1 cells. As an adjuvant, a synergistic effect was observed when EOP was combined with the rCP40 protein (G3) in comparison to the administration of each component alone (G1 and G2), resulting in higher concentrations of IgG, IgG1 and IgG2a. EOP is constituted by biologically active components with promising antiparasitic and immunostimulatory activities and can be investigated for the formulation of new vaccines or trichomonacidal drugs.

Nanoparticles of Selaginella doederleinii leaf extract inhibit human lung cancer cells A549

NASA Astrophysics Data System (ADS)

Syaefudin; Juniarti, A.; Rosiyana, L.; Setyani, A.; Khodijah, S.

2016-01-01

The aim of the present study is to evaluate cytotoxicity effect of nanoparticles of Selaginella doederleinii (S. doederleinii) leaves extract. S. doederleinii was extracted by maceration method using 70%(v/v) ethanol as solvent. Phytochemical content was analyzed qualitatively by using Harborne and Thin Layer Chromatography (TLC) methods. Nanoparticle extract was prepared by ionic gelation using chitosan as encapsulant agent. Anticancer activity was performed by using 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay. The results showed that S. doederleinii contains of flavonoids. Nanoparticle of S. doederleinii leaves extract greatly inhibited A549 cells growth (cancer cells), with IC50 of 3% or 1020 μg/ml. These nanoparticles extract also inhibited the growth of Chang cells (normal cells), with IC50 of 4% or 1442 μg/ml. The effective concentration of nanoparticles extract which inhibits cancer cells without harming the normal cells is 0.5% or 167 μg/ml. Further studies are needed to obtain the concentration of nanoparticles extract which can selectively suppress cancer cells.

Enzyme Hydrolysates from Stichopus horrens as a New Source for Angiotensin-Converting Enzyme Inhibitory Peptides

PubMed Central

Forghani, Bita; Ebrahimpour, Afshin; Bakar, Jamilah; Abdul Hamid, Azizah; Hassan, Zaiton; Saari, Nazamid

2012-01-01

Stichopus horrens flesh was explored as a potential source for generating peptides with angiotensin-converting enzyme (ACE) inhibitory capacity using 6 proteases, namely alcalase, flavourzyme, trypsin, papain, bromelain, and protamex. Degree of hydrolysis (DH) and peptide profiling (SDS-PAGE) of Stichopus horrens hydrolysates (SHHs) was also assessed. Alcalase hydrolysate showed the highest DH value (39.8%) followed by flavourzyme hydrolysate (32.7%). Overall, alcalase hydrolysate exhibited the highest ACE inhibitory activity (IC50 value of 0.41 mg/mL) followed by flavourzyme hydrolysate (IC50 value of 2.24 mg/mL), trypsin hydrolysate (IC50 value of 2.28 mg/mL), papain hydrolysate (IC50 value of 2.48 mg/mL), bromelain hydrolysate (IC50 value of 4.21 mg/mL), and protamex hydrolysate (IC50 value of 6.38 mg/mL). The SDS-PAGE results showed that alcalase hydrolysate represented a unique pattern compared to others, which yielded potent ACE inhibitory peptides with molecular weight distribution lower than 20 kDa. The evaluation of the relationship between DH and IC50 values of alcalase and flavourzyme hydrolysates revealed that the trend between those parameters was related to the type of the protease used. We concluded that the tested SHHs would be used as a potential source of functional ACE inhibitory peptides for physiological benefits. PMID:22927875

Differences in toxicity of anionic and cationic PAMAM and PPI dendrimers in zebrafish embryos and cancer cell lines

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bodewein, Lambert

Dendrimers are an emerging class of polymeric nanoparticles with beneficial biomedical applications like early diagnostics, in vitro gene transfection or controlled drug delivery. However, the potential toxic impact of exposure on human health or the environment is often inadequately defined. Thus, polyamidoamine (PAMAM) dendrimers of generations G3.0, 3.5, 4.0, 4.5 and 5.0 and polypropylenimine (PPI) dendrimers G3.0, 4.0 and 5.0 were tested in zebrafish embryos for 96 h and human cancer cell lines for 24 h, to assess and compare developmental in vivo toxicity with cytotoxicity. The zebrafish embryo toxicity of cationic PAMAM and PPI dendrimers increased over time, withmore » EC50 values ranging from 0.16 to just below 1.7 μM at 24 and 48 hpf. The predominant effects were mortality, plus reduced heartbeat and blood circulation for PPI dendrimers. Apoptosis in the embryos increased in line with the general toxicity concentration-dependently. Hatch and dechorionation of the embryos increased the toxicity, suggesting a protective role of the chorion. Lower generation dendrimers were more toxic in the embryos whereas the toxicity in the HepG2 and DU145 cell lines increased with increasing generation of cationic PAMAMs and PPI dendrimers. HepG2 were less sensitive than DU145 cells, with IC50 values ≥ 402 μM (PAMAMs) and ≤ 240 μM (PPIs) for HepG2 and ≤ 13.24 μM (PAMAMs) and ≤ 12.84 μM (PPIs) for DU145. Neither in fish embryos nor cells toxicity thresholds were determinable for anionic PAMAM G3.5 and G4.5. The study demonstrated that the cytotoxicity underestimated the in-vivo toxicity of the dendrimers in the fish embryos. - Highlights: • Zebrafish embryo toxicity of cationic PAMAM and PPI dendrimers increased over time. • Zebrafish embryo toxicity of cationic dendrimers did not increase with generation. • Cationic dendrimers induced apoptosis in zebrafish embryos. • Toxicity of cationic dendrimers was lower in HepG2 and DU145 than zebrafish embryos. • Anionic PAMAM dendrimers showed little to no toxicity in fish embryos and cells.« less

Differences in toxicity of anionic and cationic PAMAM and PPI dendrimers in zebrafish embryos and cancer cell lines.

PubMed

Bodewein, Lambert; Schmelter, Frank; Di Fiore, Stefano; Hollert, Henner; Fischer, Rainer; Fenske, Martina

2016-08-15

Dendrimers are an emerging class of polymeric nanoparticles with beneficial biomedical applications like early diagnostics, in vitro gene transfection or controlled drug delivery. However, the potential toxic impact of exposure on human health or the environment is often inadequately defined. Thus, polyamidoamine (PAMAM) dendrimers of generations G3.0, 3.5, 4.0, 4.5 and 5.0 and polypropylenimine (PPI) dendrimers G3.0, 4.0 and 5.0 were tested in zebrafish embryos for 96h and human cancer cell lines for 24h, to assess and compare developmental in vivo toxicity with cytotoxicity. The zebrafish embryo toxicity of cationic PAMAM and PPI dendrimers increased over time, with EC50 values ranging from 0.16 to just below 1.7μM at 24 and 48hpf. The predominant effects were mortality, plus reduced heartbeat and blood circulation for PPI dendrimers. Apoptosis in the embryos increased in line with the general toxicity concentration-dependently. Hatch and dechorionation of the embryos increased the toxicity, suggesting a protective role of the chorion. Lower generation dendrimers were more toxic in the embryos whereas the toxicity in the HepG2 and DU145 cell lines increased with increasing generation of cationic PAMAMs and PPI dendrimers. HepG2 were less sensitive than DU145 cells, with IC50 values≥402μM (PAMAMs) and ≤240μM (PPIs) for HepG2 and ≤13.24μM (PAMAMs) and ≤12.84μM (PPIs) for DU145. Neither in fish embryos nor cells toxicity thresholds were determinable for anionic PAMAM G3.5 and G4.5. The study demonstrated that the cytotoxicity underestimated the in-vivo toxicity of the dendrimers in the fish embryos. Copyright © 2016 Elsevier Inc. All rights reserved.

The Cytotoxicity of Dacarbazine Potentiated by Sea Cucumber Saponin in Resistant B16F10 Melanoma Cells through Apoptosis Induction

PubMed Central

Baharara, Javad; Amini, Elaheh; Nikdel, Najme; Salek-Abdollahi, Farzaneh

2016-01-01

Background: Malignant melanoma is a highly aggressive malignant melanocytic neoplasm which resists against the most conventional therapies. Sea cucumber as one of marine organisms contains bioactive compounds such as polysaccharide, terpenoid and other metabolites which have anti-cancer, anti-tumor, anti-inflammatory and antioxidant properties. The present study was designed to investigate the anticancer potential of saponin extracted from sea cucumber Holothuria leucospilata alone and in combination with dacarbazine on B16F10 melanoma cell line. Methods: The B16F10 cell line was treated with different concentrations of saponin (0, 4, 8, 12, 16, 20 μg/ml), dacarbazine (0, 1200, 1400, 1600, 18000, 1200, 1400, 1600, 2000 μg/ml) and co-administration of saponin-dacarbazine (1200 da+8 sp, 1200 da+4 sp) for 24 and 48 hr and the cytotoxic effect was examined by MTT, DAPI, acridine orange/propodium iodide, flow cytometry and caspase colorimetric assay. Results: The results exhibited that sea cucumber saponin, dacarbazine, and co-administration of saponin-dacarbazine inhibited the proliferation of melanoma cells in a dose and time dependent manner with IC50 values of 10, 1400 and 4+1200 μg/ml, respectively. Morphological observation of DAPI and acridine orange/propodium iodide staining documented typical characteristics of apoptotic cell death. Flow cytometry assay indicated accumulation of IC50 treated cells in sub-G1 peak. Additionally, saponin extracted induced intrinsic apoptosis via up-regulation of caspase-3 and caspase-9. Conclusion: These results revealed that the saponin extracted from sea cucumber as a natural anti-cancer compound may be a new treatment modality for metastatic melanoma and the application of sea cucumber saponin in combination with dacarbazine demonstrated the strongest anti-cancer activity as compared with the drug alone. PMID:27563423

Toxicity of essential oil of Satureja khuzistanica: in vitro cytotoxicity and anti-microbial activity.

PubMed

Yousefzadi, Morteza; Riahi-Madvar, Ali; Hadian, Javad; Rezaee, Fatemeh; Rafiee, Roya; Biniaz, Mehdi

2014-01-01

In nature, essential oils play an important role in the protection of the plants by exerting anti-bacterial, -viral, -fungal, -oxidative, -genotoxic, and free radical scavenging properties, as well as in some cases acting as insecticides. Several Satureja species are used in traditional medicine due to recognized therapeutic properties, namely anti-microbial and cytotoxic activities. The purpose of the present work was to determine the biologic activity of the essential oil of S. khuzistanica Jamzad (Lamiaceae) against four human cancer cell lines, as well as its inhibitory effects against a wide array (i.e. n = 11) of pathogenic bacteria and fungi. The essential oil was isolated by hydro-distillation and analyzed by GC-FID and GC-MS. Carvacrol (92.87%) and limonene (1.2%) were found to be the main components of the isolated oil. Anti-microbial activity of the essential oil was assessed using a disc diffusion method; an MTT cytotoxicity assay was employed to test effects of the oil on each cancer cell line. The oil exhibited considerable anti-microbial activity against the majority of the tested bacteria and fungi. The test oil also significantly reduced cell viability of Vero, SW480, MCF7, and JET 3 cells in a dose-dependent manner, with the IC50 values calculated for each cell type being, respectively, 31.2, 62.5, 125, and 125 μg/ml. Based on the findings, it is concluded that the essential oil of S. khuzistanica and its major constituents have a potential for further use in anti-bacterial and anti-cancer applications, pending far more extensive testing of toxicities in normal (i.e. primary) cells.

Role of Zucchini and Its Distinctive Components in the Modulation of Degenerative Processes: Genotoxicity, Anti-Genotoxicity, Cytotoxicity and Apoptotic Effects

PubMed Central

Martínez-Valdivieso, Damián; Font, Rafael; Fernández-Bedmar, Zahira; Merinas-Amo, Tania; Gómez, Pedro; Alonso-Moraga, Ángeles

2017-01-01

Zucchini (Cucurbita pepo subsp. pepo) is a seasonal vegetable with high nutritional and medical values. Many useful properties of this fruit are attributed to bioactive compounds. Zucchini fruits (“Yellow” and “Light Green” varieties) and four distinctive components (lutein, β-carotene, zeaxanthin and dehydroascorbic acid) were selected. Firstly, the lutein, β-carotene, zeaxanthin and dehydroascorbic acid contents were determined in these fruits. Then, in order to evaluate the safety and suitability of their use, different assays were carried out: (i) genotoxicity and anti-genotoxicity tests to determine the safety and DNA-protection against hydrogen peroxide; (ii) cytotoxicity; and (iii) DNA fragmentation and Annexin V/PI (Propidium Iodide) assays to evaluate the pro-apoptotic effect. Results showed that: (i) all the substances were non-genotoxic; (ii) all the substances were anti-genotoxic except the highest concentration of lutein; (iii) “Yellow” zucchini epicarp and mesocarp exhibited the highest cytotoxic activity (IC50 > 0.1 mg/mL and 0.2 mg/mL, respectively); and (iv) “Light Green” zucchini skin induced internucleosomal DNA fragmentation, β-carotene being the possible molecule responsible for its pro-apoptotic activity. To sum up, zucchini fruit could play a positive role in human health and nutrition due to this fruit and its components were safe, able to inhibit significantly the H2O2-induced damage and exhibit anti-proliferative and pro-apoptotic activities toward HL60 (human promyelocytic leukemia cells) tumor cells. The information generated from this research should be considered when selecting potential accessions for breeding program purposes. PMID:28708122

Inhibition of Procarcinogen Activating Enzyme CYP1A2 Activity and Free Radical Formation by Caffeic Acid and its Amide Analogues.

PubMed

Narongchai, Paitoon; Niwatananun, Kanokporn; Narongchai, Siripun; Kusirisin, Winthana; Jaikang, Churdsak

2016-01-01

Caffeic acid (CAF) and its amide analogues, ethyl 1-(3',4'-dihydroxyphenyl) propen amide (EDPA), phenethyl 1-(3',4'-dihydroxyphenyl) propen amide (PEDPA), phenmethyl 1- (3',4'-dihydroxyphenyl) propen amide (PMDPA) and octyl 1-(3',4'-dihydroxyphenyl) propen amide (ODPA) were investigated for the inhibition of procarcinogen activating enzyme. CYP1A2 and scavenging activity on formation of nitric oxide, superoxide anion, DPPH radical and hydroxyl radical. It was found that they inhibited CYP1A2 enzyme by uncompetitive inhibition. Apparent Ki values of CAF, EDPA, PEDPA, PMDPA and ODPA were 0.59, 0.39, 0.45, 0.75 and 0.80 µM, respectively suggesting potent inhibitors of CYP1A2. Moreover, they potentially scavenged nitric oxide radical with IC 50 values of 0.12, 0.22, 0.28, 0.22 and 0.51 mM, respectively. The IC50 values of superoxide anion scavenging were 0.20, 0.22, 0.44, 2.18 and 2.50 mM, respectively. 1, 1- diphenyl-2- picrylhydrazyl (DPPH) radical-scavenging ability, shown as IC50 values, were 0.41, 0.29, 0.30, 0.89 and 0.84 mM, respectively. Moreover, the hydroxyl radical scavenging in vitro model was shown as IC50 values of 23.22, 21.06, 17.10, 17.21 and 15.81 µM, respectively. From our results, caffeic acid and its amide analogues are in vitro inhibitors of human CYP1A2 catalytic activity and free radical formation. They may be useful to be developed as potential chemopreventive agents that block CYP1A2-mediated chemical carcinogenesis.

Antioxidant and Anti-Inflammatory Activity Determination of One Hundred Kinds of Pure Chemical Compounds Using Offline and Online Screening HPLC Assay.

PubMed

Lee, Kwang Jin; Oh, You Chang; Cho, Won Kyung; Ma, Jin Yeul

2015-01-01

This study investigated the antioxidant activity of one hundred kinds of pure chemical compounds found within a number of natural substances and oriental medicinal herbs (OMH). Three different methods were used to evaluate the antioxidant activity of DPPH radical-scavenging activity, ABTS radical-scavenging activity, and online screening HPLC-ABTS assays. The results indicated that 17 compounds exhibited better inhibitory activity against ABTS radical than DPPH radical. The IC50 rate of a more practical substance is determined, and the ABTS assay IC50 values of gallic acid hydrate, (+)-catechin hydrate, caffeic acid, rutin hydrate, hyperoside, quercetin, and kaempferol compounds were 1.03 ± 0.25, 3.12 ± 0.51, 1.59 ± 0.06, 4.68 ± 1.24, 3.54 ± 0.39, 1.89 ± 0.33, and 3.70 ± 0.15 μg/mL, respectively. The ABTS assay is more sensitive to identifying the antioxidant activity since it has faster reaction kinetics and a heightened response to antioxidants. In addition, there was a very small margin of error between the results of the offline-ABTS assay and those of the online screening HPLC-ABTS assay. We also evaluated the effects of 17 compounds on the NO secretion in LPS-stimulated RAW 264.7 cells and also investigated the cytotoxicity of 17 compounds using a cell counting kit (CCK) in order to determine the optimal concentration that would provide an effective anti-inflammatory action with minimum toxicity. These results will be compiled into a database, and this method can be a powerful preselection tool for compounds intended to be studied for their potential bioactivity and antioxidant activity related to their radical-scavenging capacity.

Design, Synthesis, and Evaluation of Novel Ferroquine and Phenylequine Analogues as Potential Antiplasmodial Agents.

PubMed

Jacobs, Leon; de Kock, Carmen; de Villiers, Katherine A; Smith, Peter J; Smith, Vincent J; van Otterlo, Willem A L; Blackie, Margaret A L

2015-12-01

7-Chloroquinoline-based antimalarial drugs are effective in the inhibition of hemozoin formation in the food vacuole of the Plasmodium parasite, the causative agent of malaria. We synthesized five series of ferroquine (FQ) and phenylequine (PQ) derivatives, which display good in vitro efficacy toward both the chloroquine-sensitive (CQS) NF54 (IC50 : 4.2 nm) and chloroquine-resistant (CQR) Dd2 (IC50 : 33.7 nm) strains of P. falciparum. Several compounds were found to have good inhibitory activity against β-hematin formation in an NP-40 detergent assay, with IC50 values ranging between 10.4 and 19.2 μm. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

The Cytotoxicity of Dacarbazine Potentiated by Sea Cucumber Saponin in Resistant B16F10 Melanoma Cells through Apoptosis Induction.

PubMed

Baharara, Javad; Amini, Elaheh; Nikdel, Najme; Salek-Abdollahi, Farzaneh

2016-01-01

Malignant melanoma is a highly aggressive malignant melanocytic neoplasm which resists against the most conventional therapies. Sea cucumber as one of marine organisms contains bioactive compounds such as polysaccharide, terpenoid and other metabolites which have anti-cancer, anti-tumor, anti-inflammatory and antioxidant properties. The present study was designed to investigate the anticancer potential of saponin extracted from sea cucumber Holothuria leucospilata alone and in combination with dacarbazine on B16F10 melanoma cell line. The B16F10 cell line was treated with different concentrations of saponin (0, 4, 8, 12, 16, 20 μg/ml), dacarbazine (0, 1200, 1400, 1600, 18000, 1200, 1400, 1600, 2000 μg/ml) and co-administration of saponin-dacarbazine (1200 da+8 sp, 1200 da+4 sp) for 24 and 48 hr and the cytotoxic effect was examined by MTT, DAPI, acridine orange/propodium iodide, flow cytometry and caspase colorimetric assay. The results exhibited that sea cucumber saponin, dacarbazine, and co-administration of saponin-dacarbazine inhibited the proliferation of melanoma cells in a dose and time dependent manner with IC50 values of 10, 1400 and 4+1200 μg/ml, respectively. Morphological observation of DAPI and acridine orange/propodium iodide staining documented typical characteristics of apoptotic cell death. Flow cytometry assay indicated accumulation of IC50 treated cells in sub-G1 peak. Additionally, saponin extracted induced intrinsic apoptosis via up-regulation of caspase-3 and caspase-9. These results revealed that the saponin extracted from sea cucumber as a natural anti-cancer compound may be a new treatment modality for metastatic melanoma and the application of sea cucumber saponin in combination with dacarbazine demonstrated the strongest anti-cancer activity as compared with the drug alone.

Validation and Clinical Utility of the hERG IC50:Cmax Ratio to Determine the Risk of Drug-Induced Torsades de Pointes: A Meta-Analysis.

PubMed

Lehmann, David F; Eggleston, William D; Wang, Dongliang

2018-03-01

Use of the QT interval corrected for heart rate (QTc) on the electrocardiogram (ECG) to predict torsades de pointes (TdP) risk from culprit drugs is neither sensitive nor specific. The ratio of the half-maximum inhibitory concentration of the hERG channel (hERG IC50) to the peak serum concentration of unbound drug (C max ) is used during drug development to screen out chemical entities likely to cause TdP. To validate the use of the hERG IC50:C max ratio to predict TdP risk from a culprit drug by its correlation with TdP incidence. Medline (between 1966 and March 2017) was accessed for hERG IC50 and C max values from the antihistamine, fluoroquinolone, and antipsychotic classes to identify cases of drug-induced TdP. Exposure to a culprit drug was estimated from annual revenues reported by the manufacturer. Inclusion criteria for TdP cases were provision of an ECG tracing that demonstrated QTc prolongation with TdP and normal serum values of potassium, calcium, and magnesium. Cases reported in patients with a prior rhythm disturbance and those involving a drug interaction were excluded. The Meta-Analysis of Observational Studies in Epidemiology checklist was used for epidemiological data extraction by two authors. Negligible risk drugs were defined by an hERG IC50:C max ratio that correlated with less than a 5% chance of one TdP event for every 100 million exposures (relative risk [RR] 1.0). The hERG IC50:C max ratio correlated with TdP risk (0.312; 95% confidence interval 0.205-0.476, p<0.0001), a ratio of 80 (RR 1.0). The RR from olanzapine is on par with loratadine; ziprasidone is comparable with ciprofloxacin. Drugs with an RR greater than 50 include astemizole, risperidone, haloperidol, and thioridazine. The hERG IC50:C max ratio was correlated with TdP incidence for culprit drugs. This validation provides support for the potential use of the hERG IC50:C max ratio for clinical decision making in instances of drug selection where TdP risk is a concern. © 2018 Pharmacotherapy Publications, Inc.

Asphodosides A-E, anti-MRSA metabolites from Asphodelus microcarpus.

PubMed

Ghoneim, Mohammed M; Elokely, Khaled M; El-Hela, Atef A; Mohammad, Abd-Elsalam I; Jacob, Melissa; Radwan, Mohamed M; Doerksen, Robert J; Cutler, Stephen J; Ross, Samir A

2014-09-01

Bioassay guided fractionation of the ethanolic extract of Asphodelus microcarpus Salzm. et Viv. (Xanthorrhoeaceae or Asphodelaceae) resulted in isolation of five compounds identified as asphodosides A-E (1-5). Compounds 2-4 showed activity against methicillin resistant Staphylococcus aureus (MRSA) with IC50 values of 1.62, 7.0 and 9.0μg/mL, respectively. They also exhibited activity against Staphylococcus aureus (non-MRSA) with IC50 values of 1.0, 3.4 and 2.2μg/mL, respectively. The structure elucidation of isolated metabolites was carried out using spectroscopic data (1D and 2D NMR), optical rotation and both experimental and calculated electronic circular dichroism (ECD). Copyright © 2014 Elsevier Ltd. All rights reserved.

Biochemical, cellular, and biophysical characterization of a potent inhibitor of mutant isocitrate dehydrogenase IDH1.

PubMed

Davis, Mindy I; Gross, Stefan; Shen, Min; Straley, Kimberly S; Pragani, Rajan; Lea, Wendy A; Popovici-Muller, Janeta; DeLaBarre, Byron; Artin, Erin; Thorne, Natasha; Auld, Douglas S; Li, Zhuyin; Dang, Lenny; Boxer, Matthew B; Simeonov, Anton

2014-05-16

Two mutant forms (R132H and R132C) of isocitrate dehydrogenase 1 (IDH1) have been associated with a number of cancers including glioblastoma and acute myeloid leukemia. These mutations confer a neomorphic activity of 2-hydroxyglutarate (2-HG) production, and 2-HG has previously been implicated as an oncometabolite. Inhibitors of mutant IDH1 can potentially be used to treat these diseases. In this study, we investigated the mechanism of action of a newly discovered inhibitor, ML309, using biochemical, cellular, and biophysical approaches. Substrate binding and product inhibition studies helped to further elucidate the IDH1 R132H catalytic cycle. This rapidly equilibrating inhibitor is active in both biochemical and cellular assays. The (+) isomer is active (IC50 = 68 nm), whereas the (-) isomer is over 400-fold less active (IC50 = 29 μm) for IDH1 R132H inhibition. IDH1 R132C was similarly inhibited by (+)-ML309. WT IDH1 was largely unaffected by (+)-ML309 (IC50 >36 μm). Kinetic analyses combined with microscale thermophoresis and surface plasmon resonance indicate that this reversible inhibitor binds to IDH1 R132H competitively with respect to α-ketoglutarate and uncompetitively with respect to NADPH. A reaction scheme for IDH1 R132H inhibition by ML309 is proposed in which ML309 binds to IDH1 R132H after formation of the IDH1 R132H NADPH complex. ML309 was also able to inhibit 2-HG production in a glioblastoma cell line (IC50 = 250 nm) and had minimal cytotoxicity. In the presence of racemic ML309, 2-HG levels drop rapidly. This drop was sustained until 48 h, at which point the compound was washed out and 2-HG levels recovered. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

In vitro antiplasmodial and cytotoxic properties of some medicinal plants from western Burkina Faso

PubMed Central

Gansane, Adama; Ouattara, Lamoussa P.; Traore, Abdoulaye; Ouedraogo, Issa N.; Tiono, Alfred; Taramelli, Donatella; Basilico, Nicoletta; Sirima, Sodiomon B.

2013-01-01

Background Resistance of malaria parasites to existing drugs complicates treatment, but an antimalarial vaccine that could protect against this disease is not yet available. It is therefore necessary to find new effective and affordable medicines. Medicinal plants could be a potential source of antimalarial agents. Some medicinal plants from Burkina Faso were evaluated for their antiplasmodial and cytotoxic properties in vitro. Methods Crude dichloromethane, methanol, water-methanol, aqueous and alkaloids extracts were prepared for 12 parts of 10 plants. Chloroquine-resistant malaria strain K1 was used for the in vitro sensibility assay. The Plasmodium lactacte dehydrogenase technique was used to determine the 50% inhibitory concentration of parasites activity (IC50). The cytotoxic effects were determined with HepG2 cells, using the tetrazolium-based colorimetric technique, and the selectivity index (SI) was calculated. Results Sixty crude extracts were prepared. Seven extracts from Terminalia avicenoides showed IC50 < 5 µg/mL. The IC50 of dichloromethane, methanol, aqueous and alkaloids extracts ranged between 1.6 µg/mL and 4.5 µg/mL. Three crude extracts from Combretum collinum and three from Ficus capraefolia had an IC50 ranging between 0.2 µg/mL and 2.5 µg/mL. Crude extracts from these three plants had no cytotoxic effect, with SI > 1. The other plants have mostly moderate or no antimalarial effects. Some extracts from Cordia myxa, Ficus capraefolia and Opilia celtidifolia showed cytotoxicity, with an SI ranging between 0.4 and 0.9. Conclusion Our study showed a good antiplasmodial in vitro activity of Terminalia avicenoides, Combretum collinum and Ficus capraefolia. These three plants may contain antiplasmodial molecules that could be isolated by bio-guided phytochemical studies. PMID:29043169

Synthesis and discovery of novel piperidone-grafted mono- and bis-spirooxindole-hexahydropyrrolizines as potent cholinesterase inhibitors.

PubMed

Kia, Yalda; Osman, Hasnah; Kumar, Raju Suresh; Murugaiyah, Vikneswaran; Basiri, Alireza; Perumal, Subbu; Wahab, Habibah A; Bing, Choi Sy

2013-04-01

Three-component reaction of a series of 1-acryloyl-3,5-bisbenzylidenepiperidin-4-ones with isatin and L-proline in 1:1:1 and 1:2:2 molar ratios in methanol afforded, respectively the piperidone-grafted novel mono- and bisspiro heterocyclic hybrids comprising functionalized piperidine, pyrrolizine and oxindole ring systems in good yields. The in vitro evaluation of cholinesterase enzymes inhibitory activity of these cycloadducts disclosed that monospiripyrrolizines (8a-k), are more active with IC50 ranging from 3.36 to 20.07 μM than either the dipolarophiles (5a-k) or bisspiropyrrolizines (9a-k). The compounds, 8i and 8e with IC50 values of 3.36 and 3.50 μM, respectively showed the maximum inhibition of acethylcholinesterase (AChE) and butrylylcholinestrase (BuChE). Molecular modeling simulation, disclosed the binding interactions of the most active compounds to the active site residues of their respective enzymes. The docking results were in accordance with the IC50 values obtained from in vitro cholinesterase assay. Copyright © 2013 Elsevier Ltd. All rights reserved.

Nira acidity and antioxidant activity of Palm sugar in Sumowono Village

NASA Astrophysics Data System (ADS)

Winarni, Sri; Arifan, Fahmi; Wisnu Broto, RTD.; Fuadi, Ariza; Alviche, Lola

2018-05-01

The palm sugar not only has potential as natural sweetener but also has antioxidant. The purpose of this study was to analyze antioxidant and pH of the nira in palm sugar. The sample in this study was palm sugar from 6 different production sites. Test of antioxidant activity used DPPH method (1.1-diphenyl-2-picrylhydrazyl) with a wavelength of 517 nm. The value of absorbance solution was measured using spectrophotometry and the value of effective concentration (IC50) was counted. The pH test was measured using a pH meter. Pearson’s correlation test revealed r=-0.045 with significant value 0.932 (>0.005). There was no correlation between pH value and antioxidant activity of palm sugar. IC50 value of palm sugar in Sumowono village revealed that it had a strong antioxidant activity (50 μg/ml - 100 μg/ml) that is 74,73 μg/ml 83.94 μg/ml 82.31 μg/ml 83.94 μg/ml 86.10 μg/ml 82.13 μg/ml 89.17 μg/ml 89.71 μg/ml 89.17 μg/ml and 84.84 μg/ml). Lower IC50 values indicate higher antioxidant activity. Palm sugar with the best antioxidant activity came from the production sites which had IC50 values of 74.73 μg/ml. Potential antioxidants can be optimized by making improvements to the processing system.

New isochromophilones VII and VIII produced by Penicillium sp. FO-4164.

PubMed

Yang, D J; Tomoda, H; Tabata, N; Masuma, R; Omura, S

1996-03-01

New isochromophilones VII and VIII were isolated from the culture broth of Penicillium sp. FO-4164. The structures were elucidated as 6H-2-benzopyran-6,8(7H)-dione, 5-chloro-3-(3',5'-dimethyl-1',3'-heptadienyl)-1,7,8a-trihydro-7, 8a-dihydroxy-7-methyl-7-acetate for isochromophilone VII and 6H-2-benzopyran-6-one,5-chloro-3-(3',5'-dimethyl-1', 3'-heptadienyl)-1,7,8,8a-tetrahydro-7,8-dihydroxy-7-methyl-8-acetate for isochromophilone VIII. Isochromophilones VII and VIII inhibited diacylglycerol acyltransferase activity with IC50 values of 20.0 and 127 microM and acyl-CoA: cholesterol acyltransferase activity with IC50 values of 24.5 and 47.0 microM, respectively.

Cancer targeting potential of folate targeted nanocarrier under comparative influence of tretinoin and dexamethasone.

PubMed

Dhakad, Raghvendra Singh; Tekade, Rakesh Kumar; Jain, Narendra Kumar

2013-08-01

The objective of this investigation was aimed to explore the cancer targeting potential of folate conjugated dendrimer (polypropylene imine, PPI) under strategic influence of folate receptor up-regulators (all trans Retinoic acid, ATRA and Dexamethasone, DEXA). The folate conjugated dendrimer nanoconjugate (FPPI) was synthesized and characterized by FTIR, and (1)H-NMR spectroscopy. The cell line studies investigations were performed on MCF-7 cells. ATRA and DEXA caused 2.17 and 1.65 folds selective up-regulation of folate receptor respectively, when compared with untreated control, after 48 h of pretreatment. ATRA caused 50.47±2.11% more up regulation of folate receptor, than DEXA treated cell. Both up regulators showed a lag phase of 12 h in up-regulating the folate receptors. After 48 h, the IC50 values of naked docetaxel (DTX) and DTX loaded dendrimer (PPI-DTX) were found to be 678.93±11.99 nM and 663.51±15.23 nM, respectively, while DTX loaded folate-anchored dendrimer (FPPI-DTX) showed a selectively lowered IC50 value of 468.56±20.86 nM. FPPI-DTX further showed a significant reduction in IC50 value in ATRA and DEXA pretreated cells, wherein IC50 values of 184.21 nM and 290.40±14.05 nM, respectively were observed. The study also concludes ATRA to be a superior receptor up-regulator as well as promoter of folate based targeting compared to DEXA.

Synthesis, characterization and in vitro anticancer activity of 18-membered octaazamacrocyclic complexes of Co(II), Ni(II), Cd(II) and Sn(II)

NASA Astrophysics Data System (ADS)

Kareem, Abdul; Zafar, Hina; Sherwani, Asif; Mohammad, Owais; Khan, Tahir Ali

2014-10-01

An effective series of 18 membered octaazamacrocyclic complexes of the type [MLX2], where X = Cl or NO3 have been synthesized by template condensation reaction of oxalyl dihydrazide with dibenzoylmethane and metal salt in 2:2:1 molar ratio. The formation of macrocyclic framework, stereochemistry and their overall geometry have been characterized by various physico-chemical studies viz., elemental analysis, electron spray ionization-mass spectrometry (ESI-MS), I.R, UV-Vis, 1H NMR, 13C NMR spectroscopy, X-ray diffraction (XRD) and TGA/DTA studies. These studies suggest formation of octahedral macrocyclic complexes of Co(II), Ni(II), Cd(II) and Sn(II). The molar conductance values suggest nonelectrolytic nature for all the complexes. Thermogravimatric analysis shows that all the complexes are stable up to 600 °C. All these complexes have been tested against different human cancer cell lines i.e. human hepatocellular carcinoma (Hep3B), human cervical carcinoma (HeLa), human breast adenocarcinoma (MCF7) and normal cells (PBMC). The newly synthesized 18-membered octaazamacrocyclic complexes during in vitro anticancer evaluation, displayed moderate to good cytotoxicity on liver (Hep3B), cervical (HeLa) and breast (MCF7) cancer cell lines, respectively. The most effective anticancer cadmium complex (C34H28N10CdO10) was found to be active with IC50 values, 2.44 ± 1.500, 3.55 ± 1.600 and 4.82 ± 1.400 in micro-molar on liver, cervical and breast cancer cell lines, respectively.

Anthraquinones inhibit tau aggregation and dissolve Alzheimer's paired helical filaments in vitro and in cells.

PubMed

Pickhardt, Marcus; Gazova, Zuzana; von Bergen, Martin; Khlistunova, Inna; Wang, Yipeng; Hascher, Antje; Mandelkow, Eva-Maria; Biernat, Jacek; Mandelkow, Eckhard

2005-02-04

The abnormal aggregation of tau protein into paired helical filaments (PHFs) is one of the hallmarks of Alzheimer's disease. Aggregation takes place in the cytoplasm and could therefore be cytotoxic for neurons. To find inhibitors of PHF aggregation we screened a library of 200,000 compounds. The hits found in the PHF inhibition assay were also tested for their ability to dissolve preformed PHFs. The results were obtained using a thioflavin S fluorescence assay for the detection and quantification of tau aggregation in solution, a tryptophan fluorescence assay using tryptophan-containing mutants of tau, and confirmed by a pelleting assay and electron microscopy of the products. Here we demonstrate the feasibility of the approach with several compounds from the family of anthraquinones, including emodin, daunorubicin, adriamycin, and others. They were able to inhibit PHF formation with IC50 values of 1-5 microm and to disassemble preformed PHFs at DC50 values of 2-4 microm. The compounds had a similar activity for PHFs made from different tau isoforms and constructs. The compounds did not interfere with the stabilization of microtubules by tau. Tau-inducible neuroblastoma cells showed the formation of tau aggregates and concomitant cytotoxicity, which could be prevented by inhibitors. Thus, small molecule inhibitors could provide a basis for the development of tools for the treatment of tau pathology in AD and other tauopathies.

The Eye Drop Preservative Benzalkonium Chloride Potently Induces Mitochondrial Dysfunction and Preferentially Affects LHON Mutant Cells.

PubMed

Datta, Sandipan; Baudouin, Christophe; Brignole-Baudouin, Francoise; Denoyer, Alexandre; Cortopassi, Gino A

2017-04-01

Benzalkonium chloride (BAK) is the most commonly used eye drop preservative. Benzalkonium chloride has been associated with toxic effects such as "dry eye" and trabecular meshwork degeneration, but the underlying biochemical mechanism of ocular toxicity by BAK is unclear. In this study, we propose a mechanistic basis for BAK's adverse effects. Mitochondrial O2 consumption rates of human corneal epithelial primary cells (HCEP), osteosarcoma cybrid cells carrying healthy (control) or Leber hereditary optic neuropathy (LHON) mutant mtDNA [11778(G>A)], were measured before and after acute treatment with BAK. Mitochondrial adenosine triphosphate (ATP) synthesis and cell viability were also measured in the BAK-treated control: LHON mutant and human-derived trabecular meshwork cells (HTM3). Benzalkonium chloride inhibited mitochondrial ATP (IC50, 5.3 μM) and O2 consumption (IC50, 10.9 μM) in a concentration-dependent manner, by directly targeting mitochondrial complex I. At its pharmaceutical concentrations (107-667 μM), BAK inhibited mitochondrial function >90%. In addition, BAK elicited concentration-dependent cytotoxicity to cybrid cells (IC50, 22.8 μM) and induced apoptosis in HTM3 cells at similar concentrations. Furthermore, we show that BAK directly inhibits mitochondrial O2 consumption in HCEP cells (IC50, 3.8 μM) at 50-fold lower concentrations than used in eye drops, and that cells bearing mitochondrial blindness (LHON) mutations are further sensitized to BAK's mitotoxic effect. Benzalkonium chloride inhibits mitochondria of human corneal epithelial cells and cells bearing LHON mutations at pharmacologically relevant concentrations, and we suggest this is the basis of BAK's ocular toxicity. Prescribing BAK-containing eye drops should be avoided in patients with mitochondrial deficiency, including LHON patients, LHON carriers, and possibly primary open-angle glaucoma patients.

The Eye Drop Preservative Benzalkonium Chloride Potently Induces Mitochondrial Dysfunction and Preferentially Affects LHON Mutant Cells

PubMed Central

Datta, Sandipan; Baudouin, Christophe; Brignole-Baudouin, Francoise; Denoyer, Alexandre; Cortopassi, Gino A.

2017-01-01

Purpose Benzalkonium chloride (BAK) is the most commonly used eye drop preservative. Benzalkonium chloride has been associated with toxic effects such as “dry eye” and trabecular meshwork degeneration, but the underlying biochemical mechanism of ocular toxicity by BAK is unclear. In this study, we propose a mechanistic basis for BAK's adverse effects. Method Mitochondrial O2 consumption rates of human corneal epithelial primary cells (HCEP), osteosarcoma cybrid cells carrying healthy (control) or Leber hereditary optic neuropathy (LHON) mutant mtDNA [11778(G>A)], were measured before and after acute treatment with BAK. Mitochondrial adenosine triphosphate (ATP) synthesis and cell viability were also measured in the BAK-treated control: LHON mutant and human-derived trabecular meshwork cells (HTM3). Results Benzalkonium chloride inhibited mitochondrial ATP (IC50, 5.3 μM) and O2 consumption (IC50, 10.9 μM) in a concentration-dependent manner, by directly targeting mitochondrial complex I. At its pharmaceutical concentrations (107–667 μM), BAK inhibited mitochondrial function >90%. In addition, BAK elicited concentration-dependent cytotoxicity to cybrid cells (IC50, 22.8 μM) and induced apoptosis in HTM3 cells at similar concentrations. Furthermore, we show that BAK directly inhibits mitochondrial O2 consumption in HCEP cells (IC50, 3.8 μM) at 50-fold lower concentrations than used in eye drops, and that cells bearing mitochondrial blindness (LHON) mutations are further sensitized to BAK's mitotoxic effect. Conclusions Benzalkonium chloride inhibits mitochondria of human corneal epithelial cells and cells bearing LHON mutations at pharmacologically relevant concentrations, and we suggest this is the basis of BAK's ocular toxicity. Prescribing BAK-containing eye drops should be avoided in patients with mitochondrial deficiency, including LHON patients, LHON carriers, and possibly primary open-angle glaucoma patients. PMID:28444329

[Study of the effect of surface-active agents on living cells, used as component parts in microemulsions, based on their chemical structures and critical micelle-formative concentration (CMC)].

PubMed

Ujhelyi, Zoltán; Vecsernyés, Miklós; Bácskay, Ildikó

2013-01-01

The aim of this study was to examine the cellular effects of two nonionic amphiphilic tenside groups and their mixtures on human Caco-2 cell monolayers as dependent upon their chemical structures and physicochemical properties. The first group of polyethylene glycol esters is represented by Polysorbates and Labrasol alone and in blends, while the members of the second group:Capryol 90, Capryol PGMC, Lauroglycol 90 and Lauroglycol FCC were used as propylene glycol esters. They are increasingly used in SMEDDS as recent tensides or co-tensides to increase the solubility of hydrophobic drug. Critical micelle concentration was measured by determination of surface tension. CMC refers to the ability of solubilization of surfactants. Cytotoxicity tests were performed on Caco-2 cell monolayers by MTT and LDH methods. Caco-2 cell monolayers are convenient and reliable in vitro models of the gastrointestinal tract. Paracellular permeability was examined with Lucifer yellow assays. The integrity of cell monolayers was observed by TransEpithelial Electrical Resistance (TEER) measurements. Tight junction alterations effected by the surfactants were also characterized as evidence for paracellular pathway. Changes in sub cellular localization of the tight junction proteins: ZO-1, Claudin-land beta-cathenin, were examined by confocal laser scanning microscopy.The results of cytotoxicity assays were in agreement and showed significant differences among the cytotoxic properties of surfactants in a concentration-dependent manner. Polysorbates 20, 60, 80 are the most toxic compounds. In the case of Labrasol, the degree of esterification and lack of sorbit component decreased cytotoxicity. If the hydrophyl head was changed from polyethylene glycol to propylene glycol, the main determined factor of cytotoxicity was the monoester content and the length of carbon chain. In our CMC experiments, we found that only Labrasol showed expressed cytotoxicity above the CMC. It refers to good ability of micelle solubilization of Labrasol. In our paracellular transport experiments each of polyethylene glycol surfactants (Polysorbates and Labrasol) altered TEER values but propylene glycol esters did not modify the monolayer integrity. Polyethylene glycol esters alone and in blends (0.05% Labrasol--0.001% Polysorbates 20, 60, 80) were able to increase Lucifer yellow permeability significantly below the IC50 concentration. On the other hand Labrasol and Polysorbates 20 have expressed effect on tight junctions of Caco-2 monolayer. It could be concluded that polyethylene glycol ester-type tensides were able to enhance the paracellular permeability by the redistribution of junctional proteins. Our results might ensure useful data for selection of suitable tensides, co-tensides and tenside mixtures for SMEDDS formulations.

Endophytic fungi associated with Sudanese medicinal plants show cytotoxic and antibiotic potential.

PubMed

Khiralla, Afra; Mohamed, Ietidal E; Tzanova, Tzvetomira; Schohn, Hervé; Slezack-Deschaumes, Sophie; Hehn, Alain; André, Philippe; Carre, Gaëlle; Spina, Rosella; Lobstein, Annelise; Yagi, Sakina; Laurain-Mattar, Dominique

2016-06-01

In this study, we isolated 15 endophytic fungi from five Sudanese medicinal plants. Each fungal endophytic strain was identified by sequencing of internal transcribed spacer (ITS) regions of rDNA. Ethyl acetate extracts were prepared from each endophyte cultivated in vitro and tested for their respective antibacterial activities and antiproliferative activities against human cancer cells. Antibacterial screening was carried out against two bacterial strains: Gram-negative Escherichia coli and Gram-positive methicillin-resistant Staphylococcus aureus, by the broth dilution method. Cell viability was evaluated by the MTT procedure after exposure of MCF7 breast cancer cells and HT29 or HCT116 human colon adenocarcinoma cells to each endophytic extract. Of interest, Byssochlamys spectabilis isolated from Euphorbia prostata showed cytotoxicity (IC50 = 1.51 ± 0.2 μg mL(-1)) against MCF7 cells, but had a low effect against HT29 or HCT116 cells (IC50 > 20 μg mL(-1)). Cladosporium cladosporioides 2, isolated from Vernonia amygdalina leaves, showed antiproliferative activities against MCF7 cells (IC50 = 10.5 ± 1.5 μg mL(-1)) only. On the other hand, B. spectabilis and Alternaria sp. extract had antibacterial activities against the S. aureus strain. The findings of this work revealed that endophytic fungi associated with medicinal plants from Sudan could be considered as an attractive source of new therapeutic compounds. © FEMS 2016. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Synthesis, characterization, cytotoxicity, cell cycle analysis of 3-(4-methoxyphenyl)-1-(pyridin-2-ylmethyl)thiourea and quantum chemical analyses

NASA Astrophysics Data System (ADS)

Mushtaque, Md.; Avecilla, Fernando; Khan, Md. Shahzad; Hafeez, Zubair Bin; Rezvi, M. Moshahid A.; Srivastava, Anurag

2017-08-01

Thiourea derivative,3-(4-methoxyphenyl)-1-(pyridin-2-ylmethyl)thiourea, was synthesized. The structure of the synthesized compound (3) was elucidated by IR, UV-visible, 1H NMR, mass Spectrometry, and X-ray single crystal structure. The computational quantum chemical studies like, IR, UV, NBO analysis were performed by DFT with Becke-3-Lee-Yang- Parr (B3LYP) exchange-correlation functional in combination with 6-311++G(d,p) basis sets. It was observed experimentally and theoretically that compound (3) exhibited syn-anti-conformation around sulphur atom. The DNA-binding constant Kb was found 3.3 × 106 Lmol-1. The docking energy of compound (3) with 1BNA was found -6.2 kcal/mol. MTT-assay against HepG2 (IC50 = 140.39) and Siha (IC50 = 119.87 μM) cell lines revealed that compound (3) wasnon-toxic up to140.39 μM against HepG2 and 119.87 μM against Siha cells respectively. It was also found that compound (3) is non-toxic against normal human cell line HEK-293(IC50 = 148.67 μM). Cell cycle analyses displayed that treated HepG2 cells at 40 μM and 80 μM showed 65% and 70% arrest in G0/G1with respect to untreated controls (60%) and Siha cells at the same concentration displayed 59% and 65% arrest with respect to G0/G1 as compared to untreated control (45%).

Antioxidant potential of n-butanol fraction from extract of Jasminum mesnyi Hance leaves.

PubMed

Borar, Sakshi; Punia, Priyanka; Kalia, A N

2011-01-01

Methanolic extract of Jasminum mesnyi Hance leaves having antidiabetic activity was subjected to fractionation to obtain antioxidant and antihyperglycemic rich fraction. Different concentrations of ethyl acetate and n-butanol fractions were subjected to antioxidant assay by DPPH method, nitric oxide scavenging activity and reducing power assay. The fractions showed dose dependent free radical scavenging property in all the models. IC50 values for ethyl acetate and n-butanol fractions were 153.45 +/- 6.65 and 6.22 +/- 0.25 microg/ml, respectively, as compared to L-ascorbic acid and rutin (as standards; IC50 values 6.54 +/- 0.24 and 5.43 +/- 0.21 microg/ml, respectively) in DPPH model. In nitric oxide scavenging activity, IC50 values were 141.54 +/- 9.95 microg/ml, 35.12 +/- 1.58 microg/ml, 21.06 +/- 0.95 microg/ml and 29.93 +/- 0.32 microg/ml for ethyl acetate, n-butanol fractions, L-ascorbic acid and rutin, respectively. n-Butanol fraction showed a good reducing potential and better free radical scavenging activity as compared to ethyl acetate fraction. Potent antioxidant n-butanol fraction showed better oral glucose tolerance test (antihyperglycemic) at par with metformin (standard drug), n-Butanol fraction contained secoiridoid glycosides which might be responsible for both antioxidant and antihyperglycemic activity.

Targeted Delivery of Proteasome Inhibitors to Somatostatin-Receptor-Expressing Cancer Cells by Octreotide Conjugation.

PubMed

Beck, Philipp; Cui, Haissi; Hegemann, Julian D; Marahiel, Mohammed A; Krüger, Achim; Groll, Michael

2015-12-01

Clinical application of proteasome inhibitors (PIs) is so far limited to peripheral blood cancers due to the pronounced cytotoxicity towards all cell types. Targeted delivery of PIs could permit the treatment of other cancers along with decreasing side effects. Herein we describe the first small-molecule proteasome inhibitor conjugate for targeted delivery, created by fusing PIs to a synthetic ligand of somatostatin receptors, which are highly expressed in a variety of tumors. X-ray crystallographic studies and in vitro IC50 measurements demonstrated that addition of the cyclopeptide octreotide as a targeting vehicle does not affect the PI's binding mode. The cytotoxicity of the conjugate against somatostatin-receptor-expressing cells was up to 11-fold higher than that of a non-targeting surrogate. We have therefore established PIs as a new payload for drug conjugates and have shown that targeted delivery thereof could be a promising approach for the broader application of this FDA-approved class of compounds. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Comparative evaluation of antiproliferative effects of Brazilian green propolis, its main source Baccharis dracunculifolia, and their major constituents artepillin C and baccharin.

PubMed

de Oliveira, Pollyanna Francielli; de Souza Lima, Ildercílio Mota; Munari, Carla Carolina; Bastos, Jairo Kenupp; da Silva Filho, Ademar Alves; Tavares, Denise Crispim

2014-04-01

This study evaluated the antiproliferative activity of the Brazilian green propolis and Baccharis dracunculifolia extracts and their major compounds artepillin C and baccharin in different tumor cell lines. The lowest IC50 values observed for Brazilian green propolis and B. dracunculifolia extracts were 41.0 ± 4.5 µg/mL for U343 and 44.9 ± 7.1 µg/mL for HepG2, respectively. Regarding artepillin C and baccharin, the lowest IC50 values were 20.1 ± 2.9 for U343 and 13.0 ± 1.5 µg/mL for B16F10, respectively. For the association of artepillin C plus baccharin, the lowest IC50 result was 35.2 ± 0.5 µg/mL for B16F10. Artepillin C and baccharin were more cytotoxic than both Brazilian green propolis and B. dracunculifolia extracts. No additive or synergistic effect was observed for the association of artepillin C plus baccharin. Georg Thieme Verlag KG Stuttgart · New York.

Curcumin-loaded lipid nanocarrier for improving bioavailability, stability and cytotoxicity against malignant glioma cells.

PubMed

Kumar, Anil; Ahuja, Alka; Ali, Javed; Baboota, Sanjula

2016-01-01

In the present study, Curcumin (CU)-loaded nanocarrier (NC) such as nanoemulsion (NE) was developed with the objective of increasing its cytotoxicity and bioavailability through lymphatic transport by enhancing its solubility and intestinal permeability. Based on the area obtained in pseudoternary phase diagram, various % combination of Labrafac Lipophile WL 1349, Solutol HS 15, Transcutol HP and distilled water were selected. Formulations which passed physical stability studies were selected for further studies such as globule size, zeta potential, in vitro release, ex vivo permeation, in vitro lipolysis studies, bioavailability studies and cytotoxicity against glioblastoma cells (U-87). The optimized NC (NE-SB1) had small average globule diameter of 67 ± 6 nm with zeta potential of -37 ± 2.5 mv which indicated long-term dispersion stability. During in vitro lipolysis study, the digestion rate of medium chain triglycerides increased with decreased globule diameter. Statistically significant difference was found in AUC0-inf of NC formulation (p < 0.05) compared to CU suspension. The relative bioavailability of NC was found 11.88 ± 0.47 with respect to CU suspension. During cytotoxicity studies, IC50 of CU solution on U87 cells was found 24.23 µM, while for the NE- SB1 it was 16.41 µM. The optimized formulation was found to be stable during 6 months of accelerated stability. The overall results revealed that the CU-loaded NC is a very effective approach for enhancing the oral absorption of poorly water-soluble drug CU and have great potential for future clinical application.

Umbelliprenin is cytotoxic against QU-DB large cell lung cancer cell line but anti-proliferative against A549 adenocarcinoma cells

PubMed Central

2012-01-01

Background Umbelliprenin is a natural compound, belonging to the class of sesquiterpene coumarins. Recently, umbelliprenin has attracted the researchers' attention for its antitumor activities against skin tumors. Its effect on lung cancer is largely unknown. The aim of our study was to investigate the effects of this natural compound, which is expected to have low adverse effects, on lung cancer. Methods The QU-DB large cell and A549 adenocarcinoma lung cancer cell lines were treated with umbelliprenin. IC50 values were estimated using methyl thiazolely diphenyl-tetrazolium bromide (MTT) assay, in which a decrease in MTT reduction can occur as a result of cell death or cell proliferation inhibition. To quantify the rate of cell death at IC50 values, flow cytometry using Annexin V-FITC (for apoptotic cells), and propidium iodide (for necrotic cells) dyes were employed. Results Data from three independent MTT experiments in triplicate revealed that IC50 values for QU-DB and A549 were 47 ± 5.3 μM and 52 ± 1.97 μM, respectively. Annexin V/PI staining demonstrated that umbelliprenin treatment at IC50 induced 50% cell death in QU-DB cells, but produced no significant death in A549 cells until increasing the umbelliprenin concentration to IC80. The pattern of cell death was predominantly apoptosis in both cell lines. When peripheral blood mononuclear cells were treated with 50 μM and less concentrations of umbelliprenin, no suppressive effect was observed. Conclusions We found cytotoxic/anti-proliferative effects of umbelliprenin against two different types of lung cancer cell lines. PMID:23351548

MMB-4 Inhibition of Aceylcholinesterase Is Similar across Species

DTIC Science & Technology

2014-11-01

version 5.4). An IC50 value was determined for AChE from each animal species by fitting the percent of AChE activity with respect to MMB 4 concentration...in GraphPad Prism (version 5) using a nonlinear regression dose response model for inhibition (normalized response with variable slope). Assessing the...Therefore, AChE activity and inhibition studies were carried out at 435 nm to reduce interference from MMB 4. Comparison of IC50 Values for MMB 4 with AChE

Essential Oil of Cymbopogon nardus (L.) Rendle: A Strategy to Combat Fungal Infections Caused by Candida Species

PubMed Central

De Toledo, Luciani Gaspar; Ramos, Matheus Aparecido Dos Santos; Spósito, Larissa; Castilho, Elza Maria; Pavan, Fernando Rogério; Lopes, Érica De Oliveira; Zocolo, Guilherme Julião; Silva, Francisca Aliny Nunes; Soares, Tigressa Helena; dos Santos, André Gonzaga; Bauab, Taís Maria; De Almeida, Margarete Teresa Gottardo

2016-01-01

Background: The incidence of fungal infections, especially those caused by Candida yeasts, has increased over the last two decades. However, the indicated therapy for fungal control has limitations. Hence, medicinal plants have emerged as an alternative in the search for new antifungal agents as they present compounds, such as essential oils, with important biological effects. Published data demonstrate important pharmacological properties of the essential oil of Cymbopogon nardus (L.) Rendle; these include anti-tumor, anti-nociceptive, and antibacterial activities, and so an investigation of this compound against pathogenic fungi is interesting. Objective: The aim of this study was to evaluate the chemical composition and biological potential of essential oil (EO) obtained from the leaves of C. nardus focusing on its antifungal profile against Candida species. Methods: The EO was obtained by hydrodistillation and analyzed by gas chromatography-mass spectrometry (GC-MS). Testing of the antifungal potential against standard and clinical strains was performed by determining the minimal inhibitory concentration (MIC), time-kill, inhibition of Candida albicans hyphae growth, and inhibition of mature biofilms. Additionally, the cytotoxicity was investigated by the IC50 against HepG-2 (hepatic) and MRC-5 (fibroblast) cell lines. Results: According to the chemical analysis, the main compounds of the EO were the oxygen-containing monoterpenes: citronellal, geranial, geraniol, citronellol, and neral. The results showed important antifungal potential for all strains tested with MIC values ranging from 250 to 1000 μg/mL, except for two clinical isolates of C. tropicalis (MIC > 1000 μg/mL). The time-kill assay showed that the EO inhibited the growth of the yeast and inhibited hyphal formation of C. albicans strains at concentrations ranging from 15.8 to 1000 μg/mL. Inhibition of mature biofilms of strains of C. albicans, C. krusei and C. parapsilosis occurred at a concentration of 10× MIC. The values of the IC50 for the EO were 96.6 μg/mL (HepG-2) and 33.1 μg/mL (MRC-5). Conclusion: As a major virulence mechanism is attributed to these types of infections, the EO is a promising compound to inhibit Candida species, especially considering its action against biofilm. PMID:27517903

Cytotoxicity, antimicrobial and antioxidant activity of eight compounds isolated from Entada abyssinica (Fabaceae).

PubMed

Dzoyem, Jean P; Melong, Raduis; Tsamo, Armelle T; Tchinda, Alembert T; Kapche, Deccaux G W F; Ngadjui, Bonaventure T; McGaw, Lyndy J; Eloff, Jacobus N

2017-03-06

Entada abyssinica is a plant traditionally used against gastrointestinal bacterial infections. Eight compounds including three flavonoids, three terpenoids, a monoglyceride and a phenolic compound isolated from E. abyssinica were investigated for their cytotoxicity, antibacterial and antioxidant activity. Compounds 7 and 2 had remarkable activity against Salmonella typhimurium with the lowest respective minimum inhibitory concentration (MIC) values of 1.56 and 3.12 µg/mL. The antioxidant assay gave IC 50 values varied from 0.48 to 2.87 μg/mL in the 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay, from 2.53 to 17.04 μg/mL in the 2,2'-Azino-bis (3-ethylbenzothiazoline-6-sulphonic acid) diammonium salt (ABTS) assay and from 1.43 to 103.98 µg/mL in the FRAP assay. Compounds had relatively low cytotoxicity (LC 50 values ranging from 22.42 to 80.55 µg/mL) towards Vero cells. Ursolic acid had the most potent cytotoxicity against THP-1 and RAW 264.7 cells with LC 50 values of 9.62 and 4.56 μg/mL respectively, and selectivity index values of 7.32 and 15.44 respectively. Our findings suggest that among the terpenoid and flavonoid compounds studied, entadanin (compound 7) possess tremendous antibacterial activity against S. typhimurium and could be developed for the treatment of bacterial diseases.

New Labdane-Type Diterpenoids and Anti-Inflammatory Constituents from Hedychium coronarium

PubMed Central

Chen, Jih-Jung; Ting, Chia-Wei; Wu, Yi-Chin; Hwang, Tsong-Long; Cheng, Ming-Jen; Sung, Ping-Jyun; Wang, Tai-Chi; Chen, Jinn-Fen

2013-01-01

Four new labdane-type diterpenoids: hedychicoronarin (1), peroxycoronarin D (2), 7β-hydroxycalcaratarin A (3), and (E)-7β-hydroxy-6-oxo-labda-8(17),12-diene-15,16-dial (4), have been isolated from the rhizomes of Hedychium coronarium, together with 13 known compounds (5–17). The structures of these new compounds were determined through spectroscopic and MS analyses. Compounds 3, 5, 6, and 10 exhibited inhibition (IC50 values ≤4.52 μg/mL) of superoxide anion generation by human neutrophils in response to formyl-L-methionyl-L-leucyl-L-phenylalanine/cytochalasin B (fMLP/CB). Compounds 3–6, 10, and 11 inhibited fMLP/CB-induced elastase release with IC50 values ≤6.17 μg/mL. PMID:23799360

Biological activities of aqueous extract from Cinnamomum porrectum

NASA Astrophysics Data System (ADS)

Farah, H. Siti; Nazlina, I.; Yaacob, W. A.

2013-11-01

A study was carried out to evaluate biological activities of an extract obtained from Cinnamomum porrectum under reflux using water. Aqueous extract of Cinnamomum porrectum was tested for antibacterial activity against six Gram-positive and eight Gram-negative bacteria as well as MRSA. The results confirmed that the aqueous extract of Cinnamomum porrectum was bactericidal. Cytotoxic tests on Vero cell culture revealed that Cinnamomum porrectum was non-toxic which IC50 value higher than 0.02 mg/mL. Antiviral activity was tested based on the above IC50 values together with the measured EC50 values to obtain Therapeutic Index. The result showed that Cinnamomum porrectum has the ability to inhibit viral replication of HSV-1 in Vero cells.

Synthesis and biological evaluation of novel tacrine derivatives and tacrine-coumarin hybrids as cholinesterase inhibitors.

PubMed

Hamulakova, Slavka; Janovec, Ladislav; Hrabinova, Martina; Spilovska, Katarina; Korabecny, Jan; Kristian, Pavol; Kuca, Kamil; Imrich, Jan

2014-08-28

A series of novel tacrine derivatives and tacrine-coumarin heterodimers were designed, synthesized, and biologically evaluated for their potential inhibitory effect on both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Of these compounds, tacrine-coumarin heterodimer 7c and tacrine derivative 6b were found to be the most potent inhibitors of human AChE (hAChE), demonstrating IC50 values of 0.0154 and 0.0263 μM. Ligands 6b, 6c, and 7c exhibited the highest levels of inhibitory activity against human BuChE (hBuChE), demonstrating IC50 values that range from 0.228 to 0.328 μM. Docking studies were performed in order to predict the binding modes of compounds 6b and 7c with hAChE/hBuChE.

Development of EGFR Targeted Nanoemulsion for Imaging and Novel Platinum Therapy of Ovarian Cancer

PubMed Central

Ganta, Srinivas; Singh, Amit; Patel, Niravkumar R.; Cacaccio, Joseph; Rawal, Yashesh H.; Davis, Barbara J.; Amiji, Mansoor M.; Coleman, Timothy P.

2014-01-01

Purpose Platinum-based chemotherapy is the treatment of choice for malignant epithelial ovarian cancers, but generalized toxicity and platinum resistance limits its use. Theranostic nanoemulsion with a novel platinum prodrug, myrisplatin, and the pro-apoptotic agent, C6-ceramide, were designed to overcome these limitations. Methods The nanoemulsions, including ones with an EGFR binding peptide and gadolinium, were made using generally regarded as safe grade excipients and a high shear microfluidization process. Efficacy was evaluated in ovarian cancer cells, SKOV3, A2780 and A2780CP. Results The nanoemulsion with particle size <150 nm were stable in plasma and parenteral fluids for 24 h. Ovarian cancer cells in vitro efficiently took up the non-targeted and EGFR-targeted nanoemulsions; improved cytotoxicity was observed for the these nanoemulsions with the latter showing a 50-fold drop in the IC50 in SKOV3 cells as compared to cisplatin alone. The addition of gadolinium did not affect cell viability in vitro, but showed relaxation times comparable to Magnevist®. Conclusion The myrisplatin/C6-ceramide nanoemulsion synergistically enhanced in vitro cytotoxicity. An EGFR binding peptide addition further increased in vitro cytotoxicity in EGFR positive cancer cells. The diagnostic version showed MR imaging similar to the clinically relevant Magnevist® and may be suitable as a theranostic for ovarian cancer. PMID:24643932

An evaluation of extracts of five traditional medicinal plants from Iran on the inhibition of mushroom tyrosinase activity and scavenging of free radicals.

PubMed

Khazaeli, P; Goldoozian, R; Sharififar, F

2009-10-01

This study aimed to evaluate the free radical scavenging and inhibition properties of five medicinal plants, including Quercus infectoria Olive., Terminalia chebula Retz., Lavendula stoechas L., Mentha longifolia L., Rheum palmatum L., toward the activity of mushroom tyrosinase using L-tyrosine and L-3,4-dihydroxyphenylalanine (L-DOPA) as the substrate.The methanol extracts of Q. infectoria and T. chebula showed strong radical scavenging effect in 2,2'-dipheny L-1-picrylhydrazyl (DPPH) assay(IC50 = 15.3 and 82.2 microg mL)1 respectively).These plants also showed inhibitory effects against the activity of mushroom tyrosinase in hydroxylation of L-tyrosine (85.9% and 82.2% inhibition,respectively). These two plants also inhibited the oxidation of l-DOPA similar to kojic acid as positive control (IC50 = 102.8 and 192.6 microg mL)1 respectively). In general Q. infectoria and T. chebula significantly inhibited tyrosinase activity and DPPH radical. Both activities were concentration dependant but not in linear manner. It is needed to study the cytotoxicity of these plant extracts in pigment cell culture before further evaluation and moving to in vivo conditions.

Isolation of Flavonoids From Wild Aquilaria sinensis Leaves by an Improved Preparative High-Speed Counter-Current Chromatography Apparatus.

PubMed

Yang, Mao-Xun; Liang, Yao-Guang; Chen, He-Ru; Huang, Yong-Fang; Gong, Hai-Guang; Zhang, Tian-You; Ito, Yoichiro

2018-01-01

Four flavonoids including apigenin-7,4'-dimethylether, genkwanin, quercetin, and kaempferol were isolated in a preparative or semi-preparative scale from the leaves of wild Aquilaria sinensis using an improved preparative high-speed counter-current chromatography apparatus. The separations were performed with a two-phase solvent system composed of hexane-ethyl acetate, methanol-water at suitable volume ratios. The obtained fractions were analyzed by HPLC, and the identification of each target compound was carried out by ESI-MS and NMR. The yields of the above four target flavonoids were 4.7, 10.0, 11.0 and 4.4%, respectively. All these four flavonoids exhibited nitrite scavenging activities with the clearance rate of 12.40 ± 0.20%, 5.84 ± 0.03%, 28.10 ± 0.17% and 5.19 ± 0.11%, respectively. Quercetin was originally isolated from the Thymelaeaceae family, while kaempferol was isolated from the Aquilaria genus for the first time. In cytotoxicity test these two flavonoids exhibited moderate inhibitory activities against HepG2 cells with the IC50 values of 12.54 ± 1.37 and 38.63 ± 4.05 μM, respectively. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Green synthesis of silver nanoparticles and investigation of their colorimetric sensing and cytotoxicity effects

NASA Astrophysics Data System (ADS)

Pahlavan Noghabi, Mohammad; Parizadeh, Mohammad Reza; Ghayour-Mobarhan, Majid; Taherzadeh, Danial; Hosseini, Hasan Ali; Darroudi, Majid

2017-10-01

The "Green" synthesis of metallic nanoparticles and investigation of their optical properties has become a useful application between nanoscience and medicine. In this work, silver nanoparticles (Ag-NPs) were successfully prepared through a facile and green method by treating silver ions with chitosan. Preparation of Ag-NPs in silver nitrate solution (0.01 M) resulted in small and spherical shapes of Ag-NPs with a mean diameter of 10.2 nm. The formation of Ag-NPs was approved by surface Plasmon resonance (SPR) absorption peaks, using UV-vis spectrophotometer, while Ag-NPs were successfully employed in colorimetric sensing of H2O2 via an analytical procedure. Degradation process of Ag-NPs, encouraged by the catalytic decomposition of H2O2, causes a significant change in the absorbance intensity of SPR band depending on the H2O2 concentration. The cytotoxicity effect of synthesized Ag-NPs was examined on HEK293 cell line. The results illustrate a concentration-dependent toxicity for the tested cells, while15.07 μg/mL of IC50 was obtained.

Evaluation of the Cytotoxicity of Satureja spicigera and Its Main Compounds

PubMed Central

Gohari, Ahmad Reza; Ostad, Seyed Nasser; Moradi-Afrapoli, Fahimeh; Malmir, Maryam; Tavajohi, Shohreh; Akbari, Hassan; Saeidnia, Soodabeh

2012-01-01

Satureja spicigera (Lamiaceae) grows wildly in Northwest of Iran. In this study, bioassay-guided isolation and identification of the main compounds has been reported using various chromatographic methods and comparison of their spectral data with those reported in the literature. Brine shrimp lethality and four cancerous cell lines HT29/219, Caco2, NIH-3T3, and T47D were used for cytotoxicity evaluations. From the aerial parts of S. spicigera, nine known compounds including two flavanones, 5,7,3′,5′-tetrahydroxy flavanone (8) and 5,4′-dihydroxy-3′-methoxyflavanone-7-(6′′-O-α-L-rhamnopyranosyl)-β-D-glucopyranoside (9), one dihydrochalcone, nubigenol (7), together with thymoquinone (1), thymol (2), carvacrol (3), β-sitosterol (4), ursolic acid (5) and oleanolic acid (6) were identified. Among the isolated chalcone and flavanones, compound 8 was effective against Artemia salina larva (LC50= 2 μg/mL) and only the compound 9 demonstrated IC50 value of 98.7 μg/mL on the T47D (human, breast, ductal carcinoma). Other compounds did not show significant inhibition of the cell growth. PMID:22623883

Decreased NK-Cell Cytotoxicity after Short Flights on the Space Shuttle

NASA Technical Reports Server (NTRS)

Mehta, Satish K.; Grimm, Elizabeth A.; Smid, Christine; Kaur, Indreshpal; Feeback, Daniel L.; Pierson, Duane L.

2000-01-01

Cytotoxic activity of natural killer (NK) cells and cell surface marker expression of peripheral blood mononuclear cells (PBMCs) isolated from 11 U.S. astronauts on two different missions were determined before and after 9 or 10 days of spaceflight aboard the space shuttle. Blood samples were collected 10 and 3 days before launch, within 3 hours after landing, and 3 days after landing. All PBMC preparations were cryopreserved and analyzed simultaneously in a 4-hour cytotoxicity "Cr-release assay using NK-sensitive K-562 target cells. Compared to preflight values, NK-cell cytotoxicity (corrected for lymphopenia observed on landing day) was significantly decreased at landing (P < 0.0125). It then apparently began to recover and approached preflight values by 3 days after landing. Consistent with decreased NK-cell cytotoxicity, significant increases from preflight values were found in plasma adrenocorticotropic hormone at landing. Plasma and urinary cortisol levels did not change significantly from preflight values. Expression of major lymphocyte surface markers (CD3, CD4, CD8, CD14, CD16, CD56), determined by flow cytometric analysis, revealed no consistent phenotypic changes in relative percent of NK or other lymphoid cells after 10 days of spaceflight.

Chemical and Antimicrobial Profiling of Propolis from Different Regions within Libya.

PubMed

Siheri, Weam; Zhang, Tong; Ebiloma, Godwin Unekwuojo; Biddau, Marco; Woods, Nicola; Hussain, Muattaz Yassein; Clements, Carol J; Fearnley, James; Ebel, RuAngelie Edrada; Paget, Timothy; Muller, Sylke; Carter, Katharine C; Ferro, Valerie A; De Koning, Harry P; Watson, David G

2016-01-01

Extracts from twelve samples of propolis collected from different regions of Libya were tested for their activity against Trypanosoma brucei, Leishmania donovani, Plasmodium falciparum, Crithidia fasciculata and Mycobacterium marinum and the cytotoxicity of the extracts was tested against mammalian cells. All the extracts were active to some degree against all of the protozoa and the mycobacterium, exhibiting a range of EC50 values between 1.65 and 53.6 μg/ml. The toxicity against mammalian cell lines was only moderate; the most active extract against the protozoan species, P2, displayed an IC50 value of 53.2 μg/ml. The extracts were profiled by using liquid chromatography coupled to high resolution mass spectrometry. The data sets were extracted using m/z Mine and the accurate masses of the features extracted were searched against the Dictionary of Natural Products (DNP). A principal component analysis (PCA) model was constructed which, in combination with hierarchical cluster analysis (HCA), divided the samples into five groups. The outlying groups had different sets of dominant compounds in the extracts, which could be characterised by their elemental composition. Orthogonal partial least squares (OPLS) analysis was used to link the activity of each extract against the different micro-organisms to particular components in the extracts.

Anti-Inflammatory Components from the Root of Solanum erianthum

PubMed Central

Chen, Yu-Chang; Lee, Hong-Zin; Chen, Hsin-Chun; Wen, Chi-Luan; Kuo, Yueh-Hsiung; Wang, Guei-Jane

2013-01-01

Two new norsesquiterpenoids, solanerianones A and B (1–2), together with nine known compounds, including four sesquiterpenoids, (−)-solavetivone (3), (+)-anhydro-β-rotunol (4), solafuranone (5), lycifuranone A (6); one alkaloid, N-trans-feruloyltyramine (7); one fatty acid, palmitic acid (8); one phenylalkanoid, acetovanillone (9), and two steroids, β-sitosterol (10) and stigmasterol (11) were isolated from the n-hexane-soluble part of the roots of Solanum erianthum. Their structures were elucidated on the basis of physical and spectroscopic data analyses. The anti-inflammatory activity of these isolates was monitored by nitric oxide (NO) production in lipopolysaccharide (LPS)-activated murine macrophage RAW264.7 cells. The cytotoxicity towards human lung squamous carcinoma (CH27), human hepatocellular carcinoma (Hep 3B), human oral squamous carcinoma (HSC-3) and human melanoma (M21) cell lines was also screened by using an MTT assay. Of the compounds tested, 3 exhibited the strongest NO inhibition with the average maximum inhibition (Emax) at 100 μM and median inhibitory concentration (IC50) values of 98.23% ± 0.08% and 65.54 ± 0.18 μM, respectively. None of compounds (1–9) was found to possess cytotoxic activity against human cancer cell lines at concentrations up to 30 μM. PMID:23771024

Synthesis and Antiplasmodial Activity of Novel Chloroquine Analogues with Bulky Basic Side Chains.

PubMed

Tasso, Bruno; Novelli, Federica; Tonelli, Michele; Barteselli, Anna; Basilico, Nicoletta; Parapini, Silvia; Taramelli, Donatella; Sparatore, Anna; Sparatore, Fabio

2015-09-01

Chloroquine is commonly used in the treatment and prevention of malaria, but Plasmodium falciparum, the main species responsible for malaria-related deaths, has developed resistance against this drug. Twenty-seven novel chloroquine (CQ) analogues characterized by a side chain terminated with a bulky basic head group, i.e., octahydro-2H-quinolizine and 1,2,3,4,5,6-hexahydro-1,5-methano-8H-pyrido[1,2-a][1,5]diazocin-8-one, were synthesized and tested for activity against D-10 (CQ-susceptible) and W-2 (CQ-resistant) strains of P. falciparum. Most compounds were found to be active against both strains with nanomolar or sub-micromolar IC50 values. Eleven compounds were found to be 2.7- to 13.4-fold more potent than CQ against the W-2 strain; among them, four cytisine derivatives appear to be of particular interest, as they combine high potency with low cytotoxicity against two human cell lines (HMEC-1 and HepG2) along with easier synthetic accessibility. Replacement of the 4-NH group with a sulfur bridge maintained antiplasmodial activity at a lower level, but produced an improvement in the resistance factor. These compounds warrant further investigation as potential drugs for use in the fight against malaria. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

The effects of a novel phosphodiesterase 7A and -4 dual inhibitor, YM-393059, on T-cell-related cytokine production in vitro and in vivo.

PubMed

Yamamoto, Satoshi; Sugahara, Shingo; Naito, Ryo; Ichikawa, Atsushi; Ikeda, Ken; Yamada, Toshimitsu; Shimizu, Yasuaki

2006-07-10

YM-393059, (+/-)-N-(4,6-dimethylpyrimidin-2-yl)-4-[2-(4-methoxy-3-methylphenyl)-5-(4-methylpiperazin-1-yl)-4,5,6,7-tetrahydro-1H-indol-1-yl]benzenesulfonamide difumarate, is a novel phosphodiesterase (PDE) inhibitor that inhibited the PDE7A isoenzyme with a high potency (IC50=14 nM) and PDE4 with a moderate potency (IC50=630 nM). In a cell-based assay, YM-393059 was found to inhibit anti-CD3 antibody, Staphylococcal enterotoxin B, and phytohaemagglutinin-induced interleukin (IL)-2 production in mouse splenocytes with IC50 values ranging from 0.48 to 1.1 microM. It also inhibited anti-CD3 antibody-induced interferon (IFN)-gamma and IL-4 production in splenocytes with IC50 values of 1.8 and 2.8 microM, respectively. YM-393059's inhibition of anti-CD3 antibody-stimulated cytokine (IL-2, IFN-gamma, and IL-4) production was 20- to 31-fold weaker than that of YM976, a selective PDE4 inhibitor. However, orally administered YM-393059 and YM976 inhibited anti-CD3 antibody-induced IL-2 production equipotently in mice. In addition, YM-393059 inhibited lipopolysaccharide-induced tumor necrosis factor-alpha production in vivo more potently than IL-2 (ED50 values of 2.1 mg/kg and 74 mg/kg). In contrast to YM976, YM-393059 did not shorten the duration of alpha2-adrenoceptor agonist-induced sleep in mice, which is a model for the assessment of the typical side effects caused by PDE4 inhibitors, nausea and emesis. YM-393059 is a novel and attractive compound for the treatment of a wide variety of T-cell-mediated diseases.

Essential Oil of Cymbopogon nardus (L.) Rendle: A Strategy to Combat Fungal Infections Caused by Candida Species.

PubMed

De Toledo, Luciani Gaspar; Ramos, Matheus Aparecido Dos Santos; Spósito, Larissa; Castilho, Elza Maria; Pavan, Fernando Rogério; Lopes, Érica De Oliveira; Zocolo, Guilherme Julião; Silva, Francisca Aliny Nunes; Soares, Tigressa Helena; Dos Santos, André Gonzaga; Bauab, Taís Maria; De Almeida, Margarete Teresa Gottardo

2016-08-09

The incidence of fungal infections, especially those caused by Candida yeasts, has increased over the last two decades. However, the indicated therapy for fungal control has limitations. Hence, medicinal plants have emerged as an alternative in the search for new antifungal agents as they present compounds, such as essential oils, with important biological effects. Published data demonstrate important pharmacological properties of the essential oil of Cymbopogon nardus (L.) Rendle; these include anti-tumor, anti-nociceptive, and antibacterial activities, and so an investigation of this compound against pathogenic fungi is interesting. The aim of this study was to evaluate the chemical composition and biological potential of essential oil (EO) obtained from the leaves of C. nardus focusing on its antifungal profile against Candida species. The EO was obtained by hydrodistillation and analyzed by gas chromatography-mass spectrometry (GC-MS). Testing of the antifungal potential against standard and clinical strains was performed by determining the minimal inhibitory concentration (MIC), time-kill, inhibition of Candida albicans hyphae growth, and inhibition of mature biofilms. Additionally, the cytotoxicity was investigated by the IC50 against HepG-2 (hepatic) and MRC-5 (fibroblast) cell lines. According to the chemical analysis, the main compounds of the EO were the oxygen-containing monoterpenes: citronellal, geranial, geraniol, citronellol, and neral. The results showed important antifungal potential for all strains tested with MIC values ranging from 250 to 1000 μg/mL, except for two clinical isolates of C. tropicalis (MIC > 1000 μg/mL). The time-kill assay showed that the EO inhibited the growth of the yeast and inhibited hyphal formation of C. albicans strains at concentrations ranging from 15.8 to 1000 μg/mL. Inhibition of mature biofilms of strains of C. albicans, C. krusei and C. parapsilosis occurred at a concentration of 10× MIC. The values of the IC50 for the EO were 96.6 μg/mL (HepG-2) and 33.1 μg/mL (MRC-5). As a major virulence mechanism is attributed to these types of infections, the EO is a promising compound to inhibit Candida species, especially considering its action against biofilm.

Heteropentanuclear Oxalato-Bridged nd–4f (n=4, 5) Metal Complexes with NO Ligand: Synthesis, Crystal Structures, Aqueous Stability and Antiproliferative Activity

PubMed Central

Kuhn, Paul-Steffen; Cremer, Laura; Gavriluta, Anatolie; Jovanović, Katarina K; Filipović, Lana; Hummer, Alfred A; Büchel, Gabriel E; Dojčinović, Biljana P; Meier, Samuel M; Rompel, Annette; Radulović, Siniša; Tommasino, Jean Bernard; Luneau, Dominique; Arion, Vladimir B

2015-01-01

A series of heteropentanuclear oxalate-bridged Ru(NO)-Ln (4d–4f) metal complexes of the general formula (nBu4N)5[Ln{RuCl3(μ-ox)(NO)}4], where Ln=Y (2), Gd (3), Tb (4), Dy (5) and ox=oxalate anion, were obtained by treatment of (nBu4N)2[RuCl3(ox)(NO)] (1) with the respective lanthanide salt in 4:1 molar ratio. The compounds were characterized by elemental analysis, IR spectroscopy, electrospray ionization (ESI) mass spectrometry, while 1, 2, and 5 were in addition analyzed by X-ray crystallography, 1 by Ru K-edge XAS and 1 and 2 by 13C NMR spectroscopy. X-ray diffraction showed that in 2 and 5 four complex anions [RuCl3(ox)(NO)]2− are coordinated to YIII and DyIII, respectively, with formation of [Ln{RuCl3(μ-ox)(NO)}4]5− (Ln=Y, Dy). While YIII is eight-coordinate in 2, DyIII is nine-coordinate in 5, with an additional coordination of an EtOH molecule. The negative charge is counterbalanced by five nBu4N+ ions present in the crystal structure. The stability of complexes 2 and 5 in aqueous medium was monitored by UV/Vis spectroscopy. The antiproliferative activity of ruthenium-lanthanide complexes 2–5 were assayed in two human cancer cell lines (HeLa and A549) and in a noncancerous cell line (MRC-5) and compared with those obtained for the previously reported Os(NO)-Ln (5d–4f) analogues (nBu4N)5[Ln{OsCl3(ox)(NO)}4] (Ln=Y (6), Gd (7), Tb (8), Dy (9)). Complexes 2–5 were found to be slightly more active than 1 in inhibiting the proliferation of HeLa and A549 cells, and significantly more cytotoxic than 5d–4f metal complexes 6–9 in terms of IC50 values. The highest antiproliferative activity with IC50 values of 20.0 and 22.4 μM was found for 4 in HeLa and A549 cell lines, respectively. These cytotoxicity results are in accord with the presented ICP-MS data, indicating five- to eightfold greater accumulation of ruthenium versus osmium in human A549 cancer cells. PMID:26260662

Cisplatin-induced cytotoxicity in BSO-exposed renal proximal tubular epithelial cells: sex, age, and species.

PubMed

Lu, Yongke; Kawashima, Akira; Horii, Ikuo; Zhong, Laifu

2005-01-01

Cisplatin (CP)-induced kidney damage and effects of DL-buthionine-(S,R)-sulfoximine (BSO) on it are species- and age-different. It remains unclear whether CP-induced cytotoxicity in renal proximal tubular epithelial cells (RTEC), the main target cells of CP, is also species- and age-different; and whether CP-induced cytotoxicity varies with the difference in age and species, if any, is one of the questions. In the present study, the effects of BSO on CP-induced cytotoxicity in primary cultures of RTEC isolated from monkeys and different age and sex rats were studied. The RTEC were isolated from 3-week-old, 2-month-old, or 5-month-old rats, and 6-8 year-old monkeys. After subculturing, RTEC was inoculated into type I collagen-coated 96-well culture plates; after preincubation, 40 microM BSO was added, 16 hours later, varying concentrations of CP were added. At that time, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assays were performed to test cell viability. The concentrations of CP that inhibited 50% cell growth (IC50) of RTEC from rats and monkeys were 1.11 and 3.03 mM at 8 hours, and 0.51 and 1.24 mM at 24 hours, respectively. The BSO made the IC50s of RTEC from rats and monkeys lower, down to 0.07 and 0.48 mM at 8 hours, and 0.02 and 0.11 mM at 24 hours, respectively. The IC50s of RTEC from different sex and age rats were almost same. These results suggested that CP-induced cytotoxicity was concentration- and time-dependent, with species-dependent differences, rat RTEC were more susceptible to CP than monkey RTEC, rat RTEC were more dependent on glutathione (GSH) during the stress state were than monkey cells; CP-induced cytotoxicity was without sex- and age-dependent differences in rat RTEC.

Potent cytotoxic effects of Calomeria amaranthoides on ovarian cancers.

PubMed

van Haaften, Caroline; Duke, Colin C; Weerheim, Arij M; Smit, Nico Pm; van Haard, Paul Mm; Darroudi, Firouz; Trimbos, Baptist Jmz

2011-03-14

Ovarian cancer remains the leading cause of death from gynaecological malignancy. More than 60% of the patients are presenting the disease in stage III or IV. In spite of combination of chemotherapy and surgery the prognosis stays poor for therapy regimen. The leaves of a plant endemic to Australia, Calomeria amaranthoides, were extracted and then fractionated by column chromatography. In vitro cytotoxicity tests were performed with fractions of the plant extract and later with an isolated compound on ovarian cancer cell lines, as well as normal fibroblasts at concentrations of 1-100 μg/mL (crude extract) and 1-10 μg/mL (compound). Cytotoxicity was measured after 24, 48 and 72 hours by using a non-fluorescent substrate, Alamar blue.In vivo cytotoxicity was tested on ascites, developed in the abdomen of nude mice after inoculation with human OVCAR3 cells intraperitoneally. The rate of change in abdomen size for the mice was determined by linear regression and statistically evaluated for significance by the unpaired t test. Two compounds were isolated by chromatographic fractionation and identified by 1H-NMR, 13C-NMR and mass spectrometry analyses, EPD, an α-methylene sesquiterpene lactone of the eremophilanolide subtype, and EPA, an α-methylene carboxylic acid.Cytotoxicity of EPD for normal fibroblasts at all time points IC50 was greater than 10 μg/mL, whereas, for OVCAR3 cells at 48 hours IC50 was 5.3 μg/mL (95% confidence interval 4.3 to 6.5 μg/mL).Both, the crude plant extract as well as EPD killed the cancer cells at a final concentration of 10 μg/mL and 5 μg/mL respectively, while in normal cells only 20% cell killing effect was observed. EPA had no cytotoxic effects.Changes in abdomen size for control versus Cisplatin treated mice were significantly different, P = 0.023, as were control versus EPD treated mice, P = 0.025, whereas, EPD versus Cisplatin treated mice were not significantly different, P = 0.13. For the first time both crude plant extract from Calomeria amaranthoides and EPD have been shown to have potent anti-cancer effects against ovarian cancer.

Spectroscopy, electrochemistry and antiproliferative properties of Au(iii), Pt(ii) and Cu(ii) complexes bearing modified 2,2':6',2''-terpyridine ligands.

PubMed

Maroń, Anna; Czerwińska, Katarzyna; Machura, Barbara; Raposo, Luis; Roma-Rodrigues, Catarina; Fernandes, Alexandra R; Małecki, Jan G; Szlapa-Kula, Agata; Kula, Slawomir; Krompiec, Stanisław

2018-05-08

Structural, spectroscopic and electrochemical properties of six complexes [AuCl(L1)](PF6)2·CH3CN (1), [AuCl(L2)](PF6)2 (2), [PtCl(L1)](BPh4)·CH3CN (3), [PtCl(L2)](SO3CF3) (4), [CuCl2(L1)] (5) and [CuCl2(L2)]·CH3CN (6) with modified 2,2':6',2''-terpyridine ligands, 4'-(4-methoxyphenyl)-2,2':6',2''-terpyridine (L1) and 4'-(4-methoxynaphthalen-1-yl)-2,2':6',2''-terpyridine (L2) were thoroughly investigated and a significant role of the substituent (4-methoxyphenyl or 4-methoxynaphthalen-1-yl) and the metal center was demonstrated. The naphthyl-based substituent was found to increase the emission quantum yield of the luminescent Au(iii) and Pt(ii) complexes. Furthermore, the antiproliferative potential of the reported complexes was examined towards human colorectal (HCT116) and ovarian (A2780) carcinoma cell lines as well as towards normal human fibroblasts. The Au(iii) complex 2 and Cu(ii) complex 5 were found to have a higher antiproliferative effect on HCT116 colorectal and A2780 ovarian carcinoma cells when compared with the Pt(ii) complex with the same ligand (4). The order of cytotoxicity in both cell lines is 2 > 6 > 1 > 3 > 4. Complex 2 seems to be more cytotoxic towards HCT116 and A2780 cancer cell lines with IC50 values 300× and 130× higher in normal human fibroblasts compared to the respective cancer cells. The viability loss induced by the complexes agrees with Hoechst 33258 staining and the typical morphological apoptotic characteristics like chromatin condensation and nuclear fragmentation and flow cytometry assay. The induction of apoptosis correlates with the induction of reactive oxygen species (ROS). Fluorescence microscopy analysis indicates that after 3 h of incubation, complexes 1-4 are localized inside HCT116 cells and the high levels of internalization correlate with their cytotoxicity.

Antiproliferative activity of king cobra (Ophiophagus hannah) venom L-amino acid oxidase.

PubMed

Li Lee, Mui; Chung, Ivy; Yee Fung, Shin; Kanthimathi, M S; Hong Tan, Nget

2014-04-01

King cobra (Ophiophagus hannah) venom L-amino acid oxidase (LAAO), a heat-stable enzyme, is an extremely potent antiproliferative agent against cancer cells when compared with LAAO isolated from other snake venoms. King cobra venom LAAO was shown to exhibit very strong antiproliferative activities against MCF-7 (human breast adenocarcinoma) and A549 (human lung adenocarcinoma) cells, with an IC50 value of 0.04±0.00 and 0.05±0.00 μg/mL, respectively, after 72-hr treatment. In comparison, its cytotoxicity was about 3-4 times lower when tested against human non-tumourigenic breast (184B5) and lung (NL 20) cells, suggesting selective antitumour activity. Furthermore, its potency in MCF-7 and A549 cell lines was greater than the effects of doxorubicin, a clinically established cancer chemotherapeutic agent, which showed an IC50 value of 0.18±0.03 and 0.63±0.21 μg/mL, respectively, against the two cell lines. The selective cytotoxic action of the LAAO was confirmed by phycoerythrin (PE) annexin V/7-amino-actinomycin (AAD) apoptotic assay, in which a significant increase in apoptotic cells was observed in LAAO-treated tumour cells than in their non-tumourigenic counterparts. The ability of LAAO to induce apoptosis in tumour cells was further demonstrated using caspase-3/7 and DNA fragmentation assays. We also determined that this enzyme may target oxidative stress in its killing of tumour cells, as its cytotoxicity was significantly reduced in the presence of catalase (a H2O2 scavenger). In view of its heat stability and selective and potent cytotoxic action on cancer cells, king cobra venom LAAO can be potentially developed for treating solid tumours. © 2013 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

Polyphenol-rich extract of Pimenta dioica berries (Allspice) kills breast cancer cells by autophagy and delays growth of triple negative breast cancer in athymic mice

PubMed Central

Zhang, Lei; Shamaladevi, Nagarajarao; Jayaprakasha, Guddadarangavvanahally K.; Patil, Bhimu S.; Lokeshwar, Bal L.

2015-01-01

Bioactive compounds from edible plants have limited efficacy in treating advanced cancers, but they have potential to increase the efficacy of chemotherapy drugs in a combined treatment. An aqueous extract of berries of Pimenta dioica (Allspice) shows promise as one such candidate for combination therapy or chemoprevention. An aqueous extract of Allspice (AAE) was tested against human breast cancer (BrCa) cells in vitro and in vivo. AAE reduced the viability and clonogenic growth of several types of BrCa cells (IC50 ≤ 100 μg/ml) with limited toxicity in non-tumorigenic, quiescent cells (IC50 >200 μg/ml). AAE induced cytotoxicity in BrCa was inconsistent with apoptosis, but was associated with increased levels of autophagy markers LC3B and LC3B-positive puncta. Silencing the expression of autophagy related genes (ATGs) prevented AAE-induced cell death. Further, AAE caused inhibition of Akt/mTOR signaling, and showed enhanced cytotoxicity when combined with rapamycin, a chemotherapy drug and an inhibitor of mTOR signaling. Oral administration (gavage) of AAE into athymic mice implanted with MDA-MB231 tumors inhibited tumor growth slightly but not significantly (mean decrease ~ 14%, p ≥ 0.20) if mice were gavaged post-tumor implant. Tumor growth showed a significant delay (38%) in tumor palpability and growth rate (time to reach tumor volume ≥ 1,000 mm3) when mice were pre-dosed with AAE for two weeks. Analysis of tumor tissues showed increased levels of LC3B in AAE treated tumors, indicating elevated autophagic tumor cell death in vivo in treated mice. These results demonstrate antitumor and chemo-preventive activity of AAE against BrCa and potential for adjuvant to mTOR inhibition. PMID:25945840

In vitro antibacterial, antioxidant and cytotoxic activity of acetone leaf extracts of nine under-investigated Fabaceae tree species leads to potentially useful extracts in animal health and productivity

PubMed Central

2014-01-01

Background The Fabaceae family is the second largest family of medicinal plants, containing more than 490 species which are being used as traditional medicine. The aim of this study was to determine the antioxidant and antibacterial activity as well as the cytotoxicity of acetone leaf extracts of nine tree species from the Fabaceae family that have not been investigated well previously for possible use in animal health and production. Methods The antibacterial activity was determined by a serial microdilution method against three Gram-positive and three Gram-negative bacteria. Antioxidant activity was determined using free-radical scavenging assays. The safety of the extracts was ascertained using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay on Vero African green monkey kidney cells. Results Six of the nine acetone extracts had significant antibacterial activity against at least one of the six bacterial species with (MIC 20–80 μg/mL). The Crotalaria capensis extract had the highest activity against Salmonella typhimurium, followed by Indigofera cylindrica with MICs of 20 μg/mL and 40 μg/mL respectively. The Dalbergia nitidula extract had free radical scavenging capacity (IC50 of 9.31 ± 2.14 μg/mL) close to that of the positive control Trolox in the DPPH assay. The Xylia torreana extract also had high activity (IC50 of 14.56 ± 3.96 μg/mL) in the ABTS assay. There was a good correlation between antioxidant activity and total phenolic content (R2 values > 0.8). The extracts had weak or no toxicity to Vero cells, compared to the positive control doxorubicin with the LC50 varying from 10.70 ± 3.47 to 131.98 ± 24.87 μg/mL at the concentrations tested. Conclusion Extracts of D. nitidula, X. torreana, C. capensis and I. cylindrica had a low cytotoxicity and high antimicrobial and/or antioxidant activity. These species are therefore promising candidates for the development of useful antimicrobial/antioxidant preparations with a low cytotoxicity that may be useful in promoting animal health and productivity. PMID:24885143

Design and Synthesis of Human ABCB1 (P-Glycoprotein) Inhibitors by Peptide Coupling of Diverse Chemical Scaffolds on Carboxyl and Amino Termini of (S)-Valine-Derived Thiazole Amino Acid

PubMed Central

2015-01-01

P-glycoprotein (P-gp) serves as a therapeutic target for the development of multidrug resistance reversal agents. In this study, we synthesized 21 novel compounds by peptide coupling at corresponding carboxyl and amino termini of (S)-valine-based bis-thiazole and monothiazole derivatives with diverse chemical scaffolds. Using calcein-AM efflux assay, we identified compound 28 (IC50 = 1.0 μM) carrying 3,4,5-trimethoxybenzoyl and 2-aminobenzophenone groups, respectively, at the amino and carboxyl termini of the monothiazole zwitter-ion. Compound 28 inhibited the photolabeling of P-gp with [125I]-iodoarylazidoprazosin with IC50 = 0.75 μM and stimulated the basal ATP hydrolysis of P-gp in a concentration-dependent manner (EC50 ATPase = 0.027 μM). Compound 28 at 3 μM reduced resistance in cytotoxicity assay to paclitaxel in P-gp-expressing SW620/Ad300 and HEK/ABCB1 cell lines. Biochemical and docking studies showed site-1 to be the preferable binding site for 28 within the drug-binding pocket of human P-gp. PMID:24773054

Synthesis and biochemical evaluation of benzoylbenzophenone thiosemicarbazone analogues as potent and selective inhibitors of cathepsin L

PubMed Central

Parker, Erica N.; Song, Jiangli; Kumar, G. D. Kishore; Odutola, Samuel O.; Chavarria, Gustavo E.; Charlton-Sevcik, Amanda K.; Strecker, Tracy E.; Barnes, Ashleigh L.; Sudhan, Dhivya R.; Wittenborn, Thomas R.; Siemann, Dietmar W.; Horsman, Michael R.; Chaplin, David J.; Trawick, Mary Lynn; Pinney, Kevin G.

2016-01-01

Upregulation of cathepsin L in a variety of tumors and its ability to promote cancer cell invasion and migration through degradation of the extracellular matrix suggest that cathepsin L is a promising biological target for the development of anti-metastatic agents. Based on encouraging results from studies on benzophenone thiosemicarbazone cathepsin inhibitors, a series of fourteen benzoylbenzophenone thiosemicarbazone analogues were designed, synthesized, and evaluated for their inhibitory activity against cathepsins L and B. Thiosemicarbazone inhibitors 3-benzoylbenzophenone thiosemicarbazone 1, 1,3-bis(4-fluorobenzoyl)benzene thiosemicarbazone 8, and 1,3-bis(2-fluorobenzoyl)-5-bromobenzene thiosemicarbazone 32 displayed the greatest potency against cathepsin L with low IC50 values of 9.9 nM, 14.4 nM, and 8.1 nM, respectively. The benzoylbenzophenone thiosemicarbazone analogues evaluated were selective in their inhibition of cathepsin L compared to cathepsin B. Thiosemicarbazone analogue 32 inhibited invasion through Matrigel of MDA-MB-231 breast cancer cells by 70% at 10 μM. Thiosemicarbazone analogue 8 significantly inhibited the invasive potential of PC-3ML prostate cancer cells by 92% at 5 μM. The most active cathepsin L inhibitors from this benzoylbenzophenone thiosemicarbazone series (1, 8, and 32) displayed low cytotoxicity toward normal primary cells [in this case human umbilical vein endothelial cells (HUVECs)]. In an initial in vivo study, 3-benzoylbenzophenone thiosemicarbazone (1) was well-tolerated in a CDF1 mouse model bearing an implanted C3H mammary carcinoma, and showed efficacy in tumor growth delay. Low cytotoxicity, inhibition of cell invasion, and in vivo tolerability are desirable characteristics for anti-metastatic agents functioning through an inhibition of cathepsin L. Active members of this structurally diverse group of benzoylbenzophenone thiosemicarbazone cathepsin L inhibitors show promise as potential anti-metastatic, pre-clinical drug candidates. PMID:26462052

In vitro antioxidant, anti-inflammatory and anticancer activities of ethyl acetate soluble proanthocyanidins of the inflorescence of Cocos nucifera L.

PubMed

Padumadasa, Chayanika; Dharmadana, Durga; Abeysekera, Ajit; Thammitiyagodage, Mayuri

2016-09-05

Proanthocyanidins belong to a class of polyphenolic compounds called flavonoids and have been reported to exhibit important biological activities. The immature inflorescence of Cocos nucifera L. is used by Ayurvedic and traditional medical practitioners for the treatment of menorrhagia in Sri Lanka. Our studies have shown that the inflorescence of Cocos nucifera L. predominantly contains proanthocyanidins. To determine the antioxidant, anti-inflammatory and anticancer activities of ethyl acetate soluble proanthocyanidins (EASPA) of immature inflorescence of Cocos nucifera L. EASPA fraction of an acetone/water (7:3) extract of Cocos nucifera L. inflorescence was purified on Sephadex LH-20 and was used for the study. Antioxidant activity of EASPA was determined using DPPH and SOR scavenging assays. Anti-inflammatory activity of EASPA was determined by oxidative burst assay using chemiluminescence technique. MTT colorimetric assay was used to evaluate the cytotoxicity of EASPA to both PC3 and HeLa cells. EASPA showed radical scavenging activity against both DPPH and superoxide radicals with IC50 values of 11.02 ± 0.60 μg/mL and 26.11 ± 0.72 μg/mL. In both assays, EASPA showed less antioxidant activity than the standards used. It exhibited similar anti-inflammatory activity (IC50 = 10.31 ± 1.11 μg/mL) to ibuprofen (IC50 = 11.20 ± 1.90 μg/mL) (P ≥ 0.05). EASPA also showed stronger cytotoxic activity towards Hela cells (IC50 = 18.78 ± 0.90 μg/mL) than tamoxifen (IC50 = 28.80 ± 1.94 μg/mL) (P ≤ 0.05), while low cytotoxicity was observed against PC3 cells (IC50 = 44.21 ± 0.73 μg/mL) compared to doxorubicin (IC50 = 1.38 ± 0.16 μg/mL). EASPA showed antioxidant, anti-inflammatory and anticancer activities.

AlgiMatrix™ Based 3D Cell Culture System as an In-Vitro Tumor Model for Anticancer Studies

PubMed Central

Godugu, Chandraiah; Patel, Apurva R.; Desai, Utkarsh; Andey, Terrick; Sams, Alexandria; Singh, Mandip

2013-01-01

Background Three-dimensional (3D) in-vitro cultures are recognized for recapitulating the physiological microenvironment and exhibiting high concordance with in-vivo conditions. Taking the advantages of 3D culture, we have developed the in-vitro tumor model for anticancer drug screening. Methods Cancer cells grown in 6 and 96 well AlgiMatrix™ scaffolds resulted in the formation of multicellular spheroids in the size range of 100–300 µm. Spheroids were grown in two weeks in cultures without compromising the growth characteristics. Different marketed anticancer drugs were screened by incubating them for 24 h at 7, 9 and 11 days in 3D cultures and cytotoxicity was measured by AlamarBlue® assay. Effectiveness of anticancer drug treatments were measured based on spheroid number and size distribution. Evaluation of apoptotic and anti-apoptotic markers was done by immunohistochemistry and RT-PCR. The 3D results were compared with the conventional 2D monolayer cultures. Cellular uptake studies for drug (Doxorubicin) and nanoparticle (NLC) were done using spheroids. Results IC50 values for anticancer drugs were significantly higher in AlgiMatrix™ systems compared to 2D culture models. The cleaved caspase-3 expression was significantly decreased (2.09 and 2.47 folds respectively for 5-Fluorouracil and Camptothecin) in H460 spheroid cultures compared to 2D culture system. The cytotoxicity, spheroid size distribution, immunohistochemistry, RT-PCR and nanoparticle penetration data suggested that in vitro tumor models show higher resistance to anticancer drugs and supporting the fact that 3D culture is a better model for the cytotoxic evaluation of anticancer drugs in vitro. Conclusion The results from our studies are useful to develop a high throughput in vitro tumor model to study the effect of various anticancer agents and various molecular pathways affected by the anticancer drugs and formulations. PMID:23349734

Gold(I) Complexes of 9-Deazahypoxanthine as Selective Antitumor and Anti-Inflammatory Agents

PubMed Central

Vančo, Ján; Gáliková, Jana; Hošek, Jan; Dvořák, Zdeněk; Paráková, Lenka; Trávníček, Zdeněk

2014-01-01

The gold(I) mixed-ligand complexes involving O-substituted derivatives of 9-deazahypoxanthine (HLn) and triphenylphosphine (PPh3) with the general formula [Au(Ln)(PPh3)] (1–5) were prepared and thoroughly characterized by elemental analysis, FT-IR and multinuclear NMR spectroscopy, ESI+ mass spectrometry, single crystal X-ray (HL5 and complex 2) and TG/DTA analyses. Complexes 1–5 were evaluated for their in vitro antitumor activity against nine human cancer lines, i.e. MCF7 (breast carcinoma), HOS (osteosarcoma), A549 (adenocarcinoma), G361 (melanoma), HeLa (cervical cancer), A2780 (ovarian carcinoma), A2780R (ovarian carcinoma resistant to cisplatin), 22Rv1 (prostate cancer) and THP-1 (monocytic leukaemia), for their in vitro anti-inflammatory activity using a model of LPS-activated macrophages, and for their in vivo antiedematous activity by λ-carrageenan-induced hind paw edema model on rats. The results showed that the complexes 1–5 exhibit selective in vitro cytotoxicity against MCF7, HOS, 22Rv1, A2780 and A2780R, with submicromolar IC50 values for 2 against the MCF7 (0.6 µM) and HOS (0.9 µM). The results of in vitro cytotoxicity screening on primary culture of human hepatocytes (HEP220) revealed up to 30-times lower toxicity of compounds against healthy cells as compared with cancer cells. Additionally, the complexes 1–5 significantly influence the secretion and expression of pro-inflammatory cytokines TNF-α and IL-1β by a similar manner as a commercially used anti-arthritic drug Auranofin. The tested complexes also significantly influence the rate and overall volume of the edema, caused by the intraplantar application of λ-carrageenan polysaccharide to rats. Based on these promising results, the presented compounds could qualify to become feasible candidates for advanced testing as potential antitumor and anti-inflammatory drug-like compounds. PMID:25333949

Gamabufotalin triggers c-Myc degradation via induction of WWP2 in multiple myeloma cells.

PubMed

Yu, Zhenlong; Li, Tao; Wang, Chao; Deng, Sa; Zhang, Baojing; Huo, Xiaokui; Zhang, Bo; Wang, Xiaobo; Zhong, Yuping; Ma, Xiaochi

2016-03-29

Deciding appropriate therapy for multiple myeloma (MM) is challenging because of the occurrence of multiple chromosomal changes and the fatal nature of the disease. In the current study, gamabufotalin (GBT) was isolated from toad venom, and its tumor-specific cytotoxicity was investigated in human MM cells. We found GBT inhibited cell growth and induced apoptosis with the IC50 values <50 nM. Mechanistic studies using functional approaches identified GBT as an inhibitor of c-Myc. Further analysis showed that GBT especially evoked the ubiquitination and degradation of c-Myc protein, thereby globally repressing the expression of c-Myc target genes. GBT treatment inhibited ERK and AKT signals, while stimulating the activation of JNK cascade. An E3 ubiquitin-protein ligase, WWP2, was upregulated following JNK activation and played an important role in c-Myc ubiquitination and degradation through direct protein-protein interaction. The antitumor effect of GBT was validated in a xenograft mouse model and the suppression of MM-induced osteolysis was verified in a SCID-hu model in vivo. Taken together, our study identified the potential of GBT as a promising therapeutic agent in the treatment of MM.

New Abietane and Kaurane Type Diterpenoids from the Stems of Tripterygium regelii

PubMed Central

Fan, Dongsheng; Zhou, Shuangyan; Zheng, Zhiyuan; Zhu, Guo-Yuan; Yao, Xiaojun; Yang, Ming-Rong; Jiang, Zhi-Hong; Bai, Li-Ping

2017-01-01

Eleven new abietane type (1‒11), and one new kaurane (12), diterpenes, together with eleven known compounds (13–23), were isolated and identified from the stems of Tripterygium regelii, which has been used as a traditional folk Chinese medicine for the treatment of rheumatoid arthritis in China. The structures of new compounds were characterized by means of the interpretation of high-resolution electrospray ionization mass spectrometry (HRESIMS), extensive nuclear magnetic resonance (NMR) spectroscopic data and comparisons of their experimental CD spectra with calculated electronic circular dichroism (ECD) spectra. Compound 1 is the first abietane type diterpene with an 18→1 lactone ring. Compound 19 was isolated from the plants of the Tripterygium genus for the first time, and compounds 14–17 were isolated from T. regelii for the first time. Triregelin I (9) showed significant cytotoxicity against A2780 and HepG2 with IC50 values of 5.88 and 11.74 µM, respectively. It was found that this compound was inactive against MCF-7 cells. The discovery of these twelve new diterpenes not only provided information on chemical substances of T. regelii, but also contributed to the chemical diversity of natural terpenoids. PMID:28098763

Gastroprotective effect of the Mapuche crude drug Araucaria araucana resin and its main constituents.

PubMed

Schmeda-Hirschmann, Guillermo; Astudillo, Luis; Rodríguez, Jaime; Theoduloz, Cristina; Yáñez, Tania

2005-10-03

The resin from the tree Araucaria araucana (Araucariaceae) has been used since pre-columbian times by the Mapuche amerindians to treat ulcers. The gastroprotective effect of the resin was assessed in the ethanol-HCl-induced gastric ulcer in mice showing a dose-dependent gastroprotective activity at 100, 200 and 300 mg/kg per os. The main three diterpene constituents of the resin, namely imbricatolic acid, 15-hydroxyimbricatolal and 15-acetoxyimbricatolic acid were isolated and evaluated for gastroprotective effect at doses of 50, 100 and 200 mg/kg. A dose-related gastroprotective effect with highly significant activity (P<0.01) was observed at doses up to 200 mg/kg. At 100 mg/kg, the highest gastroprotective activity was provided by 15-hydroxyimbricatolal and 15-acetoxyimbricatolic acid, all of them being as active as the reference drug lansoprazole at 20 mg/kg. The cytotoxicity of the main diterpenes as well as lansoprazole was studied towards human lung fibroblasts (MRC-5) and determined by the MTT reduction assay. A concentration-dependent cell viability inhibition was found with IC50 values ranging from 125 up to 290 microM. Our results support the traditional use of the Araucaria araucana resin by the Mapuche culture.

Antiproliferative mechanism of the methanolic extract of Enterolobium cyclocarpum (Jacq.) Griseb. (Fabaceae).

PubMed

Sowemimo, Abimbola; Venables, Luanne; Odedeji, Modeola; Koekemoer, Trevor; van de Venter, Maryna; Hongbing, Liu

2015-01-15

Enterolobium cyclocarpum (Jacq.) Griseb. is a tropical tree that has folkloric implications against many ailments and diseases including cancer. To explore the ethnopharmacological claims against cancer, the cytotoxicity of the methanolic extract of the leaves, was investigated using the brine shrimp lethality assay, MTT assay using cervical (HeLa) and breast (MCF7) cancer cell lines, cell cycle analysis and Annexin V-FITC/PI assay. In the brine shrimp lethality assay, the extract showed cytotoxic activity with LC50 value of 31.63 µg/mL. Significant growth inhibition was observed in both cell lines with IC50 values of 2.07 ± 1.30 µg/mL and 11.84 ± 1.18 µg/mL for HeLa and MCF7, respectively. Cell cycle analysis indicated that HeLa cells were arrested in the G2/M phase while MCF7 cells arrested in the G1/G0 phase. The Annexin V-FITC/PI assay revealed phosphatidylserine translocation in both cell lines and thus apoptosis induction upon treatment with the extract. The study demonstrated the potential antiproliferative activity of Enterolobium cyclocarpum thereby supporting the traditional claim and provides basis for further mechanistic studies and isolation of active constituents. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

SVCT-2 determines the sensitivity to ascorbate-induced cell death in cholangiocarcinoma cell lines and patient derived xenografts.

PubMed

Wang, Changzheng; Lv, Hongwei; Yang, Wen; Li, Ting; Fang, Tian; Lv, Guishuai; Han, Qin; Dong, Liwei; Jiang, Tianyi; Jiang, Beige; Yang, Guangshun; Wang, Hongyang

2017-07-10

Cholangiocarcinoma (CC) is a devastating malignancy with late diagnosis and poor response to conventional chemotherapy. Recent studies have revealed anti-cancer effect of vitamin C (l-ascorbic acid, ascorbate) in several types of cancer. However, the effect of l-ascorbic acid (AA) in CC remains elusive. Herein, we demonstrated that AA induced cytotoxicity in CC cells by generating intracellular reactive oxygen species (ROS), and subsequently DNA damage, ATP depletion, mTOR pathway inhibition. Moreover, AA worked synergistically with chemotherapeutic agent cisplatin to impair CC cells growth both in vitro and in vivo. Intriguingly, sodium-dependent vitamin C transporter 2 (SVCT-2) expression was inversely correlated with IC50 values of AA. Knockdown of SVCT-2 dramatically alleviated DNA damage, ATP depletion, and inhibition of mTOR pathway induced by AA. Furthermore, SVCT-2 knockdown endowed CC cells with the resistance to AA treatment. Finally, the inhibitory effects of AA were further confirmed in patient-derived CC xenograft models. Thus, our results unravel therapeutic potential of AA alone or in combination with cisplatin for CC. SVCT2 expression level may serve as a positive outcome predictor for AA treatment in CC. Copyright © 2017 Elsevier B.V. All rights reserved.

Evaluation of Anticancer and Antioxidant Activity of a Commercially Available CO2 Supercritical Extract of Old Man's Beard (Usnea barbata).

PubMed

Zugic, Ana; Jeremic, Ivica; Isakovic, Aleksandra; Arsic, Ivana; Savic, Snezana; Tadic, Vanja

2016-01-01

There is a worldwide ongoing investigation for novel natural constituents with cytotoxic and antioxidant properties. The aim of this study was to investigate chemical profile and stated biological activities of the supercritical CO2 extract (SCE) of old man's beard compared to the extracts obtained using the conventional techniques (Soxhlet extracts and macerate). The most abundant compound identified was usnic acid, which content was inversely proportional to the polarity of the solvent used and was the highest in the SCE, which was the sample revealing the highest cytotoxic activity in tested tumor cell lines (B16 mouse melanoma and C6 rat glioma), with lower IC50 values compared to pure usnic acid. Further investigations suggested both SCE and usnic acid to induce apoptosis and/or autophagy in B16 and C6, indicating higher cytotoxicity of SCE to be related to the higher degree of ROS production. A good correlation of usnic acid content in the extracts and their antioxidant capacity was established, extricating SCE as the most active one. Presented results support further investigations of SCE of old man's beard as a prospective therapeutic agent with potential relevance in the treatment of cancer and/or in oxidative stress-mediated conditions.

Complexes of platinum and palladium with β-diketones and DMSO: Synthesis, characterization, molecular modeling, and biological studies

NASA Astrophysics Data System (ADS)

do Couto Almeida, J.; Marzano, I. M.; de Paula, F. C. Silva; Pivatto, M.; Lopes, N. P.; de Souza, P. C.; Pavan, F. R.; Formiga, A. L. B.; Pereira-Maia, E. C.; Guerra, W.

2014-10-01

This work reports on the synthesis and characterization of new complexes of the type [MCl(L)DMSO], where L = 4,4,4-trifluoro-1-phenyl-1,3-butanedione (HTPB) or 4,4,4-trifluoro-1-(2-thienyl)-1,3-butanedione (HTTA) and M = Pt2+ or Pd2+. These complexes were characterized by elemental analyses, conductivity measurements, FT-IR, UV-Vis, high-resolution mass spectra (HRESIMS) and TG/DTA. In the complexes, the metallic ions bind to β-diketone via the oxygen atoms and to DMSO molecule via sulfur atom. The structures of complexes were optimized and theoretical data showed good agreement with the experimental results. The cytotoxic activity of the compounds was evaluated in a chronic myelogenous leukemia cell line. The platinum complexes were more cytotoxic than the free ligands and carboplatin and are promising candidates for further investigations. As example, the compound [PtCl(TPB)(DMSO)] inhibits the growth of K562 cells with an IC50 value equal to 2.5 μM. Furthermore, microbiological assays against Mycobacterium tuberculosis showed that all complexes exhibit low cytotoxicity against this bacterial strain while the free ligands exhibited MIC values of approximately 10 μg mL-1.

Bioactivity-guided isolation of laevicarpin, an antitrypanosomal and anticryptococcal lactam from Piper laevicarpu (Piperaceae).

PubMed

da Silva A Maciel, Dayany; Freitas, Viviane P; Conserva, Geanne A Alves; Alexandre, Tatiana R; Purisco, Sonia U; Tempone, Andre G; Melhem, Márcia Souza C; Kato, Massuo J; Guimarães, Elsie F; Lago, João Henrique G

2016-06-01

Crude CH2Cl2 extract from leaves of Piper laevicarpu (Piperaceae) displayed antitrypanosomal activity against trypomastigote forms of Trypanosoma cruzi (Y strain) and antimicrobial potential against Cryptococcus gattii (strain-type WM 178). Bioactivity-guided fractionation of crude extract afforded one new natural bioactive lactam derivative, named laevicarpin. The structure of isolated compound, which displayed a very rare ring system, was elucidated based on NMR, IR and MS spectral analysis. Using MTT assay, the trypomastigotes of T. cruzi demonstrated susceptibility to laevicarpin displaying IC50 value of 14.7μg/mL (49.6μM), about 10-fold more potent than the standard drug benznidazole. The mammalian cytotoxicity of laevicarpin was verified against murine fibroblasts (NCTC cells) and demonstrated a CC50 value of 100.3μg/mL (337.7μM-SI=7). When tested against Cryptococcus gattii, laevicarpin showed an IC50 value of 2.3μg/mL (7.9μM) and a MIC value of 7.4μg/mL (25μM). Based in the obtained results, laevicarpin could be used as a scaffold for future drug design studies against the Chagas disease and anti-cryptococosis agents. Copyright © 2016 Elsevier B.V. All rights reserved.

Synthesis and biological evaluation of some novel pyrido[1,2-a]pyrimidin-4-ones as antimalarial agents.

PubMed

Mane, Uttam R; Mohanakrishnan, D; Sahal, Dinkar; Murumkar, Prashant R; Giridhar, Rajani; Yadav, Mange Ram

2014-05-22

Novel pyrido[1,2-a]pyrimidin-4-ones have been synthesized and evaluated for their antimalarial activity by SYBR Green I assay against erythrocytic stages of chloroquine (CQ) sensitive Pf 3D7 strain. The antimalarial screening of 42 different compounds revealed that 3-Fluorobenzyl(4-oxo-4H-pyrido [1,2-a]pyrimidin-3-yl)carbamate (21, IC50 value 33 μM) and 4-Oxo-N-[4-(trifluoromethyl)benzyl]-4H-pyrido[1,2-a]pyrimidine-3-carboxamide (37, IC50 value 37 μM) showed moderate antimalarial activity. Cytotoxicity study was performed against mammalian cell line (Huh-7) by using the MTT assay for the moderately active compounds. Structural activity relationship (SAR) studies displayed that B-ring unsubstituted pyrido[1,2-a]pyrimidine scaffold is responsible for the antimalarial activities of the evaluated derivatives. This SAR based antimalarial screening supported that pyrido[1,2-a]pyrimidin-4-one can be considered as a lead heterocyclic structure for further development of more potent derivatives for antimalarial activity. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Understanding drugs in breast cancer through drug sensitivity screening.

PubMed

Uhr, Katharina; Prager-van der Smissen, Wendy J C; Heine, Anouk A J; Ozturk, Bahar; Smid, Marcel; Göhlmann, Hinrich W H; Jager, Agnes; Foekens, John A; Martens, John W M

2015-01-01

With substantial numbers of breast tumors showing or acquiring treatment resistance, it is of utmost importance to develop new agents for the treatment of the disease, to know their effectiveness against breast cancer and to understand their relationships with other drugs to best assign the right drug to the right patient. To achieve this goal drug screenings on breast cancer cell lines are a promising approach. In this study a large-scale drug screening of 37 compounds was performed on a panel of 42 breast cancer cell lines representing the main breast cancer subtypes. Clustering, correlation and pathway analyses were used for data analysis. We found that compounds with a related mechanism of action had correlated IC50 values and thus grouped together when the cell lines were hierarchically clustered based on IC50 values. In total we found six clusters of drugs of which five consisted of drugs with related mode of action and one cluster with two drugs not previously connected. In total, 25 correlated and four anti-correlated drug sensitivities were revealed of which only one drug, Sirolimus, showed significantly lower IC50 values in the luminal/ERBB2 breast cancer subtype. We found expected interactions but also discovered new relationships between drugs which might have implications for cancer treatment regimens.

CYTOTOXIC, α-CHYMOTRYPSIN AND UREASE INHIBITION ACTIVITIES OF THE PLANT Heliotropium dasycarpum L.

PubMed Central

Ghaffari, Muhammad Abuzar; Chaudhary, Bashir Ahmed; Uzair, Muhammad; Ashfaq, Khuram

2016-01-01

Background: The aim of this study was to investigate Cytotoxic, α-Chymotrypsin and Urease inhibition activities of the plant Heliotropium dasycarpum. Materials & Methods: Dichloromethane and methanol extracts of the plant were evaluated for cytotoxic, α-Chymotrypsin and Urease inhibition by using in vivo Brine Shrimp lethality bioassay and in vitro enzymatic inhibition assays respectively. Results: The methanol extract of the plant exhibited significant cytotoxic activity. Out of 30 brine shrimp larvae, 2 (6%), 26 (86%) and 28 (93%) larvae were survived at concentration of 1000μg/ml, 100μg/ml and 10μg/ml respectively with LD50; 215.837. Similarly 21 (70%), 25 (83%), 29 (96%) larvae were survived of dichloromethane plant extract with LD50; 6170.64. The methanol and dichloromethane extract exhibited 10.50±0.18% and 41.51±0.15% α-chymotrypsin enzyme inhibition respectively with IC50 values of greater than 500 μmol. The methanol extract showed 24.39±0.21% Urease enzyme inhibition with IC50 values of greater than 400 μmol While dichloromethane extract has 11.46±0.09% enzyme inhibition with IC50 values of greater than 500 μmol Conclusion: The results clearly indicated that Heliotropium dasycarpum has cytotoxic potential and enzyme inhibition properties. Further study is needed to screen out antitumor and anti-ulcerative agents. PMID:28480379

Ecotoxicological responses of three ornamental herb species to cadmium.

PubMed

Liu, Zhouli; He, Xingyuan; Chen, Wei; Zhao, Mingzhu

2013-08-01

Cadmium is one of the most toxic elements. The ideal vegetal cover should be ensured by the selection of appropriate plant species for successful phytoremediation. In the present study, the ecotoxicological effects of Cd on the following 3 ornamental herbs were investigated: Italian ryegrass (Lolium multiflorum Lam.), white clover (Trifolium repens L.), and alfalfa (Medicago sativa L.). Based on the inhibition rate of seed germination, root and shoot elongation, early seedling growth, median inhibition concentration (IC50) values, and index of tolerance (IT) values, ecotoxicological indicators were determined. The results showed that 10 μM to 50 μM Cd had little effect on seed germination or root and shoot elongation of the 3 ornamental herbs (p > 0.01). With an increase in Cd concentrations, alfalfa (M. sativa) was the most sensitive to Cd toxicity in terms of seed germination and root elongation. Based on the IC50 of root elongation, Italian ryegrass (L. multiflorum) was the least sensitive to Cd. Based on the IC50 of seed germination and shoot elongation, white clover had the least sensitivity to Cd. Among the 3 ornamental herbs, based on the IC50 of seed germination and root and shoot elongation, alfalfa (M. sativa) was all the most sensitive plant. According to the index of tolerance, Italian ryegrass (L. multiflorum) was the most tolerant plant. Copyright © 2013 SETAC.

Assessment of antimalarial activity against Plasmodium falciparum and phytochemical screening of some Yemeni medicinal plants

PubMed Central

Alshawsh, Mohammed A.; Al-shamahy, Hassan A.; Alsllami, Salah F.; Lindequist, Ulrike

2009-01-01

Developing countries, where malaria is one of the most prevalent diseases, still rely on traditional medicine as a source for the treatment of this disease. In the present study, six selected plants (Acalypha fruticosa, Azadirachta indica, Cissus rotundifolia, Echium rauwalfii, Dendrosicyos socotrana and Boswellia elongata) commonly used in Yemen by traditional healers for the treatment of malaria as well as other diseases, were collected from different localities of Yemen, dried and extracted with methanol and water successfully. The antiplasmodial activity of the extracts was evaluated against fresh clinical isolates of Plasmodium falciparum. The selectivity parameters to evaluate the efficacy of these medicinal plants were measured by in vitro micro test (Mark III) according to World Health Organization (WHO) 1996 & WHO 2001 protocols of antimalarial drug tests. Among the investigated 12 extracts, three were found to have significant antiplasmodial activity with IC50 values less than 4 µg/ml, namely the water extracts of A. fruticosa, A. indica and D. socotrana. Six extracts showed moderate activity with IC50 values ranging from 10 to 30 µg/ml and three appeared to be inactive with IC50 values more than 30 µg/ml. In addition, preliminary phytochemical screening of the methanolic and aqueous extracts indicated the presence of saponins, tannins, flavonoids, terpenoids, polysaccharides and peptides. PMID:18955251

Desacetylmatricarin, an anti-allergic component from Taraxacum platycarpum.

PubMed

Cheong, H; Choi, E J; Yoo, G S; Kim, K M; Ryu, S Y; Ho, C

1998-08-01

The bioassay-guided fractionation of Taraxacum platycarpum (Compositae) extract led to the isolation of a desacetylmatricarin (1) as an active principle responsible for the anti-allergic property. It showed a potent inhibitory activity upon the beta-hexosaminidase release from RBL-2H3 cells in a dose-dependent manner and the IC50 was 7.5 microM. Two structurally related guaianolide sesquiterpenes, achillin and leucodin, were also examined and their IC50 values were determined as 100 microM and 80 microM, respectively.

Gedunin and Azadiradione: Human Pancreatic Alpha-Amylase Inhibiting Limonoids from Neem (Azadirachta indica) as Anti-Diabetic Agents.

PubMed

Ponnusamy, Sudha; Haldar, Saikat; Mulani, Fayaj; Zinjarde, Smita; Thulasiram, Hirekodathakallu; RaviKumar, Ameeta

2015-01-01

Human pancreatic α-amylase (HPA) inhibitors offer an effective strategy to lower postprandial hyperglycemia via control of starch breakdown. Limonoids from Azadirachta indica known for their therapeutic potential were screened for pancreatic α-amylase inhibition, a known anti-diabetic target. Studies were carried out to reveal their mode of action so as to justify their hypoglycemic potential. Of the nine limonoids isolated/semi-synthesized from A.indica and screened for α-amylase inhibition, azadiradione and exhibited potential inhibition with an IC50 value of 74.17 and 68.38 μM, respectively against HPA under in vitro conditions. Further screening on AR42J α-amylase secretory cell line for cytotoxicity and bioactivity revealed that azadiradione and gedunin exhibited cytotoxicity with IC50 of 11.1 and 13.4μM. Maximal secreted α-amylase inhibition of 41.8% and 53.4% was seen at 3.5 and 3.3μM, respectively. Michaelis-Menten kinetics suggested a mixed mode of inhibition with maltopentaose (Ki 42.2, 18.6 μM) and starch (Ki' 75.8, 37.4 μM) as substrate with a stiochiometry of 1:1 for both azadiradione and gedunin, respectively. The molecular docking simulation indicated plausible π-alkyl and alkyl-alkyl interactions between the aromatic amino acids and inhibitors. Fluorescence and CD confirmed the involvement of tryptophan and tyrosine in ligand binding to HPA. Thermodynamic parameters suggested that binding is enthalpically and entropically driven with ΔG° of -21.25 kJ mol-1 and -21.16 kJ mol-1 for azadiradione and gedunin, respectively. Thus, the limonoids azadiradione and gedunin could bind and inactivate HPA (anti-diabetic target) and may prove to be lead drug candidates to reduce/control post-prandial hyperglycemia.

A defucosylated bispecific multivalent molecule exhibits broad HIV-1 neutralizing activity and enhanced ADCC against reactivated HIV-1 latently infected cells.

PubMed

Kong, Desheng; Wang, Yan; Ji, Ping; Li, Wei; Ying, Tianlei; Huang, Jinghe; Wang, Chen; Wu, Yanling; Wang, Yanping; Chen, Weizao; Hao, Yanling; Hong, Kunxue; Shao, Yiming; Dimitrov, Dimiter S; Jiang, Shibo; Ma, Liying

2018-05-11

Current treatments cannot completely eradicate HIV-1 owing to the presence of latently infected cells which harbor transcriptionally silent HIV-1. However, defucosylated antibodies can readily kill latently infected cells after their activation to express envelope glycoprotein (Env) through antibody-dependent cellular cytotoxicity (ADCC). We herein aimed to test a defucosylated bispecific multivalent molecule consisting of domain-antibody and single-domain CD4, LSEVh-LS-F, for its HIV-1 neutralizing activity and ADCC against the reactivated latently infected cells, compared with the non-defucosylated molecule LSEVh-LS. LSEVh-LS-F's neutralizing activity against a panel of newly characterized Chinese HIV-1 clinical isolates was assessed by using TZM-bl- and PBMC-based assays. LSEVh-LS-F-mediated ADCC in the presence of NK cells against cell lines that stably express Env proteins, HIV-1-infected cells and LRA-reactivated HIV-1 latent cells, was measured using a lactate dehydrogenase (LDH) cytotoxicity assay or flow cytometry. LSEVh-LS-F and LSEVh-LS were equally effective in neutralized infection of all HIV-1 isolates tested with IC50 and IC90 values 3∼4-fold lower than those of VRC01. LSEVh-LS-F was more effective in NK-mediated killing of HIV-1 Env-expressing cell lines, HIV-1-infected cells, latency reactivation agents-reactivated ACH2 cells, and reactivated latently infected resting CD4 T cell line as well as resting CD4 T lymphocytes isolated from patients receiving highly active anti-retroviral therapy (HAART). LSEVh-LS-F exhibits broad HIV-1 neutralizing activity and enhanced ADCC against HIV-1-infected cells, reactivated latently infected cell lines and primary CD4 T cells, thus being a promising candidate therapeutic for eradicating the HIV-1 reservoir.

The enhanced inhibitory effect of different antitumor agents in self-microemulsifying drug delivery systems on human cervical cancer HeLa cells.

PubMed

Ujhelyi, Zoltán; Kalantari, Azin; Vecsernyés, Miklós; Róka, Eszter; Fenyvesi, Ferenc; Póka, Róbert; Kozma, Bence; Bácskay, Ildikó

2015-07-21

The aim of this study was to develop topical self-microemulsifying drug delivery systems (SMEDDS) containing antitumor agents (bleomycin, cisplatin and ifosfamide) and to investigate their inhibitory potential in SMEDDS on human cervical cancer HeLa cells. The physicochemical properties of cytostatic drug loaded SMEDDS were characterized. The cytotoxicity of main components of SMEDDS was also investigated. Their IC50 values were determined. HeLa cells were treated by different concentrations of cisplatin, bleomycin and ifosfamide alone and in various SMEDDS. The inhibitory effect on cell growth was analyzed by MTT cell viability assay. Inflammation is a driving force that accelerates cancer development. The inhibitory effect of these antitumor agents has also been tested on HeLa cells in the presence of inflammatory mediators (IL-1-β, TNF-α) as an in vitro model of inflamed human cervix. Significant differences in the cytotoxicity of cytostatic drugs alone and in SMEDDS have been found in a concentration-dependent manner. The self-micro emulsifying system may potentiate the effectiveness of bleomycin, cisplatin and ifosfamide topically. The effect of SMEDDS containing antitumor agents was decreased significantly in the presence of inflammatory mediators. According to our experiments, the optimal SMEDDS formulation is 1:1:2:6:2 ratios of Isopropyl myristate, Capryol 90, Kolliphor RH 40, Cremophor RH40, Transcutol HP and Labrasol. It can be concluded that SMEDDS may increase the inhibitory effect of bleomycin, ifosfamide and cisplatin on human cervical cancer HeLa cells. Inflammation on HeLa cells hinders the effectiveness of SMEDDS containing antitumor agents. Our results might ensure useful data for development of optimal antitumor formulations.

In Vitro Co-Delivery Evaluation of Novel Pegylated Nano-Liposomal Herbal Drugs of Silibinin and Glycyrrhizic Acid (Nano-Phytosome) to Hepatocellular Carcinoma Cells

PubMed Central

Ochi, Mohammad Mahdi; Amoabediny, Ghasem; Rezayat, Seyed Mahdi; Akbarzadeh, Azim; Ebrahimi, Bahman

2016-01-01

Objective This study aimed to evaluate a co-encapsulated pegylated nano-liposome system based on two herbal anti-tumor drugs, silibinin and glycyrrhizic acid, for delivery to a hepatocellular carcinoma (HCC) cell line (HepG2). Materials and Methods In this experimental study, co-encapsulated nano-liposomes by the thin layer film hydration method with HEPES buffer and sonication at 60% amplitude. Liposomes that co-encapsulated silibinin and glycyrrhizic acid were prepared with a specified molar ratio of dipalmitoylphosphatidylcholine (DPPC), cholesterol (CHOL), and methoxy-polyethylene glycol 2000 (PEG2000)–derived distearoyl phosphatidylethanolamine (mPEG2000-DSPE). We used the MTT technique to assess cytotoxicity for various concentrations of co-encapsulated nano-liposomes, free silibinin (25% w/v) and glycyrrhizic acid (75% w/v) on HepG2 and fibroblast cell lines over a 48-hour period. Results Formulation of pegylated nano-liposomes showed a narrow size distribution with an average diameter of 46.3 nm. The encapsulation efficiency (EE) for silibinin was 24.37%, whereas for glycyrrhizic acid it was 68.78%. Results of in vitro cytotoxicity showed significantly greater co-encapsulated nano-liposomes on the HepG2 cell line compared to the fibroblast cell line. The half maximal inhibitory concentration (IC50) for co-encapsulated pegylated nanoliposomal herbal drugs was 48.68 µg/ml and free silibinin with glycyrrhizic acid was 485.45 µg/ml on the HepG2 cell line. Conclusion This in vitro study showed that nano-liposome encapsulation of silibinin with glycyrrhizic acid increased the biological activity of free drugs, increased the stability of silibinin, and synergized the therapeutic effect of silibinin with glycyrrhizic acid. The IC50 of the co-encapsulated nano-liposomes was lower than the combination of free silibinin and glycyrrhizic acid on the HepG2 cell line. PMID:27540518

Glycosyl glycerides from hydroponic Panax ginseng inhibited NO production in lipopolysaccharide-stimulated RAW264.7 cells

PubMed Central

Cha, Byeong-Ju; Park, Ji-Hae; Shrestha, Sabina; Baek, Nam-In; Lee, Sang Min; Lee, Tae Hoon; Kim, Jiyoung; Kim, Geum-Soog; Kim, Seung-Yu; Lee, Dae-Young

2014-01-01

Background Although the aerial parts of hydroponic Panax ginseng are reported to contain higher contents of total ginsenosides than those of roots, the isolation and identification of active metabolites from the aerial parts of hydroponic P. ginseng have not been carried out so far. Methods The aerial parts of hydroponic P. ginseng were applied on repeated silica gel and octadecylsilane columns to yield four glycosyl glycerides (Compounds 1–4), which were identified based on nuclear magnetic resonance, infrared, fast atom bombardment mass spectrometry, and gas chromatography/mass spectrometry data. Compounds 1–4 were evaluated for inhibition activity on NO production in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. Results and conclusion The glycosyl glycerides were identified to be (2S)-1-O-7(Z),10(Z),13(Z)-hexadecatrienoyl-3-O-β-d-galactopyranosyl-sn-glycerol (1), (2S)-1-O-linolenoyl-3-O-β-d-galactopyranosyl-sn-glycerol (2), (2S)-1-O-linolenoyl-2-O-linolenoyl-3-O-β-d-galactopyranosyl-sn-glycerol (3), and 2(S)-1-O-linoleoyl-2-O-linoleoyl-3-O-β-d-galactopyranosyl-sn-glycerol (4). Compounds 1 and 2 showed moderate inhibition activity on NO production in LPS-stimulated RAW264.7 cells [half maximal inhibitory concentration (IC50): 63.8 ± 6.4μM and 59.4 ± 6.8μM, respectively] without cytotoxicity at concentrations < 100μM, whereas Compounds 3 and 4 showed good inhibition effect (IC50: 7.7 ± 0.6μM and 8.0 ± 0.9μM, respectively) without cytotoxicity at concentrations < 20μM. All isolated compounds showed reduced messenger RNA (mRNA) expression of interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α in LPS-induced macrophage cells with strong inhibition of mRNA activity observed for Compounds 3 and 4. PMID:26045690