Science.gov

Sample records for naphthoquinones

  1. The trypanocidal activity of naphthoquinones: a review.

    PubMed

    Pinto, Antônio Ventura; de Castro, Solange Lisboa

    2009-01-01

    Naphthoquinones are compounds present in several families of higher plants. Their molecular structures confer redox properties, and they are involved in multiple biological oxidative processes. In folk medicine, especially among Indian populations, plants containing naphthoquinones have been employed for the treatment of various diseases. The biological redox cycle of quinones can be initiated by one electron reduction leading to the formation of semiquinones, unstable intermediates that react rapidly with molecular oxygen, generating free radicals. Alternatively, the reduction by two electrons, mediated by DT-diphorase, leads to the formation of hydroquinone. Lapachol, alpha-lapachone and beta-lapachone, which are isolated from the heartwood of trees of the Bignoniaceae family, are examples of bioactive naphthoquinones. In this review, we will discuss studies investigating the activity of these natural products and their derivatives in the context of the search for alternative drugs for Chagas disease, caused by Trypanosoma cruzi, a neglected illness that is endemic in Latin America. PMID:19924086

  2. Synthesis, Characterization, and Antileukemic Properties of Naphthoquinone Derivatives of Lawsone.

    PubMed

    Inagaki, Ryuta; Ninomiya, Masayuki; Tanaka, Kaori; Koketsu, Mamoru

    2015-08-01

    Naphthoquinones are considered privileged structures for anticancer drug molecules. The Heck reaction of 2-hydroxy-1,4-naphthoquinone (lawsone) with 1-bromo-3-methyl-2-butene offered easy access to lapachol. Several naturally occurring linear and angular heterocyclic quinoids (?-lapachone, ?-lapachone, dunnione, and related analogues) were prepared from lapachol. Furthermore, we demonstrated that the synthetic naphthoquinones inhibit cell proliferation in human leukemia HL-60 cells. In particular, angular-type derivatives were found to possess moderate cytotoxicity and to elevate the levels of intracellular glutathione disulfide (GSSG). Our work highlights the significant potential of naturally occurring angular-series naphthoquinones as antileukemic agents. PMID:26088596

  3. Anthraquinone and naphthoquinone derivatives from the roots of Coptosapelta flavescens.

    PubMed

    Kongyen, Wipapan; Rukachaisirikul, Vatcharin; Phongpaichit, Souwalak; Sawangjaroen, Nongyao; Songsing, Phruksa; Madardam, Hattaya

    2014-02-01

    Investigation of the acetone and methanol extracts of the roots of Coptosapelta flavescens using various chromatographic techniques led to the isolation of four anthraquinones (1 and 3-5) and one naphthoquinone (2). 1,4-Dimethoxy-2-methylanthraquinone (1) and 2-amino-3-methoxycarbonyl-1,4-naphthoquinone (2) are reported as natural compounds for the first time. This is the first report on the phytochemistry and biological activity of compounds from C. flavescens. PMID:24689295

  4. STABILITY OF HEMOGLOBIN AND ALBUMIN ADDUCTS OF NAPHTHALENE OXIDE, 1,2-NAPHTHOQUINONE, AND 1,4-NAPHTHOQUINONE

    EPA Science Inventory

    Naphthalene is an important industrial chemical, which has recently been shown to cause tumors of the respiratory tract in rodents. It is thought that one or more reactive metabolites of naphthalene, namely, naphthalene-1,2-oxide (NPO), 1,2-naphthoquinone (1,2-NPQ), and 1,4-na...

  5. Further evidence that naphthoquinone inhibits Toxoplasma gondii growth in vitro.

    PubMed

    da Silva, Luciana Lemos Rangel; Portes, Juliana de Araujo; de Araújo, Marlon Heggdorne; Silva, Jéssica Lays Sant'ana; Rennó, Magdalena Nascimento; Netto, Chaquip Daher; da Silva, Alcides José Monteiro; Costa, Paulo Roberto Ribeiro; De Souza, Wanderley; Seabra, Sergio Henrique; DaMatta, Renato Augusto

    2015-12-01

    Toxoplasmosis is a widely disseminated disease caused by Toxoplasma gondii, an intracellular protozoan parasite. Standard treatment causes many side effects, such as depletion of bone marrow cells, skin rashes and gastrointestinal implications. Therefore, it is necessary to find chemotherapeutic alternatives for the treatment of this disease. It was shown that a naphthoquinone derivative compound is active against T. gondii, RH strain, with an IC50 around 2.5 ?M. Here, three different naphthoquinone derivative compounds with activity against leukemia cells and breast carcinoma cell were tested against T. gondii (RH strain) infected LLC-MK2 cell line. All the compounds were able to inhibit parasite growth in vitro, but one of them showed an IC50 activity below 1 ?M after 48 h of treatment. The compounds showed low toxicity to the host cell. In addition, these compounds were able to induce tachyzoite-bradyzoite conversion confirmed by morphological changes, Dolichus biflorus lectin cyst wall labeling and characterization of amylopectin granules in the parasites by electron microscopy analysis using the Thierry technique. Furthermore, the compounds induced alterations on the ultrastructure of the parasite. Taken together, our results point to the naphthoquinone derivative (LQB 151) as a potential compound for the development of new drugs for the treatment of toxoplasmosis. PMID:26335616

  6. Parameters determining the relative efficacy of hydroxy-naphthoquinone inhibitors of the cytochrome bc1 complex

    E-print Network

    Trumpower, Bernard L.

    , Steven R. Meshnick d , Bernard L. Trumpower a, a Department of Biochemistry, Dartmouth Medical School-naphthoquinones with aromatic, cyclic, and non-cyclic alkyl side-chain substitutions at carbon-3 on the hydroxy-quinone ring. We-naphthoquinones with aromatic, cyclic, and non-cyclic alkyl side-chains at position 3 on the hydroxy-quinone ring for inhibition

  7. Development of Polyclonal Antibodies for Detection of Protein Modification by 1,2-Naphthoquinone

    E-print Network

    Hammock, Bruce D.

    Development of Polyclonal Antibodies for Detection of Protein Modification by 1,2-Naphthoquinone raised polyclonal antibodies by immunizing rabbits with 1,2-naphthoquinone protein adducts. A high titer of polyclonal antibodies was obtained by antiserum dilution tests. Competitive ELISA showed that the antibodies

  8. A new and efficient procedure for the synthesis of hexahydropyrimidine-fused 1,4-naphthoquinones

    PubMed Central

    Reis, Marcelo Isidoro P; Campos, Vinícius R; Resende, Jackson A L C; Silva, Fernando C

    2015-01-01

    Summary A new and efficient method for the synthesis of hexahydropyrimidine-fused 1,4-naphthoquinones in one step with high yields from the reaction of lawsone with 1,3,5-triazinanes was developed. PMID:26425181

  9. Modulation of Basophils' Degranulation and Allergy-Related Enzymes by Monomeric and Dimeric Naphthoquinones

    PubMed Central

    Pinho, Brígida R.; Sousa, Carla; Valentão, Patrícia; Oliveira, Jorge M. A.; Andrade, Paula B.

    2014-01-01

    Allergic disorders are characterized by an abnormal immune response towards non-infectious substances, being associated with life quality reduction and potential life-threatening reactions. The increasing prevalence of allergic disorders demands for new and effective anti-allergic treatments. Here we test the anti-allergic potential of monomeric (juglone, menadione, naphthazarin, plumbagin) and dimeric (diospyrin and diosquinone) naphthoquinones. Inhibition of RBL-2H3 rat basophils' degranulation by naphthoquinones was assessed using two complementary stimuli: IgE/antigen and calcium ionophore A23187. Additionally, we tested for the inhibition of leukotrienes production in IgE/antigen-stimulated cells, and studied hyaluronidase and lipoxidase inhibition by naphthoquinones in cell-free assays. Naphthazarin (0.1 µM) decreased degranulation induced by IgE/antigen but not A23187, suggesting a mechanism upstream of the calcium increase, unlike diospyrin (10 µM) that reduced degranulation in A23187-stimulated cells. Naphthoquinones were weak hyaluronidase inhibitors, but all inhibited soybean lipoxidase with the most lipophilic diospyrin, diosquinone and menadione being the most potent, thus suggesting a mechanism of competition with natural lipophilic substrates. Menadione was the only naphthoquinone reducing leukotriene C4 production, with a maximal effect at 5 µM. This work expands the current knowledge on the biological properties of naphthoquinones, highlighting naphthazarin, diospyrin and menadione as potential lead compounds for structural modification in the process of improving and developing novel anti-allergic drugs. PMID:24587235

  10. Antitumoral activity of new polyamine-naphthoquinone conjugates.

    PubMed

    Esteves-Souza, Andressa; Lucio, Kelly Araújo; Da Cunha, Andréa Sousa; Da Cunha Pinto, Angelo; Da Silva Lima, Edson Luiz; Camara, Celso Amorim; Vargas, Maria Domingues; Gattass, Cerli Rocha

    2008-07-01

    Polyamine-naphthoquinone conjugates 5a-c were synthesized by nucleophilic displacement of 2-methoxy-lawsone 3a, 2-methoxylapachol 3b and 2-methoxy-nor-lapachol 3c with the polyamine N1-Boc-N5-Bn-spermidine 4. Unprotected derivatives 6a-c were synthesized to evaluate the effect of the protective Boc group on the activity of compounds 5a-c. The colorimetric MTT assay was used to evaluate their cytotoxic activity. All compounds were active against human lines of promyelocytic leukemia (HL-60), lung cancer (GLC4), Burkitt lymphoma (Daudi) and a mouse breast tumor (Ehrlich carcinoma), but only unprotected 6a-c showed activity against the human line of melanoma (MV-3). IC50 values were obtained from dose response curves by linear regression. DNA fragmentation was measured by quantification of the subG1 peak of the cell cycle. Apoptosis of HL-60 treated with 5c was dose-dependent. The amount of DNA fragmentation observed by exposure of HL-60 to 25 microM of compounds 5a-c and 6a-c is compatible with the decrease in viability induced by the drugs at this concentration. Production of ROS was measured by H2-CFDA. Kinetics of HL-60 DNA fragmentation and ROS formation by 5c indicated that production of ROS precedes cell death. In conclusion, spermidine-1,4-naphthoquinone conjugates exhibited an increase in activity compared with the natural products and induced apoptosis of tumor cell lines by a mechanism that is mediated, at least in part, by ROS production. PMID:18575741

  11. MEASUREMENT OF HEMOGLOBIN AND ALBUMIN ADDUCTS OF NAPHTHALENE-1,2-OXIDE, 1,2-NAPHTHOQUINONE AND 1,4-NAPHTHOQUINONE AFTER ADMINISTRATION OF NAPHTHALENE TO F344 RATS

    EPA Science Inventory

    Naphthalene-1,2-oxide (NPO), 1,2-naphthoquinone (1,2-NPQ) and 1,4-naphthoquinone (1,4-NPQ) are the major metabolites of naphthalene that are thought to be responsible for the cytotoxicity and genotoxicity of this chemical. We measured cysteinyl adducts of these metabolites in ...

  12. Effect of hydroxy substituent on the prooxidant action of naphthoquinone compounds.

    PubMed

    Murakami, Keiko; Haneda, Miyako; Iwata, Shouko; Yoshino, Masataka

    2010-04-01

    Prooxidant activity of naphthoquinone compounds was analyzed by lipid peroxidation, and the formation of base adduct in DNA. Naphthoquinones with electron-repelling hydroxyl group in the benzene moiety such as juglone and shikonin of lower concentrations stimulated the microsomal lipid peroxidation, but lawsone and lapachol with hydroxyl group in the quinone moiety did not enhance the formation of lipid peroxides. Naphthoquinone-dependent lipid peroxidation was closely related to the enhancement of Fe(2+) autooxidation. Treatment of DNA with juglone a representative of 5-hydroxylated naphthoquinone stimulated the formation of 8-hydroxy-2'-deoxyguanosine, whereas lawsone and lapachol showed negligible formation of DNA base adduct. ESR spectra showed that juglone can form semiquinone radical in the presence of ferrous ion, but lawsone cannot. Biological toxicity of juglone with the potent electron-repelling group at 5-position may be due to the reactive oxygen species formed by semiquinone radical, but naphthoquinone compounds with an electron-repelling group in the quinone moiety, lawsone shows weak toxicity with only a little ability producing reactive oxygen species by the negligible formation of semiquinone. PMID:19961919

  13. Antitumor activity of two derivatives from 2-acylamine-1, 4-naphthoquinone in mice bearing S180 tumor.

    PubMed

    Bezerra, Daniel Pereira; Alves, Ana Paula Negreiros Nunes; de Alencar, Nylane Maria Nunes; Mesquita, Rodney de Oliveira; Lima, Michael Will; Pessoa, Cláudia; de Moraes, Manoel Odorico; Lopes, José Norberto Callegari; Lopes, Norberto Peporine; Costa-Lotufo, Letícia Veras

    2008-01-01

    Drugs containing a quinone moiety, such as anthracyclines, mitoxantrones and lapachol, show excellent anticancer activity. In this study, 2-butanoylamine-1,4-naphthoquinone (1) and 2-propanoylamine-1,4-naphthoquinone (2) derivatives from 2-amine-1 ,4-naphthoquinone were synthesized, and their antitumor activity in mice bearing Sarcoma 180 tumor were examined. In addition, hematology and biochemistry analyses, as well as, histopathological and morphological analyses were performed in order to evaluate the toxicological aspects of the naphthoquinones treatment. Both naphthoquinones showed potente antitumor activity. The inhibition rates were 33.48 and 42.35% for (1) and 37.65 and 55.24% for (2) at the dose of 25 and 50 mg/kg/day, respectively. In the histopathological analysis, the naphthoquinones showed only weak toxicity. Neither enzimatic activity of transaminases (aspartate aminotransferase-AST nor alanine aminotransferase-ALT), urea level nor hematological paramenter were significantly modified after naphthoquinones treatment. These data reinforce the anticancer potential of naphthoquinones derivatives. PMID:18771085

  14. Phytotoxic action of naphthoquinone juglone demonstrated on lettuce seedling roots.

    PubMed

    Babula, Petr; Vaverkova, Veronika; Poborilova, Zuzana; Ballova, Ludmila; Masarik, Michal; Provaznik, Ivo

    2014-11-01

    Juglone, 5-hydroxy-1,4-naphthoquinone, is the plant secondary metabolite with allelopathic properties, which was isolated especially from the plant species belonging to family Juglandaceae A. Rich. ex Kunth (walnut family). The mechanism of phytotoxic action of juglone was investigated on lettuce seedlings Lactuca sativa L. var. capitata L. cv. Merkurion by determining its effect at different levels. We have found that juglone inhibits mitosis (mitotic index 8.5 ± 0.6% for control versus 2.2 ± 0.9% for 250 ?M juglone), changes mitotic phase index with accumulation of the cells in prophase (56.5 ± 2.6% for control versus 85.3 ± 5.0% for 250 ?M juglone), and decreases meristematic activity in lettuce root tips (51.07 ± 3.62% for control versus 5.27 ± 2.29% for 250 ?M juglone). In addition, juglone induced creation of reactive oxygen species and changed levels of reactive nitrogen species. Amount of malondialdehyde, a product of lipid peroxidation, increased from 24.0 ± 4.0 ng g(-1) FW for control to 55.5 ± 5.4 ng g(-1) FW for 250 ?M juglone. We observed also changes in cellular structure, especially changes in the morphology of endoplasmic reticulum. Reactive oxygen species induced damage of plasma membrane. All these changes resulted in the disruption of the mitochondrial membrane potential, increase in free intracellular calcium ions, and DNA fragmentation and programmed cell death that was revealed by two methods, TUNEL test and DNA electrophoresis. The portion of TUNEL-positive cells increase from 0.96 ± 0.5% for control to 7.66 ± 1.5% for 250 ?M juglone. Results of the study indicate complex mechanism of phytotoxic effect of juglone in lettuce root tips and may indicate mechanism of allelopathic activity of this compound. PMID:25240266

  15. NAD-dependent dehydrogenase bioelectrocatalysis: the ability of a naphthoquinone redox polymer to regenerate NAD.

    PubMed

    Abdellaoui, Sofiene; Milton, Ross D; Quah, Timothy; Minteer, Shelley D

    2016-01-01

    Electron mediation between NAD-dependent enzymes using quinone moieties typically requires the use of a diaphorase as an intermediary enzyme. The ability for a naphthoquinone redox polymer to independently oxidize enzymatically-generated NADH is demonstrated for application to glucose/O2 enzymatic fuel cells. PMID:26618758

  16. Naphthoquinone spiroketal with allelochemical activity from the new endophytic fungus Edenia gomezpompae

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Bioassay-guided isolation from the culture of Edenia gomezpompae, a new endophytic fungus isolated from the leaves of Callicarpa acuminata (Verbenaceae) from the ecological reserve El Eden, Quintana Roo, Mexico, led to the isolation of four naphthoquinone spiroketals, including three new compounds. ...

  17. The Synthesis of 2-acetyl-1,4-naphthoquinone: A Multi-step Synthesis.

    ERIC Educational Resources Information Center

    Green, Ivan R.

    1982-01-01

    Outlines 2 procedures for synthesizing 2-acetyl-1,4-naphthoquinone to compare relative merits of the two pathways. The major objective of the exercise is to demonstrate that certain factors should be considered when selecting a pathway for synthesis including availability of starting materials, cost of reagents, number of steps involved,…

  18. Selective binding of naphthoquinone derivatives to serum albumin proteins and their effects on cytotoxicity.

    PubMed

    Jali, Bigyan R; Kuang, Yuting; Neamati, Nouri; Baruah, Jubaraj B

    2014-05-01

    Naphthoquinone derivatives such as lapachol, plumbagin, dichloroallyl lawsone show anticancer activity and generally cytotoxicity measurements are carried out in presence of bovine serum albumin; so understanding on the ability of serum albumin binding with such derivatives are essential. We have investigated cytotoxicity and serum albumin binding of a series of structurally related naphthoquinone derivatives. Substrate dependency and high selectivity in binding of naphthoquinone tethered carboxylic acids or pyridines with bovine serum albumin (BSA) and human serum albumin (HSA) are observed. For example, the binding constant of BSA with 3-(1,4-dihydro-2-methyl-1,4-dioxonaphthalen-3yl-thio)propanoic acid is ?594 times higher than 3-(1,4-dioxo-1,4-dihydronaphthalen-2-yl-amino)benzoic acid; whereas 4-(1,4-dioxo-1,4-dihydronaphthalen-2-yl-amino)benzoic acid shows ?367 times higher binding constant than the latter compound. The BSA weakly bind to pyridine tethered naphthoquinones, whereas HSA does not binds with them. The binding constant of HSA with 2-(1,4-dihydro-2-methyl-1,4-dioxonaphthalene-3-ylthio)benzoic acid is 134 times higher than the HSA binding constant with 2,2'-(1,4-dihydro-1,4-dioxo-naphthalen-2,3-diylthio)dipropanoic acid. Among the naphthoquinone carboxylic acids, the 3-(1,4-dioxo-1,4-dihydronaphthalen-2-yl-amino)benzoic acid binds selectively to BSA, but it does not bind to HSA. The 2-hydroxybenzoic acid or 4-mercaptobenzoic acid strongly binds to BSA. The binding of BSA with 4-hydroxybenzoic acid or 2-mercaptobenzoic acid are insignificant. We have not observed clear relationships of structure of naphthoquinone derivatives versus serum albumin binding, but could identify the compound having the best IC50 values of cytotoxicity among the twelve naphthoquinone compounds. The compound 3-(1,2-dihydro-1,2-dioxonaphthalen-4-yl-thio)propanoic acid in four cancer cell lines has IC50 values in the range 2.7-7.6?M. This compound also has optimum binding constant with BSA (35.042×10(3)Lmol(-1)) or HSA (21.427×10(3)Lmol(-1)). The cytotoxicity values of the compounds were influenced by concentration of BSA. PMID:24560625

  19. 1,4-Naphthoquinones as inducers of oxidative damage and stress signaling in HaCaT human keratinocytes.

    PubMed

    Klaus, Viola; Hartmann, Tobias; Gambini, Juan; Graf, Peter; Stahl, Wilhelm; Hartwig, Andrea; Klotz, Lars-Oliver

    2010-04-15

    Selected biological effects of 1,4-naphthoquinone, menadione (2-methyl-1,4-naphthoquinone) and structurally related quinones from natural sources--the 5-hydroxy-naphthoquinones juglone, plumbagin and the 2-hydroxy-naphthoquinones lawsone and lapachol--were studied in human keratinocytes (HaCaT). 1,4-naphthoquinone and menadione as well as juglone and plumbagin were highly cytotoxic, strongly induced reactive oxygen species (ROS) formation and depleted cellular glutathione. Moreover, they induced oxidative DNA base damage and accumulation of DNA strand breaks, as demonstrated in an alkaline DNA unwinding assay. Neither lawsone nor lapachol (up to 100 microM) were active in any of these assays. Cytotoxic and oxidative action was paralleled by stimulation of stress signaling: all tested quinones except lawsone and lapachol strongly induced phosphorylation of the epidermal growth factor receptor (EGFR) and the related ErbB2 receptor tyrosine kinase. EGFR activation by plumbagin, juglone and menadione was attenuated by a superoxide dismutase mimetic, indicating that ROS-related mechanisms contribute to EGFR activation by these naphthoquinones. PMID:20153715

  20. The Study of Naphthoquinones and Their Complexes with DNA by Using Raman Spectroscopy and Surface Enhanced Raman Spectroscopy: New Insight into Interactions of DNA with Plant Secondary Metabolites

    PubMed Central

    Vrana, Oldrich; Adam, Vojtech

    2014-01-01

    Naphthoquinones represent the group of plant secondary metabolites with cytotoxic properties based on their ability to generate reactive oxygen species and interfere with the processes of cell respiration. Due to this fact, the possible cytotoxic mechanisms on cellular and subcellular levels are investigated intensively. There are many targets of cytotoxic action on the cellular level; however, DNA is a critical target of many cytotoxic compounds. Due to the cytotoxic properties of naphthoquinones, it is necessary to study the processes of naphthoquinones, DNA interactions (1,4-naphthoquinone, binapthoquinone, juglone, lawsone, plumbagin), especially by using modern analytical techniques. In our work, the Raman spectroscopy was used to determine the possible binding sites of the naphthoquinones on the DNA and to characterize the bond of naphthoquinone to DNA. Experimental data reveals the relationships between the perturbations of structure-sensitive Raman bands and the types of the naphthoquinones involved. The modification of DNA by the studied naphthoquinones leads to the nonspecific interaction, which causes the transition of B-DNA into A-DNA conformation. The change of the B-conformation of DNA for all measured DNA modified by naphthoquinones except plumbagin is obvious. PMID:25045679

  1. Thiourea-catalyzed Diels–Alder reaction of a naphthoquinone monoketal dienophile

    PubMed Central

    Kramer, Carsten S

    2013-01-01

    Summary A variety of organocatalysts were screened for the catalysis of the naphthoquinone monoketal Diels–Alder reaction. In this study we found that Schreiner's thiourea catalyst 10 and Jacobson's thiourea catalyst 12 facilitate the cycloaddition of the sterically hindered naphthoquinone monoketal dienophile 3 with diene 4. The use of thiourea catalysis allowed for the first time the highly selective synthesis of the exo-product 2a in up to 63% yield. In this reaction a new quaternary center was built. The so formed cycloaddition product 2a represents the ABC tricycle of beticolin 0 (1) and is also a valuable model substrate for the total synthesis of related natural products. PMID:23946836

  2. Antitrypanosomal Activities and Cytotoxicity of Some Novel Imido-substituted 1,4-Naphthoquinone Derivatives

    PubMed Central

    Khraiwesh, Mozna H.; Lee, Clarence M.; Brandy, Yakini; Akinboye, Emmanuel S.; Berhe, Solomon; Gittens, Genelle; Abbas, Muneer M.; Ampy, Franklin R.; Ashraf, Mohammad

    2013-01-01

    The antitrypanosomal activities, cytotoxicity, and selectivity indices of eleven imido-substituted 1,4-naphthoquinone derivatives and nifurtimox have been studied. Compared to nifurtimox (IC50 = 10.67 µM), all the imido-naphthoquinone analogs (IMDNQ1-IMDNQ11) are more potent on Trypanosoma cruzi with IC50 values ranging from 0.7 µM to 6.1 µM (p < 0.05). Studies of the cytotoxic activities of these compounds on a Balb/C 3T3 mouse fibroblast cell line revealed that four of these compounds, IMDNQ1, IMDNQ2, IMDNQ3, and IMDNQ10 displayed selectivity indices of 60.25, 53.97, 31.83, and 275.3, respectively, rendering them significantly (p < 0.05) more selective in inhibiting the parasite growth than nifurtimox (selectivity index = 10.86). PMID:22297740

  3. Synthetic 1,4-Pyran Naphthoquinones Are Potent Inhibitors of Dengue Virus Replication

    PubMed Central

    da Costa, Emmerson C. B.; Amorim, Raquel; da Silva, Fernando C.; Rocha, David R.; Papa, Michelle P.; de Arruda, Luciana B.; Mohana-Borges, Ronaldo; Ferreira, Vitor F.; Tanuri, Amilcar

    2013-01-01

    Dengue virus infection is a serious public health problem in endemic areas of the world where 2.5 billion people live. Clinical manifestations of the Dengue infection range from a mild fever to fatal cases of hemorrhagic fever. Although being the most rapidly spreading mosquito-borne viral infection in the world, until now no strategies are available for effective prevention or control of Dengue infection. In this scenario, the development of compounds that specifically inhibit viral replication with minimal effects to the human hosts will have a substantial effect in minimizing the symptoms of the disease and help to prevent viral transmission in the affected population. The aim of this study was to screen compounds with potential activity against dengue virus from a library of synthetic naphthoquinones. Several 1,2- and 1,4-pyran naphthoquinones were synthesized by a three-component reaction of lawsone, aldehyde (formaldehyde or arylaldehydes) and different dienophiles adequately substituted. These compounds were tested for the ability to inhibit the ATPase activity of the viral NS3 enzyme in in vitro assays and the replication of dengue virus in cultured cells. We have identified two 1,4-pyran naphthoquinones, which inhibited dengue virus replication in mammal cells by 99.0% and three others that reduced the dengue virus ATPase activity of NS3 by two-fold in in vitro assays. PMID:24376541

  4. Antifungal activity of synthetic naphthoquinones against dermatophytes and opportunistic fungi: preliminary mechanism-of-action tests

    PubMed Central

    2014-01-01

    This study evaluated the antifungal activities of synthetic naphthoquinones against opportunistic and dermatophytic fungi and their preliminary mechanisms of action. The minimum inhibitory concentrations (MICs) of four synthetic naphthoquinones for 89 microorganisms, including opportunistic yeast agents, dermatophytes and opportunistic filamentous fungi, were determined. The compound that exhibited the best activity was assessed for its action against the cell wall (sorbitol test), for interference associated with ergosterol interaction, for osmotic balance (K+ efflux) and for membrane leakage of substances that absorb at the wavelength of 260 nm. All tested naphthoquinones exhibited antifungal activity, and compound IVS320 (3a,10b-dihydro-1H-cyclopenta [b] naphtho [2,3-d] furan-5,10-dione)-dione) demonstrated the lowest MICs across the tested species. The MIC of IVS320 was particularly low for dermatophytes (values ranging from 5–28 ?g/mL) and Cryptococcus spp. (3–5 ?g/mL). In preliminary mechanism-of-action tests, IVS320 did not alter the fungal cell wall but did cause problems in terms of cell membrane permeability (efflux of K+ and leakage of substances that absorb at 260 nm). This last effect was unrelated to ergosterol interactions with the membrane. PMID:24998949

  5. Evaluation of naphthoquinones identified the acetylated isolapachol as a potent and selective antiplasmodium agent.

    PubMed

    Moreira, Diogo R M; de Sá, Matheus S; Macedo, Taís S; Menezes, Maria N; Reys, José Rui M; Santana, Antônio E G; Silva, Thaissa L; Maia, Gabriela L A; Barbosa-Filho, José M; Camara, Celso A; da Silva, Tania M S; da Silva, Katia N; Guimaraes, Elisalva T; dos Santos, Ricardo R; Goulart, Marília O F; Soares, Milena B P

    2015-01-01

    This study reports on the design, synthesis and antiparasitic activity of three new semi-synthetic naphthoquinones structurally related to the naturally-occurring lapachol and lapachone. Of the compounds tested, 3-(3-methylbut-1-en-1-yl)-1,4-dioxo-1,4-dihydronaphthalen-2-yl acetate (1) was the most active against Plasmodium falciparum among both natural and semi-synthetic naphthoquinones, showing potent and selective activity. Compound 1 was able to reduce the in vitro parasite burden, in vitro parasite cell cycle, as well as the blood parasitemia in Plasmodium berghei-infected mice. More importantly, infection reduction under compound 1-treatment was achieved without exhibiting mouse genotoxicity. Regarding the molecular mechanism of action, this compound inhibited the hemozoin crystal formation in P. falciparum treated cells, and this was further confirmed by observing that it inhibits the ?-hematin polymerization process similarly to chloroquine. Interestingly, this compound did not affect either mitochondria structure or cause DNA fragmentation in parasite treated cells. In conclusion, we identified a semi-synthetic antimalarial naphthoquinone closely related to isolapachol, which had stronger antimalarial activity than lapachol. PMID:25431148

  6. Cytotoxicity of lapachol, ?-lapachone and related synthetic 1,4-naphthoquinones against oesophageal cancer cells.

    PubMed

    Sunassee, Suthananda N; Veale, Clinton G L; Shunmoogam-Gounden, Nelusha; Osoniyi, Omalaja; Hendricks, Denver T; Caira, Mino R; de la Mare, Jo-Anne; Edkins, Adrienne L; Pinto, Antônio V; da Silva Júnior, Eufrânio N; Davies-Coleman, Michael T

    2013-04-01

    Naphthoquinones have been found to have a wide range of biological activities, including cytotoxicity to cancer cells. The secondary metabolites lapachol, ?- and ?-lapachone and a series of 25 related synthetic 1,4-naphthoquinones were screened against the oesophageal cancer cell line (WHCO1). Most of the compounds exhibited enhanced cytotoxicity (IC50 1.6-11.7 ?M) compared to the current drug of choice cisplatin (IC50 = 16.5 ?M). This study also established that the two new synthetic halogenated compounds 12a and 16a (IC50 = 3.0 and 7.3 ?M) and the previously reported compound 11a (IC50 = 3.9 ?M), were non-toxic to NIH3T3 normal fibroblast cells. Cell death of oesophageal cancer cells by processes involving PARP cleavage caused by 11a was shown to be associated with elevated c-Jun levels, suggesting a role for this pathway in the mechanism of action of this cohort of naphthoquinone compounds. PMID:23353747

  7. Naphthoquinone based chemosensor 2-(2?-aminomethylpyridine)-3-chloro-1,4-naphthoquinone for metal ions: Single crystal X-ray structure, experimental and TD-DFT study

    NASA Astrophysics Data System (ADS)

    Ware, Anuja P.; Patil, Amit; Khomane, Sonali; Weyhermüller, Thomas; Pingale, Subhash S.; Salunke-Gawali, Sunita

    2015-08-01

    Naphthoquinone based redox active chemosensor 1; 2-(2?-aminomethylpyridine)-3-chloro-1,4-naphthoquinone ligand has been synthesized and characterized. Chemosensor 1 crystallizes in monoclinic space group P21/n. Molecules showed intramolecular N-H⋯O and N-H⋯N, intermolecular N-H⋯O, C-H⋯O and slipped ?-? stacking interactions. Chemosensor 1 showed orange colored solution in methanol and specifically detects Cu2+ ions by deprotonation of N-H. The deprotonation of amino N-H can also be achieved by mild base viz. triethylamine and chemosensor 1 can be used to detect several metal ions for example Ni2+, Mn2+ etc. that could observed by naked eye. Color changes observed were monitored by UV-visible and fluorescence spectra. Chemosensor 1 could provide either bidentate or tridentate coordination sites to metal ions. Redox nature of chemosensor 1 was evaluated by cyclic voltammetry studies. Electronic transition wavelengths of chemosensor 1 ligand have been evaluated in methanol, water and triethylamine by TD-DFT studies and comparative studies were performed with experimental results.

  8. Synthesis and Biological Evaluation of 1,4-Naphthoquinones and Quinoline-5,8-diones as Antimalarial and Schistosomicidal Agents

    PubMed Central

    Lanfranchi, Don Antoine; Cesar-Rodo, Elena; Bertrand, Benoît; Huang, Hsin-Hung; Day, Latasha; Johann, Laure; Elhabiri, Mourad; Becker, Katja; Williams, David L.

    2012-01-01

    Improving the solubility of polysubstituted 1,4-naphthoquinone derivatives was achieved by introducing nitrogen in two different positions of the naphthoquinone core, at C-5 and at C-8 of menadione through a two-step, straightforward synthesis based on the regioselective hetero-Diels-Alder reaction. The antimalarial and the antischistosomal activities of these polysubstituted aza-1,4-naphthoquinone derivatives were evaluated and led to the selection of distinct compounds for antimalarial versus antischistosomal action. The AgII-assisted oxidative radical decarboxylation of the phenyl acetic acids using AgNO3 and ammonium peroxodisulfate was modified to generate the 3-picolinyl-menadione with improved pharmacokinetic parameters, high antimalarial effects and capacity to inhibit the formation of ?-hematin. PMID:22777178

  9. Newbouldiaquinone and newbouldiamide: a new naphthoquinone-anthraquinone coupled pigment and a new ceramide from Newbouldia laevis.

    PubMed

    Eyong, Kenneth Oben; Krohn, Karsten; Hussain, Hidayat; Folefoc, Gabriel Ngosong; Nkengfack, Augustin Ephram; Schulz, Barbara; Hu, Qunxiu

    2005-06-01

    Newbouldiaquinone (1), a new naphthoquinone-anthraquinone coupled pigment and a new ceramide named newbouldiamide (2), have been isolated from Newbouldia laevis, besides the known compounds lapachol (3), canthic acid, oleanolic acid, 2-methyl-9,10-anthracenedione, 2-acetylfuro-1,4-naphthoquinone, 2,3-dimethoxy-1,4-benzoquinone, 2-(4-hydroxyphenyl)ethyl triacontanoate, beta-sitosterol and beta-sitosterol glucopyranoside. The structure elucidations of the isolated new compounds were performed on the basis of spectroscopic and chemical evidence. Preliminary studies showed that 1 is moderately antibacterial against Gram-positive Bacillus megaterium and that 3 has moderate herbicidal and antibacterial activities. PMID:15930769

  10. 1,4-Naphthoquinone Cations as Antiplasmodial Agents: Hydroxy-, Acyloxy-, and Alkoxy-Substituted Analogues

    PubMed Central

    2012-01-01

    Cations of hydroxy-substituted 1,4-naphthoquinones were synthesized and evaluated as antiplasmodial agents against Plasmodium falciparum. The atovaquone analogues were found to be inactive as antagonists of parasite growth, which was attributed to ionization of the acidic hydroxyl moiety. Upon modification to an alkoxy substituent, the antiplasmodial activity was restored in the sub-100 nM range. Optimal inhibitors were found to possess IC50 values of 17.4–49.5 nM against heteroresistant P. falciparum W2. PMID:24936235

  11. Induced production of antifungal naphthoquinones in the pitchers of the carnivorous plant Nepenthes khasiana

    PubMed Central

    Eilenberg, Haviva; Pnini-Cohen, Smadar; Rahamim, Yocheved; Sionov, Edward; Segal, Esther; Carmeli, Shmuel; Zilberstein, Aviah

    2010-01-01

    Nepenthes spp. are carnivorous plants that have developed insect capturing traps, evolved by specific modification of the leaf tips, and are able to utilize insect degradation products as nutritional precursors. A chitin-induced antifungal ability, based on the production and secretion to the trap liquid of droserone and 5-O-methyldroserone, is described here. Such specific secretion uniquely occurred when chitin injection was used as the eliciting agent and probably reflects a certain kind of defence mechanism that has been evolved for protecting the carnivory-based provision of nutritional precursors. The pitcher liquid containing droserone and 5-O-methyldroserone at 3:1 or 4:1 molar ratio, as well as the purified naphthoquinones, exerted an antifungal effect on a wide range of plant and human fungal pathogens. When tested against Candida and Aspergillus spp., the concentrations required for achieving inhibitory and fungicidal effects were significantly lower than those causing cytotoxicity in cells of the human embryonic kidney cell line, 293T. These naturally secreted 1,4-naphthoquinone derivatives, that are assumed to act via semiquinone enhancement of free radical production, may offer a new lead to develop alternative antifungal drugs with reduced selectable pressure for potentially evolved resistance. PMID:20018905

  12. Targeting of Helicobacter pylori thymidylate synthase ThyX by non-mitotoxic hydroxy-naphthoquinones

    PubMed Central

    Skouloubris, Stéphane; Djaout, Kamel; Lamarre, Isabelle; Lambry, Jean-Christophe; Anger, Karine; Briffotaux, Julien; Liebl, Ursula; de Reuse, Hilde; Myllykallio, Hannu

    2015-01-01

    ThyX is an essential thymidylate synthase that is mechanistically and structurally unrelated to the functionally analogous human enzyme, thus providing means for selective inhibition of bacterial growth. To identify novel compounds with anti-bacterial activity against the human pathogenic bacterium Helicobacter pylori, based on our earlier biochemical and structural analyses, we designed a series of eighteen 2-hydroxy-1,4-naphthoquinones (2-OH-1,4-NQs) that target HpThyX. Our lead-like molecules markedly inhibited the NADPH oxidation and 2?-deoxythymidine-5?-monophosphate-forming activities of HpThyX enzyme in vitro, with inhibitory constants in the low nanomolar range. The identification of non-cytotoxic and non-mitotoxic 2-OH-1,4-NQ inhibitors permitted testing their in vivo efficacy in a mouse model for H. pylori infections. Despite the widely assumed toxicity of naphthoquinones (NQs), we identified tight-binding ThyX inhibitors that were tolerated in mice and can be associated with a modest effect in reducing the number of colonizing bacteria. Our results thus provide proof-of-concept that targeting ThyX enzymes is a highly feasible strategy for the development of therapies against H. pylori and a high number of other ThyX-dependent pathogenic bacteria. We also demonstrate that chemical reactivity of NQs does not prevent their exploitation as anti-microbial compounds, particularly when mitotoxicity screening is used to prioritize these compounds for further experimentation. PMID:26040760

  13. The hydroxy-naphthoquinone lapachol arrests mycobacterial growth and immunomodulates host macrophages.

    PubMed

    Oliveira, Renato A S; Azevedo-Ximenes, Eulalia; Luzzati, Roberto; Garcia, Rodolfo C

    2010-11-01

    The present study reports the anti-mycobacterial activity of 2-hydroxy-3-(3-methyl-2-butenyl)-1,4-naphthoquinone (lapachol) as well as its influence on macrophage functions. Lapachol (L) did not induce apoptosis/necrosis of THP-1 macrophages at ?32 ?g/mL. Mycobacterium avium liquid growth was arrested by ?32 ?g/mL and intra-macrophage proliferation by ?16 ?g/mL lapachol. The main immuno-modulatory effects of lapachol observed were an up-regulation of interferon-?-receptor 1 (IFN-?R1) and major histocompatibility complex class II (MHCII) surface expression, and a marked inhibition of IL-10 secretion. Lapachol did not affect resting, IFN-?- or toll-like receptor 2 (TLR2)-induced levels of oxygen and nitrogen metabolism key proteins nor the TLR2-mediated secretion of TNF-?, nor induced either oxidative or endoplasmic reticulum (ER) stress. Lapachol inhibited the surface expression of the co-stimulatory molecule CD86 but not that of CD80 and CD83. The results obtained indicate that the substituted naphthoquinone lapachol exhibits an anti-mycobacterial activity that is more efficient intra- than extra-cellularly, and exerts immuno-modulatory effects some of which may enhance the capacity of the host cell to control mycobacterial growth. The immune-modulatory action of lapachol could contribute to its more efficient intra-macrophage anti-mycobacterial activity. PMID:20837170

  14. Inhibitory potential of naphthoquinones leached from leaves and exuded from roots of the invasive plant Impatiens glandulifera.

    PubMed

    Ruckli, Regina; Hesse, Katharina; Glauser, Gaetan; Rusterholz, Hans-Peter; Baur, Bruno

    2014-04-01

    Exploring the effects of allelopathic plant chemicals on the growth of native vegetation is essential to understand their ecological roles and importance in exotic plant invasion. Naphthoquinones have been identified as potential growth inhibitors produced by Impatiens glandulifera, an exotic annual plant that recently invaded temperate forests in Europe. However, naphthoquinone release and inhibitory potential have not been examined. We quantified the naphthoquinone content in cotyledons, leaves, stems, and roots from plants of different ages of both the invasive I. glandulifera and native Impatiens noli-tangere as well as in soil extracts and rainwater rinsed from leaves of either plant species by using ultra-high pressure liquid chromatography-mass spectrometry (UHPLC-MS). We identified the compound 2-methoxy-1,4-naphthoquinone (2-MNQ) exclusively in plant organs of I. glandulifera, in resin bags buried into the soil of patches invaded by I. glandulifera, and in rainwater rinsed from its leaves. This indicates that 2-MNQ is released from the roots of I. glandulifera and leached from its leaves by rain. Specific bioassays using aqueous shoot and root extracts revealed a strong inhibitory effect on the germination of two native forest herbs and on the mycelium growth of three ectomycorrhiza fungi. These findings suggest that the release of 2-MNQ may contribute to the invasion success of I. glandulifera and support the novel weapons hypothesis. PMID:24722883

  15. Is Nitric Oxide Decrease Observed with Naphthoquinones in LPS Stimulated RAW 264.7 Macrophages a Beneficial Property?

    PubMed Central

    Pinho, Brígida R.; Sousa, Carla; Valentão, Patrícia; Andrade, Paula B.

    2011-01-01

    The search of new anti-inflammatory drugs has been a current preoccupation, due to the need of effective drugs, with less adverse reactions than those used nowadays. Several naphthoquinones (plumbagin, naphthazarin, juglone, menadione, diosquinone and 1,4-naphthoquinone), plus p-hydroquinone and p-benzoquinone were evaluated for their ability to cause a reduction of nitric oxide (NO) production, when RAW 264.7 macrophages were stimulated with lipopolysaccharide (LPS). Dexamethasone was used as positive control. Among the tested compounds, diosquinone was the only one that caused a NO reduction with statistical importance and without cytotoxicity: an IC25 of 1.09±0.24 µM was found, with 38.25±6.50% (p<0.001) NO reduction at 1.5 µM. In order to elucidate if this NO decrease resulted from the interference of diosquinone with cellular defence mechanisms against LPS or to its conversion into peroxynitrite, by reaction with superoxide radical formed by naphthoquinones redox cycling, 3-nitrotyrosine and superoxide determination was also performed. None of these parameters showed significant changes relative to control. Furthermore, diosquinone caused a decrease in the pro-inflammatory cytokines: tumour necrosis factor-alpha (TNF-?) and interleukin 6 (IL-6). Therefore, according to the results obtained, diosquinone, studied for its anti-inflammatory potential for the first time herein, has beneficial effects in inflammation control. This study enlightens the mechanisms of action of naphthoquinones in inflammatory models, by checking for the first time the contribution of oxidative stress generated by naphthoquinones to NO reduction. PMID:21887376

  16. Designing Light-Activated Charge-Separating Proteins with a Naphthoquinone Amino Acid.

    PubMed

    Lichtenstein, Bruce R; Bialas, Chris; Cerda, José F; Fry, Bryan A; Dutton, P Leslie; Moser, Christopher C

    2015-11-01

    The first principles design of manmade redox-protein maquettes is used to clarify the physical/chemical engineering supporting the mechanisms of natural enzymes with a view to recapitulate and surpass natural performance. Herein, we use intein-based protein semisynthesis to pair a synthetic naphthoquinone amino acid (Naq) with histidine-ligated photoactive metal-tetrapyrrole cofactors, creating a 100??s photochemical charge separation unit akin to photosynthetic reaction centers. By using propargyl groups to protect the redox-active para-quinone during synthesis and assembly while permitting selective activation, we gain the ability to employ the quinone amino acid redox cofactor with the full set of natural amino acids in protein design. Direct anchoring of quinone to the protein backbone permits secure and adaptable control of intraprotein electron-tunneling distances and rates. PMID:26366882

  17. Antiproliferative activity of synthetic naphthoquinones related to lapachol. First synthesis of 5-hydroxylapachol.

    PubMed

    Bonifazi, Evelyn L; Ríos-Luci, Carla; León, Leticia G; Burton, Gerardo; Padrón, José M; Misico, Rosana I

    2010-04-01

    A series of 5-hydroxy-1,4-naphthoquinones analogues was synthesized from juglone (6) and their antiproliferative activity against a representative panel of six human solid tumor cell lines has been investigated. The 2,5-dihydroxy-3-(3-methylbut-2-enyl)naphthalene-1,4-dione (4) and 2,3-dihydro-5-hydroxy-2-(prop-1-en-2-yl)naphtho[2,3-b]furan-4,9-dione (27) were the most potent antiproliferative agents with GI(50) values of 0.42-8.1 and 0.80-2.2microM, respectively. The results provide insight into the correlation between some structural properties of 5-hydroxynaphthoquinones and their antiproliferative activity. PMID:20304655

  18. Naphthalene and Naphthoquinone: Distributions and Human Exposure in the Los Angeles Basin

    NASA Astrophysics Data System (ADS)

    Lu, R.; Wu, J.; Turco, R.; Winer, A. M.; Atkinson, R.; Paulson, S.; Arey, J.; Lurmann, F.

    2003-12-01

    Naphthalene is the simplest and most abundant of the polycyclic aromatic hydrocarbons (PAHs). Naphthalene is found primarily in the gas-phase and has been detected in both outdoor and indoor samples. Evaporation from naphthalene-containing products (including gasoline), and during refining operations, are important sources of naphthalene in air. Naphthalene is also emitted during the combustion of fossil fuels and wood, and is a component of vehicle exhaust. Exposure to high concentrations of naphthalene can damage or destroy red blood cells, causing hemolytic anemia. If inhaled over a long period of time, naphthalene may cause kidney and liver damage, skin allergy and dermatitis, cataracts and retinal damage, as well as attack the central nervous system. Naphthalene has been found to cause cancer as a result of inhalation in animal tests. Naphthoquinones are photooxidation products of naphthalene and the potential health effects of exposure to these quinones are a current focus of research. We are developing and applying models that can be used to assess human exposure to naphthalene and its photooxidation products in major air basins such as California South Coast Air Basin (SoCAB). The work utilizes the Surface Meteorology and Ozone Generation (SMOG) airshed model, and the REgional Human EXposure (REHEX) model, including an analysis of individual exposure. We will present and discuss simulations of basin-wide distributions of, and human exposures to, naphthalene and naphthoquinone, with emphasis on the uncertainties in these estimates of atmospheric concentrations and human exposure. Regional modeling of pollutant sources and exposures can lead to cost-effective and optimally health-protective emission control strategies.

  19. Naphthoquinone Derivatives Exert Their Antitrypanosomal Activity via a Multi-Target Mechanism

    PubMed Central

    Mazet, Muriel; Perozzo, Remo; Bergamini, Christian; Prati, Federica; Fato, Romana; Lenaz, Giorgio; Capranico, Giovanni; Brun, Reto; Bakker, Barbara M.; Michels, Paul A. M.; Scapozza, Leonardo; Bolognesi, Maria Laura; Cavalli, Andrea

    2013-01-01

    Background and Methodology Recently, we reported on a new class of naphthoquinone derivatives showing a promising anti-trypanosomatid profile in cell-based experiments. The lead of this series (B6, 2-phenoxy-1,4-naphthoquinone) showed an ED50 of 80 nM against Trypanosoma brucei rhodesiense, and a selectivity index of 74 with respect to mammalian cells. A multitarget profile for this compound is easily conceivable, because quinones, as natural products, serve plants as potent defense chemicals with an intrinsic multifunctional mechanism of action. To disclose such a multitarget profile of B6, we exploited a chemical proteomics approach. Principal Findings A functionalized congener of B6 was immobilized on a solid matrix and used to isolate target proteins from Trypanosoma brucei lysates. Mass analysis delivered two enzymes, i.e. glycosomal glycerol kinase and glycosomal glyceraldehyde-3-phosphate dehydrogenase, as potential molecular targets for B6. Both enzymes were recombinantly expressed and purified, and used for chemical validation. Indeed, B6 was able to inhibit both enzymes with IC50 values in the micromolar range. The multifunctional profile was further characterized in experiments using permeabilized Trypanosoma brucei cells and mitochondrial cell fractions. It turned out that B6 was also able to generate oxygen radicals, a mechanism that may additionally contribute to its observed potent trypanocidal activity. Conclusions and Significance Overall, B6 showed a multitarget mechanism of action, which provides a molecular explanation of its promising anti-trypanosomatid activity. Furthermore, the forward chemical genetics approach here applied may be viable in the molecular characterization of novel multitarget ligands. PMID:23350008

  20. A Structure-Activity Relationship Study of Naphthoquinone Derivatives as Antitubercular Agents Using Molecular Modeling Techniques.

    PubMed

    Sharma, Mukesh C

    2015-12-01

    Tuberculosis (TB) is one of the major causes of death worldwide. Mycobacterium tuberculosis, the leading causative agent of TB, is responsible for the morbidity and mortality of a large population worldwide. In view of above and as a part of our effort to develop new and potent anti-TB agents, a series of substituted naphthoquinone derivatives were subjected to molecular modeling using various feature selection methods. The statistically significant best 2D-QSAR model having correlation coefficient [Formula: see text] and cross-validated squared correlation coefficient [Formula: see text] with external predictive ability of [Formula: see text] was developed by SA-PLS, and group-based QSAR model having [Formula: see text] and [Formula: see text] with [Formula: see text] was developed by SA-PLS. Further analysis using three-dimensional QSAR technique identifies a suitable model obtained by SA-partial least square method leading to antitubercular activity prediction. k-nearest neighbor molecular field analysis was used to construct the best 3D-QSAR model using SA-PLS method, showing good correlative and predictive capabilities in terms of [Formula: see text] and [Formula: see text]. The pharmacophore analysis results obtained from this study show that the distance between the aromatic/hydrophobic and the naphthoquinone moiety sites to the aliphatic and acceptor groups should be connected with almost the same distance for significant antitubercular activity. The information rendered by QSAR models may lead to a better understanding of structural requirements of antitubercular activity and also can help in the design of novel potent antitubercular activity. PMID:26159131

  1. Newbouldiaquinone A: A naphthoquinone-anthraquinone ether coupled pigment, as a potential antimicrobial and antimalarial agent from Newbouldia laevis.

    PubMed

    Eyong, Kenneth Oben; Folefoc, Gabriel Ngosong; Kuete, Victor; Beng, Veronique Penlap; Krohn, Karsten; Hussain, Hidayat; Nkengfack, Augustin Ephram; Saeftel, Michael; Sarite, Salem Ramadan; Hoerauf, Achim

    2006-03-01

    The study of the chemical constituents of the roots of Newbouldia laevis (Bignoniaceae) has resulted in the isolation and characterization of a naphthoquinone-anthraquinone coupled pigment named newbouldiaquinone A (1) together with 14 known compounds: apigenin, chrysoeriol, newbouldiaquinone, lapachol, 2-methylanthraquinone, 2-acetylfuro-1,4-naphthoquinone, 2,3-dimethoxy-1,4-benzoquinone, oleanolic acid, canthic acid, 2-(4-hydroxyphenyl)ethyl triacontanoate, newbouldiamide, 5,7-dihydroxydehydroiso-alpha-lapachone, beta-sitosterol, and beta-sitosterol glucopyranoside. The structure elucidation of the isolated compounds was established based on spectroscopic studies, notably of the 2D NMR spectra. The antimalarial activity of compound (1) against Plasmodium falciparum in vitro shows moderate chemo suppression of parasitic growth. Its antimicrobial activity against a wide range of microorganisms was 13- and 24-fold more active against Candida gabrata and Enterobacter aerogens than the reference antibiotics nystatin and gentamycin. PMID:16442576

  2. OCTAN-1-OL/WATER PARTITION COEFFICIENTS OF P-BENZO- AND P-NAPHTHOQUINONES CORRECTED FOR PH EFFECT

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The effect of pH of the aqueous phase on the octan-1-ol / water partition coefficients (kow) of quinones was demontrated. The kow of a series of p-benzo- and p-naphthoquinones were determined using a mildly buffered aqueous phase (1 mM Hepes, pH 7.0) to correct for the pH effects on the lipophilicit...

  3. Gas-phase reactivity of 2-hydroxy-1,4-naphthoquinones: a computational and mass spectrometry study of lapachol congeners.

    PubMed

    Vessecchi, Ricardo; Emery, Flávio S; Galembeck, Sérgio E; Lopes, Norberto P

    2012-12-01

    In order to understand the influence of alkyl side chains on the gas-phase reactivity of 1,4-naphthoquinone derivatives, some 2-hydroxy-1,4-naphthoquinone derivatives have been prepared and studied by electrospray ionization tandem mass spectrometry in combination with computational quantum chemistry calculations. Protonation and deprotonation sites were suggested on the basis of gas-phase basicity, proton affinity, gas-phase acidity (?G(acid) ), atomic charges and frontier orbital analyses. The nature of the intramolecular interaction as well as of the hydrogen bond in the systems was investigated by the atoms-in-molecules theory and the natural bond orbital analysis. The results were compared with data published for lapachol (2-hydroxy-3-(3-methyl-2-butenyl)-1,4-naphthoquinone). For the protonated molecules, water elimination was verified to occur at lower proportion when compared with side chain elimination, as evidenced in earlier studies on lapachol. The side chain at position C(3) was found to play important roles in the fragmentation mechanisms of these compounds. PMID:23280754

  4. Synthesis and SAR study of novel anticancer and antimicrobial naphthoquinone amide derivatives.

    PubMed

    Sreelatha, Thonthula; Kandhasamy, Subramani; Dinesh, Raghu; Shruthy, Suresh; Shweta, Sinha; Mukesh, Doble; Karunagaran, Devarajan; Balaji, Ravichandran; Mathivanan, Narayanasamy; Perumal, Paramasivan Thirumalai

    2014-08-01

    A series of novel naphthoquinone amide derivatives of the bioactive quinones, plumbagin, juglone, menadione and lawsone, with various amino acids were synthesized. The compounds were characterized by (1)H NMR, (13)C NMR, Mass, IR and elemental analysis. All the compounds were evaluated for their anticancer activity against HeLa and SAS cancer cell lines and 3D-QSAR indicated the presence of electron donating group near sulphur enhanced the activity against HeLa cells. Among the derivatives synthesized, compounds 11f, 10a, 10b and 10g were the most active with IC50 values of 16, 12, 14 and 24.5 ?M, respectively. The analogues were also screened for antimicrobial activity against two human bacterial pathogens, the Gram-positive Methicillin resistant Staphylococcus aureus (MRSA) and the Gram-negative Pseudomonas aeruginosa and a human yeast pathogen, Fluconazole resistant Candida albicans (FRCA). Among the synthesized compounds, 8g, 10g and 11g exhibited maximum antibacterial activity towards MRSA and antifungal activity against FRCA in well diffusion method. PMID:24913712

  5. Beyond topoisomerase inhibition: antitumor 1,4-naphthoquinones as potential inhibitors of human monoamine oxidase.

    PubMed

    Coelho-Cerqueira, Eduardo; Netz, Paulo A; do Canto, Vanessa P; Pinto, Angelo C; Follmer, Cristian

    2014-04-01

    Monoamine oxidase (MAO) action has been involved in the regulation of neurotransmitters levels, cell signaling, cellular growth, and differentiation as well as in the balance of the intracellular polyamine levels. Although so far obscure, MAO inhibitors are believed to have some effect on tumors progression. 1,4-naphthoquinone (1,4-NQ) has been pointed out as a potential pharmacophore for inhibition of both MAO and DNA topoisomerase activities, this latter associated with antitumor activity. Herein, we demonstrated that certain antitumor 1,4-NQs, including spermidine-1,4-NQ, lapachol, and nor-lapachol display inhibitory activity on human MAO-A and MAO-B. Kinetic studies indicated that these compounds are reversible and competitive MAO inhibitors, being the enzyme selectivity greatly affected by substitutions on 1,4-NQ ring. Molecular docking studies suggested that the most potent MAO inhibitors are capable to bind to the MAO active site in close proximity of flavin moiety. Furthermore, ability to inhibit both MAO-A and MAO-B can be potentialized by the formation of hydrogen bonds between these compounds and FAD and/or the residues in the active site. Although spermidine-1,4-NQs exhibit antitumor action primarily by inhibiting topoisomerase via DNA intercalation, our findings suggest that their effect on MAO activity should be taken into account when their application in cancer therapy is considered. PMID:24165164

  6. Surface enhanced Raman spectral studies of 2-bromo-1,4-naphthoquinone

    NASA Astrophysics Data System (ADS)

    Geetha, K.; Umadevi, M.; Sathe, G. V.; Vanelle, P.; Terme, T.; Khoumeri, O.

    2015-03-01

    Silver nanoparticles have been synthesized by a simple and inexpensive solution combustion method with urea as fuel. The structural and morphology of the silver nanoparticles were investigated through X-ray powder diffraction (XRD), Field Emission Scanning Electron Microscopy (FESEM) and Energy Dispersion Spectra (EDS) techniques. Structural and morphological results confirmed the nanocrystalline nature of the silver nanoparticles. Density Functional Theory (DFT) calculations were also performed to study the ground and excited state behavior of 2-bromo-1,4-naphthoquinone (2-BrNQ) and 2-BrNQ on silver nanoparticles. Surface-Enhanced Raman Scattering (SERS) spectra of 2-BrNQ adsorbed on silver nanoparticles were investigated. The Cdbnd O, Csbnd H in-plane bending and Csbnd Br stretching modes were enhanced in SERS spectrum with respect to normal Raman spectrum. The spectral analysis reveals that the 2-BrNQ adsorbed 'stand-on' orientation on the silver surface. Density Functional Theory (DFT) calculations are also performed to study the vibrational features of 2-BrNQ molecule and 2-BrNQ molecule on silver surface.

  7. A Rare Class of New Dimeric Naphthoquinones from Diospyros lotus have Multidrug Reversal and Antiproliferative Effects

    PubMed Central

    Rauf, Abdur; Uddin, Ghias; Siddiqui, Bina S.; Molnár, Joseph; Csonka, Ákos; Ahmad, Bashir; Szabó, Diana; Farooq, Umar; Khan, Ajmal

    2015-01-01

    Three new dimeric naphthoquinones, 5,4?-dihydroxy-1?-methoxy-6,6?-dimethyl-7,3?-binaphthyl-1,4,5?,8?-tetraone (1), 5?,8?-dihydroxy-5-methoxy-6,6?-dimethyl-7,3?-binaphthyl-1,4,1?,4?-tetraone (2) and 8,5?,8?-trihydroxy-6,6?-dimethyl-7,3?-binaphthyl-1,4,1?,4?-tetraone (3), were isolated from the roots of Diospyros lotus. Their structures were elucidated by spectroscopic techniques, including 1D and 2D NMR, such as HSQC, HMBS, NOESY, and J-resolved. Compounds 1–3 were evaluated for their effects on the reversion of multidrug resistance (MDR) mediated by P-glycoprotein through use of the rhodamine-123 exclusion screening test on human ABCB1 gene transfected L5178Y mouse T-cell lymphoma. Compounds 1–3 were also assessed for their antiproliferative and cytotoxic effects on L5178 and L5178Y mouse T-cell lymphoma lines. Both 1 and 2 exhibited promising antiproliferative and MDR-reversing effects in a dose-dependent manner. The effects of the tested compounds on the activity of doxorubicin were observed to vary from slight antagonism to antagonism.

  8. 1,2,3-triazole-, arylamino- and thio-substituted 1,4-naphthoquinones: potent antitumor activity, electrochemical aspects, and bioisosteric replacement of C-ring-modified lapachones.

    PubMed

    da Cruz, Eduardo H G; Hussene, Caio M B; Dias, Gleiston G; Diogo, Emilay B T; de Melo, Isadora M M; Rodrigues, Bernardo L; da Silva, Mauro G; Valença, Wagner O; Camara, Celso A; de Oliveira, Ronaldo N; de Paiva, Yen G; Goulart, Marilia O F; Cavalcanti, Bruno C; Pessoa, Claudia; da Silva Júnior, Eufrânio N

    2014-03-01

    1,2,3-Triazole-, arylamino- and thio-substituted naphthoquinones (24, 8, and 2 representatives, respectively) were synthesized in moderate yields and evaluated against several human cancer cell lines (blood, ovarian, breast, central nervous system, colon, and prostate cancers and melanoma), showing, for some of them, IC50 values below 2 ?M. The cytotoxic potential of the tested naphthoquinones was also assayed on non-tumor cells such as human peripheral blood mononucluear cells (PBMC) and two murine fibroblast lines (L929 and V79 cells). ?-Lapachone- and nor-?-lapachone-based 1,2,3-triazoles and arylamino-substituted naphthoquinones showed potent cytotoxicity against different cancer cell lines. The compounds may represent promising new lead derivatives for anticancer drug development. The electrochemical properties of selected compounds were evaluated in an attempt to correlate them with antitumor activity. PMID:24530030

  9. A Novel Ferrocenyl Naphthoquinone Fused Crown Ether as a Multisensor for Water Determination in Acetonitrile and Selective Cation Binding.

    PubMed

    Dagdevren, Metin; Yilmaz, Ismail; Yucel, Baris; Emirik, Mustafa

    2015-09-24

    A multisensor which is based on a novel multifunctional triad molecule, ferrocenyl naphthoquinone fused crown ether (Fc-cnq) bearing ferrocene, quinone, and crown ether functional groups together, was synthesized and characterized in this study. Sensing performance of a trace amount of water and the selective cation binding capabilities of this multisensor were carried out by the electrochemical, spectroelectrochemical, and spectrophotometric titration techniques in acetonitrile (CH3CN). It was shown that the potential separation (E((Fc))1/2 - E((2))1/2) between the second reduction of naphthoquinone and the oxidation processes of ferrocene in the triad molecule Fc-cnq was proportional to the amount of water due to the hydrogen-bonding interactions between water and the doubly reduced species (Fc-cnq(2-)). This property enabled Fc-cnq to detect the trace amount of water in CH3CN. The half-wave potential (E((Fc))1/2) of the ferrocene in Fc-cnq was used as an internal reference potential, and it defined the accuracy of the detection. In addition, by using the UV-vis spectrophotometric titration technique in CH3CN, it was also shown that the Fc-cnq multisensor could bind Ba(2+) and Ca(2+) cations selectively. We proposed that the intramolecular charge-transfer (CT) transition which occurred between the donor ferrocene and the acceptor naphthoquinone was the principle mechanism for the selective binding property of this multisensor. Quantum chemical calculations were also performed to investigate optical and electronic properties of the Fc-cnq molecule. PMID:26352463

  10. Substituted 3?acyl?2?phenylamino?1,4?naphthoquinones intercalate into DNA and cause genotoxicity through the increased generation of reactive oxygen species culminating in cell death.

    PubMed

    Farias, Mirelle Sifroni; Pich, Claus Tröger; Kviecinski, Maicon Roberto; Bucker, Nádia Cristina Falcão; Felipe, Karina Bettega; Da Silva, Fabiana Ourique; Günther, Tânia Mara Fisher; Correia, João Francisco; Ríos, David; Benites, Julio; Valderrama, Jaime A; Calderon, Pedro Buc; Pedrosa, Rozangela Curi

    2014-07-01

    Naphthoquinones interact with biological systems by generating reactive oxygen species (ROS) that can damage cancer cells. The cytotoxicity and the antitumor activity of 3?acyl?2?phenylamino?1,4?naphthoquinones (DPB1?DPB9) were evaluated in the MCF7 human breast cancer cell line and in male Ehrlich tumor?bearing Balb/c mice. DPB4 was the most cytotoxic derivative against MCF7 cells (EC50 15 µM) and DPB6 was the least cytotoxic one (EC50 56 µM). The 1,4?naphthoquinone derivatives were able to cause DNA damage and promote DNA fragmentation as shown by the plasmid DNA cleavage assay (FII form). In addition, 1,4?naphthoquinone derivatives possibly interacted with DNA as intercalating agents, which was demonstrated by the changes caused in the fluorescence of the DNA?ethidium bromide complexes. Cell death of MCF7 cells induced by 3?acyl?2?phenylamino?1,4?naphthoquinones was mostly due to apoptosis. The DNA fragmentation and subsequent apoptosis may be correlated to the redox potential of the 1,4?naphthoquinone derivatives that, once present in the cell nucleus, led to the increased generation of ROS. Finally, certain 1,4?naphthoquinone derivatives and particularly DPB4 significantly inhibited the growth of Ehrlich ascites tumors in mice (73%). PMID:24756411

  11. A Small Library of Synthetic Di-Substituted 1, 4-Naphthoquinones Induces ROS-Mediated Cell Death in Murine Fibroblasts

    PubMed Central

    Ramirez, Oscar; Motta-Mena, Laura B.; Cordova, Amanda; Garza, Kristine M.

    2014-01-01

    Synthesis of compound libraries and their concurrent assessment as selective reagents for probing and modulating biological function continues to be an active area of chemical biology. Microwave-assisted solid-phase Dötz benzannulation reactions have been used to inexpensively synthesize 2, 3-disubstituted-1, 4-naphthoquinone derivatives. Herein, we report the biological testing of a small library of such compounds using a murine fibroblast cell line (L929). Assessment of cellular viability identified three categories of cytotoxic compounds: no toxicity, low/intermediate toxicity and high toxicity. Increased levels of Annexin-V-positive staining and of caspase 3 activity confirmed that low, intermediate, and highly toxic compounds promote cell death. The compounds varied in their ability to induce mitochondrial depolarization and formation of reactive oxygen species (ROS). Both cytotoxic and non-cytotoxic compounds triggered mitochondrial depolarization, while one highly cytotoxic compound did not. In addition, all cytotoxic compounds promoted increased intracellular ROS but the cells were only partially protected from compound-induced apoptosis when in the presence of superoxide dismutase, catalase, or ascorbic acid suggesting utilization of additional pro-death mechanisms. In summary, nine of twelve (75%) 1, 4-naphthoquinone synthetic compounds were cytotoxic. Although the mitochondria did not appear to be a central target for induction of cell death, all of the cytotoxic compounds induced ROS formation. Thus, the data demonstrate that the synthesis regime effectively created cytotoxic compounds highlighting the potential use of the regime and its products for the identification of biologically relevant reagents. PMID:25197824

  12. Comparison of the cytotoxic effect of lapachol, alpha-lapachone and pentacyclic 1,4-naphthoquinones on human leukemic cells.

    PubMed

    Salustiano, Eduardo J S; Netto, Chaquip D; Fernandes, Renata F; da Silva, Alcides J M; Bacelar, Thiago S; Castro, Carolina P; Buarque, Camilla D; Maia, Raquel C; Rumjanek, Vivian M; Costa, Paulo R R

    2010-04-01

    The pentacyclic 1,4-naphthoquinones 1a-d were cytotoxic (IC(50) approximately 2-7 microM) to human leukemic cell lines K562 (oxidative stress-resistant), Lucena-1 (MDR phenotype) and Daudi. Fresh leukemic cells obtained from patients, some with the MDR phenotype, were also sensitive to these compounds. The pentacyclic 1,4-naphthoquinones 1a and 1c induced apoptotic cell death in cells from leukemic patients as determined by flow cytometry. Conversely, the cell lines were highly insensitive to lapachol (2) and alpha-lapachone (3). Mitomycin-C inhibited cell proliferation at concentrations as low as 0.5 microM. The low toxicity against lymphocytes activated by phytohemagglutinin shows that these compounds are selective for the cancer cells studied. Previous data suggest that these compounds (1a-d) can be bioactivated in situ by reduction followed by rearrangement leading to enones, which are powerful alkylating agents. In contrast, lapachol (2) and beta-lapachone (3), which cannot be bioactivated by reduction, showed little activity against the same cell lines. PMID:19255723

  13. Natural and synthetic naphthoquinones active against Trypanosoma cruzi: an initial step towards new drugs for Chagas disease.

    PubMed

    Salas, Cristian O; Faúndez, Mario; Morello, Antonio; Maya, Juan Diego; Tapia, Ricardo A

    2011-01-01

    Chagas disease is one of the most important endemic diseases in Latin America, caused by Trypanosoma cruzi. The drugs used for the treatment of this disease, nifurtimox and benznidazole, are toxic and present severe side effects. The need of effective drugs, without adverse effects, has stimulated the search for new compounds with potential clinical utility. An overview of a number of natural naphthoquinones tested against T. cruzi parasites is provided. Among natural naphthoquinones, lapachol, ?-lapachone and its ?-isomer have demonstrated useful trypanocidal activities. In the search for new trypanocidal agents, this review outlines different structural modifications of natural quinones, as well as synthetic quinones, which have been subjected to trypanocidal studies. This review summarizes the mechanism of action and structure-activity relationships of the quinone derivatives, including some theoretical calculations that discuss the correlation of stereo electronic properties with the trypanocidal activity. In this context, this review will be useful for the development of new antichagasic drugs based mainly on structural modification of natural quinones. PMID:21110810

  14. Naphthoquinone-mediated Inhibition of Lysine Acetyltransferase KAT3B/p300, Basis for Non-toxic Inhibitor Synthesis*

    PubMed Central

    Vasudevarao, Mohankrishna Dalvoy; Mizar, Pushpak; Kumari, Sujata; Mandal, Somnath; Siddhanta, Soumik; Swamy, Mahadeva MM; Kaypee, Stephanie; Kodihalli, Ravindra C; Banerjee, Amrita; Naryana, Chandrabhas; Dasgupta, Dipak; Kundu, Tapas K.

    2014-01-01

    Hydroxynaphthoquinone-based inhibitors of the lysine acetyltransferase KAT3B (p300), such as plumbagin, are relatively toxic. Here, we report that free thiol reactivity and redox cycling properties greatly contribute to the toxicity of plumbagin. A reactive 3rd position in the naphthoquinone derivatives is essential for thiol reactivity and enhances redox cycling. Using this clue, we synthesized PTK1, harboring a methyl substitution at the 3rd position of plumbagin. This molecule loses its thiol reactivity completely and its redox cycling ability to a lesser extent. Mechanistically, non-competitive, reversible binding of the inhibitor to the lysine acetyltransferase (KAT) domain of p300 is largely responsible for the acetyltransferase inhibition. Remarkably, the modified inhibitor PTK1 was a nearly non-toxic inhibitor of p300. The present report elucidates the mechanism of acetyltransferase activity inhibition by 1,4-naphthoquinones, which involves redox cycling and nucleophilic adduct formation, and it suggests possible routes of synthesis of the non-toxic inhibitor. PMID:24469461

  15. Flow Injection Analysis Coupled with Carbon Electrodes as the Tool for Analysis of Naphthoquinones with Respect to Their Content and Functions in Biological Samples

    PubMed Central

    Babula, Petr; Huska, Dalibor; Hanustiak, Pavel; Baloun, Jiri; Krizkova, Sona; Adam, Vojtech; Hubalek, Jaromir; Havel, Ladislav; Zemlicka, Milan; Horna, Ales; Beklova, Miroslava; Kizek, Rene

    2006-01-01

    Naphthoquinones are one of the groups of secondary metabolites widespread in nature, where they mostly appear as chromatic pigments. They embody broad-range of biological actions from phytotoxic to fungicidal. An anticancer effect of naphthoquinones stimulates an interest in determination and characterization of single derivatives of 1,2- and 1,4-quinones in biological samples. The main aim of this work was to suggest a technique suitable to determine lawsone, juglone and/or plumbagin in biological samples and to study of their influence on BY-2 tobacco cells. The BY-2 tobacco cells were cultivated in the presence of the naphthoquinones of interest (500 ?g.l-1) for 24 h and then the morphological changes were observed. We found out that naphthoquinones triggered the programmed cell death at BY-2 cells, which can be confirmed by the apoptotic bodies in nucleus. After that we suggested and optimized different electrochemical techniques such differential pulse voltammetry (DPV) coupled with hanging mercury drop (HMDE) and carbon paste electrode, micro flow device coupled with carbon screen printed electrodes and flow injection analysis coupled with Coulochem III detector to determine them. The detection limits of naphthoquinones of interest were expressed as 3S/N and varied from units to hundreds of ng per millilitres according to methods used. Moreover, we utilized DPV coupled with HMDE and micro flow device to determine content of juglone in leaves Persian walnut (Juglans regia). We determined that the leaves contained juglone tenths of g per 100 g of fresh weight. The results obtained show the convincing possibilities of using of these methods in analysis of plant secondary metabolites.

  16. Evaluation of selected benzoquinones, naphthoquinones, and anthraquinones as replacements for phylloquinone in the A sub 1 acceptor site of the photosystem I reaction center

    SciTech Connect

    Biggins, J. )

    1990-08-07

    Selected substituted 1,4-benzoquinones, 1,4-naphthoquinones, and 9,10-anthraquinones were investigated as possible replacement quinones in spinach photosystem I (PSI) preparations that had been depleted of endogenous phylloquinone by extraction with hexane/methanol. As a criterion for successful biochemical reconstitution, the restoration of electron transfer was determined by measuring P-430 turnover at room temperature from flash-induced absorbance transients. Restoration of complete electron transfer between A{sub 0}{sup {minus}} and P-430 (terminal iron-sulfur centers, F{sub A}F{sub B}) was demonstrated by using phylloquinone, 2-methyl-3-decyl-1,4-naphthoquinone, 2-methyl-3-(isoprenyl){sub 2}-1,4-naphthoquinone, and 2-methyl-3-(isoprenyl){sub 4}-1,4-naphthoquinone. All other quinones tested did not restore P-430 turnover but acted as electron acceptors and oxidized A{sub 0}{sup {minus}}. It is concluded that the specificity of the replacement quinone for interaction with the primary acceptor, A{sub 0}{sup {minus}}, is low but additional structural constraints are required for the quinone occupying the A{sub 1} site to donate to the iron-sulfur center, F{sub x}. It is suggested that the 3-phytyl side chain of phylloquinone and the 3-alkyl tails of the three naphthoquinones that restored P-430 turnover may be required for interaction with a hydrophobic domain of the A{sub 1} site in the PSI core to promote electron transfer to F{sub x} and then to F{sub A}F{sub B}.

  17. Anti-proliferative actions of 2-decylamino-5,8-dimethoxy-1,4-naphthoquinone in vascular smooth muscle cells

    SciTech Connect

    Lee, Jung-Jin; Institute of Drug Research and Development, Chungnam National University, Daejeon 305-764 ; Zhang, Wei-Yun; Yi, Hyoseok; Kim, Yohan; Kim, In-Su; Shen, Gui-Nan; Song, Gyu-Yong; Myung, Chang-Seon; Institute of Drug Research and Development, Chungnam National University, Daejeon 305-764

    2011-07-22

    Highlights: {yields} 2-Decylamino-DMNQ inhibited PDGF-BB-induced VSMC proliferation in a dose-dependent manner with no apparent cytotoxicity. {yields} 2-Decylamino-DMNQ inhibited PDGF-BB-induced phosphorylation of Erk1/2 and PLC{gamma}1. {yields} 2-Decylamino-DMNQ arrested a G{sub 0}/G{sub 1} cell cycle progression in association with pRb phosphorylation and PCNA expression. {yields} Both U0126, an Erk inhibitor, and U73122, a PLC{gamma} inhibitor, arrested a G{sub 0}/G{sub 1} phase of the cell cycle. -- Abstract: Naphthoquinone derivatives have been reported to possess various pharmacological activities, such as antiplatelet, anticancer, antifungal, and antiviral properties. In this study, we investigated the effects of a newly-synthesized naphthoquinone derivative, 2-decylamino-5,8-dimethoxy-1,4-naphthoquinone (2-decylamino-DMNQ), on VSMC proliferation and examined the molecular basis of the underlying mechanism. In a dose-dependent manner, 2-decylamino-DMNQ inhibited PDGF-stimulated VSMC proliferation with no apparent cytotoxic effect. While 2-decylamino-DMNQ did not affect PDGF-R{beta} or Akt, it did inhibit the phosphorylation of Erk1/2 and PLC{gamma}1 induced by PDGF. Moreover, 2-decylamino-DMNQ suppressed DNA synthesis through the arrest of cell cycle progression at the G{sub 0}/G{sub 1} phase, including the suppression of pRb phosphorylation and a decrease in PCNA expression, which was related to the downregulation of cell cycle regulatory factors, such as cyclin D1/E and CDK 2/4. It was demonstrated that both U0126, an Erk1/2 inhibitor, and U73122, a PLC{gamma} inhibitor, increased the proportion of cells in the G{sub 0}/G{sub 1} phase of the cell cycle. Thus, these results suggest that 2-decylamino DMNQ has an inhibitory effect on PDGF-induced VSMC proliferation and the mechanism of this action is through cell cycle arrest at the G{sub 0}/G{sub 1} phase. This may be a useful tool for studying interventions for vascular restenosis in coronary revascularization procedures and stent implantation.

  18. Surface Enhanced Raman Spectroscopic investigations of 2-bromo-3-methylamino-1,4-naphthoquinone on silver nanoparticles

    NASA Astrophysics Data System (ADS)

    Geetha, K.; Umadevi, M.; Sathe, G. V.; Vanelle, P.; Terme, T.; Khoumeri, O.

    2015-02-01

    Surface Enhanced Raman Spectroscopic technique has been employed to investigate the orientation of 2-bromo-3-methylamino-1,4-naphthoquinone (BMANQ) on silver nanoparticles. Silver nanoparticles have been prepared by solution combustion method with citric acid as fuel. Silver nanoparticles were characterized by X-ray Diffraction (XRD), High Resolution Transmission Electron Microscopy (HRTEM) and Scanning Electron Microscopy (SEM). XRD and morphological results confirmed the nanocrystalline nature of the prepared silver nanoparticles. The observed intense Cdbnd O stretching, Csbnd Br stretching and NH2 vibration suggests that the BMANQ molecule may be adsorbed in a 'stand-on' orientation to the silver surface. The calculated highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) energy show that charge transfer occurs within the molecule.

  19. Using of liquid chromatography coupled with diode array detector for determination of naphthoquinones in plants and for investigation of influence of pH of cultivation medium on content of plumbagin in Dionaea muscipula.

    PubMed

    Babula, Petr; Mikelova, Radka; Adam, Vojtech; Kizek, Rene; Havel, Ladislav; Sladky, Zdenek

    2006-09-14

    The interest of many investigators in naphthoquinones is due to their broad-range of biological actions from phytotoxic to fungicidal. The main aim of this work was to investigate the influence of different pH values of cultivation medium on naphthoquinone content in Dionaea muscipula. For this purpose, we optimized the simultaneous analysis of the most commonly occurring naphthoquinones (1,4-naphthoquinone, lawsone, juglone and plumbagin) by high performance liquid chromatography coupled with diode array detector (HPLC-DAD). The most suitable chromatographic conditions were as follows: mobile phase: 0.1 mol l-1 acetic acid:methanol in ratio of 33:67 (%, v/v), flow rate: 0.75 ml min-1 and temperature: 42 degrees C. Moreover, we looked for the most suitable technique for preparation of plant samples (D. muscipula, Juglans regia, Paulownia tomentosa, Impatience glandulifera, Impatience parviflora, Drosera rotundifolia, Drosera spathulata and Drosera capensis) due to their consequent analysis by HPLC-DAD. It clearly follows from the results obtained that sonication were the most suitable technique for preparation of J. regia plants. We also checked the recoveries of the determined naphthoquinones, which were from 96 to 104%. Finally, we investigated the changes in content of plumbagin in D. muscipula plants according to different pH of cultivation medium. The content increased with increasing pH up to 5 and, then, changed gradually. The lower content of plumbagin at lower pH values was of interest to us. Therefore, we determined the content of this naphthoquinone in the cultivation medium, what has not been studied before. We discovered that the lower tissue content of plumbagin was due to secretion of this naphthoquinone into the cultivation medium. PMID:16765109

  20. Synthesis, spectral characterization, molecular structure and pharmacological studies of N'-(1, 4-naphtho-quinone-2yl) isonicotinohyWdrazide

    NASA Astrophysics Data System (ADS)

    Kavitha Rani, P. R.; Fernandez, Annette; George, Annie; Remadevi, V. K.; Sudarsanakumar, M. R.; Laila, Shiny P.; Arif, Muhammed

    2015-01-01

    A simple and efficient procedure was employed for the synthesis of N'-(1,4-naphtho-quinone-2-yl) isonicotinohydrazide (NIH) by the reaction of 2-hydroxy-1,4-naphthaquinone (lawsone) and isonicotinoyl hydrazine in methanol using ultrasonic irradiation. Lawsone is the principal dye, isolated from the leaves of henna (Lawsonia inermis). Structural modification was done on the molecule aiming to get a more active derivative. The structure of the parent compound and the derivative was characterized by elemental analyses, infrared, electronic, 1H, 13C NMR and GC-MS spectra. The fluorescence spectral investigation of the compound was studied in DMSO and ethanol. Single crystal X-ray diffraction studies reveal that NIH crystallizes in monoclinic space group. The DNA cleavage study was monitored by gel electrophoresis method. The synthesized compound was found to have significant antioxidant activity against DPPH radical (IC50 = 58 ?M). The in vitro cytotoxic studies of the derivative against two human cancer cell lines MCF-7 (human breast cancer) and HCT-15 (human colon carcinoma cells) using MTT assay revealed that the compound exhibited higher cytotoxic activity with a lower IC50 value indicating its efficiency in killing the cancer cells even at low concentrations. These results suggest that the structural modifications performed on lawsone could be considered a good strategy to obtain a more active drug.

  1. 1,4-Naphthoquinones and Others NADPH-Dependent Glutathione Reductase-Catalyzed Redox Cyclers as Antimalarial Agents

    PubMed Central

    Belorgey, Didier; Lanfranchi, Don Antoine; Davioud-Charvet, Elisabeth

    2013-01-01

    The homodimeric flavoenzyme glutathione reductase catalyzes NADPH-dependent glutathione disulfide reduction. This reaction is important for keeping the redox homeostasis in human cells and in the human pathogen Plasmodium falciparum. Different types of NADPH-dependent disulfide reductase inhibitors were designed in various chemical series to evaluate the impact of each inhibition mode on the propagation of the parasites. Against malaria parasites in cultures the most potent and specific effects were observed for redox-active agents acting as subversive substrates for both glutathione reductases of the Plasmodium-infected red blood cells. In their oxidized form, these redox-active compounds are reduced by NADPH-dependent flavoenzyme-catalyzed reactions in the cytosol of infected erythrocytes. In their reduced forms, these compounds can reduce molecular oxygen to reactive oxygen species, or reduce oxidants like methemoglobin, the major nutrient of the parasite, to indigestible hemoglobin. Furthermore, studies on a fluorinated suicide-substrate of the human glutathione reductase indicate that the glutathione reductase-catalyzed bioactivation of 3-benzylnaphthoquinones to the corresponding reduced 3-benzoyl metabolites is essential for the observed antimalarial activity. In conclusion, the antimalarial lead naphthoquinones are suggested to perturb the major redox equilibria of the targeted cells. These effects result in development arrest of the parasite and contribute to the removal of the parasitized erythrocytes by macrophages. PMID:23116403

  2. Synthesis and anticancer activity of some novel 5,6-fused hybrids of juglone based 1,4-naphthoquinones.

    PubMed

    Mallavadhani, Uppuluri Venkata; Prasad, Chakka Vara; Shrivastava, Shweta; Naidu, V G M

    2014-08-18

    Six novel 5,6-fused hybrids such as dihydrobenzofuran-quinone (4a and 4b), benzofuran-quinone (5a and 5b) and chromene-quinone (6a and 6b) of juglone based 1,4-naphthoquinones were synthesized by employing a three step protocol with the cyclisation of o-allyl phenol as the key step. The anticancer activity of the newly synthesized compounds was evaluated in vitro against seven human cancer cell lines including cervix (ME-180 and HeLa), breast (MCF-7, MDA-MB-453 and MDA-MB-231), prostate (PC-3) and colon (HT-29) by using MTT assay. The screening results showed that majority of the synthesized compounds exhibited significant anticancer activity. In particular, compounds 6a and 6b showed potent activities than the standard drug etoposide against prostate and breast cancer cell lines respectively. Flow cytometric analysis revealed that compounds 6a and 6b induced apoptosis and arrested the cell cycle at G2/M phase in PC-3 and MDA-MB-453 cells respectively. PMID:24953027

  3. Synthesis, spectral characterization, molecular structure and pharmacological studies of N'-(1, 4-naphtho-quinone-2yl) isonicotinohydrazide.

    PubMed

    Kavitha Rani, P R; Fernandez, Annette; George, Annie; Remadevi, V K; Sudarsanakumar, M R; Laila, Shiny P; Arif, Muhammed

    2015-01-25

    A simple and efficient procedure was employed for the synthesis of N'-(1,4-naphtho-quinone-2-yl) isonicotinohydrazide (NIH) by the reaction of 2-hydroxy-1,4-naphthaquinone (lawsone) and isonicotinoyl hydrazine in methanol using ultrasonic irradiation. Lawsone is the principal dye, isolated from the leaves of henna (Lawsonia inermis). Structural modification was done on the molecule aiming to get a more active derivative. The structure of the parent compound and the derivative was characterized by elemental analyses, infrared, electronic, (1)H, (13)C NMR and GC-MS spectra. The fluorescence spectral investigation of the compound was studied in DMSO and ethanol. Single crystal X-ray diffraction studies reveal that NIH crystallizes in monoclinic space group. The DNA cleavage study was monitored by gel electrophoresis method. The synthesized compound was found to have significant antioxidant activity against DPPH radical (IC50=58 ?M). The in vitro cytotoxic studies of the derivative against two human cancer cell lines MCF-7 (human breast cancer) and HCT-15 (human colon carcinoma cells) using MTT assay revealed that the compound exhibited higher cytotoxic activity with a lower IC50 value indicating its efficiency in killing the cancer cells even at low concentrations. These results suggest that the structural modifications performed on lawsone could be considered a good strategy to obtain a more active drug. PMID:25153640

  4. Direct detection of a triplet vinylnitrene, 1,4-naphthoquinone-2-ylnitrene, in solution and cryogenic matrices.

    PubMed

    Sarkar, Sujan K; Sawai, Asako; Kanahara, Kousei; Wentrup, Curt; Abe, Manabu; Gudmundsdottir, Anna D

    2015-04-01

    The photolysis of 2-azido-1,4-naphthoquinone (1) in argon matrices at 8 K results in the corresponding triplet vinylnitrene (3)2, which was detected directly by IR spectroscopy. Vinylnitrene (3)2 is stable in argon matrices but forms 2-cyanoindane-1,3-dione (3) upon further irradiation. Similarly, the irradiation of azide 1 in 2-methyltetrahydrofuran (MTHF) matrices at 5 K resulted in the ESR spectrum of vinylnitrene (3)2, which is stable up to at least 100 K. The zero-field splitting parameters for nitrene (3)2, D/hc = 0.7292 cm(-1) and E/hc = 0.0048 cm(-1), verify that it has significant 1,3-biradical character. Vinylnitrene (3)2 (?max ? 460 nm, ? = 22 ?s) is also observed directly in solution at ambient temperature with laser flash photolysis of 1. Density functional theory (DFT) calculations support the characterization of vinylnitrene (3)2 and the proposed mechanism for its formation. Because vinylnitrene (3)2 is relatively stable, it has potential use as a building-block for high-spin assemblies. PMID:25760227

  5. 1,2-Naphthoquinone activates vanilloid receptor 1 through increased protein tyrosine phosphorylation, leading to contraction of guinea pig trachea

    SciTech Connect

    Kikuno, Shota; Taguchi, Keiko; Iwamoto, Noriko; Yamano, Shigeru; Cho, Arthur K.; Froines, John R.; Kumagai, Yoshito . E-mail: yk-em-tu@md.tsukuba.ac.jp

    2006-01-15

    1,2-Naphthoquinone (1,2-NQ) has recently been identified as an environmental quinone in diesel exhaust particles (DEP) and atmospheric PM{sub 2.5}. We have found that this quinone is capable of causing a concentration-dependent contraction of tracheal smooth muscle in guinea pigs with EC{sub 5} value of 18.7 {mu}M. The contraction required extracellular calcium and was suppressed by L-type calcium channel blockers nifedipine and diltiazem. It was found that 1,2-NQ activated phospholipase A2 (PLA2)/lipoxygenase (LO)/vanilloid receptor (VR1) signaling. Additionally, 1,2-NQ was capable of transactivating protein tyrosine kinases (PTKs) such as epidermal growth factor receptor (EGFR) in guinea pig trachea, suggesting that phosphorylation of PTKs contributes to 1,2-NQ-induced tracheal contraction. Consistent with this notion, this action was blocked by the PTKs inhibitor genistein and the EGFR antagonist PD153035, indicating that contraction was, at least in part, attributable to PTKs phosphorylation that activates VR1, resulting in increased intracellular calcium content in the smooth muscle cells.

  6. Determination of lapachol in the presence of other naphthoquinones using 3MPA-CdTe quantum dots fluorescent probe.

    PubMed

    Aucélio, Ricardo Q; Peréz-Cordovés, Ana I; Xavier Lima, Juliano L; Ferreira, Aurélio Baird B; Esteva Guas, Ana M; da Silva, Andrea R

    2013-01-01

    3MPA-CdTe QDs in aqueous dispersion was used as a fluorescent probe for the determination of lapachol, a natural naphthoquinone found in plants of the Bignoniaceae family genus Tabebuia. Working QDs dispersions (4.5×10(-8) mol L(-1) of QDs) was prepared in aqueous media containing Tris-HCl buffer pH 7.4 and methanol (10% in volume). The excitation was made at 380 nm with signal measurement at 540 nm. To establish a relationship between fluorescence (corrected to inner filter effect) and concentration of lapachol, a Stern-Volmer model was used. The linear range obtained was from 1.0×10(-5) to 1.0×10(-4) mol L(-1). The limit of detection (x(b)-3s(b)) was 8.0×10(-6) mol L(-1). The 3MPA-CdTe QDs probe was tested in the determination of lapachol in urine, previously cleansed in an acrylic polymer. The average recovery was satisfactory. PMID:22591798

  7. Addition of thiols to o-quinone methide: new 2-hydroxy-3-phenylsulfanylmethyl[1,4]naphthoquinones and their activity against the human malaria parasite Plasmodium falciparum (3D7).

    PubMed

    Sharma, Abhinay; Santos, Isabela O; Gaur, Pratibha; Ferreira, Vitor F; Garcia, Celia R S; da Rocha, David R

    2013-01-01

    A series of 36 new phenylsulfanylmethyl[1,4]naphthoquinones (7-42) were synthesized by a three-component reaction that involves lawsone, the appropriate aldehyde and thiols with variable substitution patterns. These reactions involve the in situ generation of o-quinone methides (o-QM) via Knoevenagel condensation and 1,4-nucleophilic addition under conventional heating or microwave irradiation. The new naphthoquinones obtained by this methodology were shown to have moderate to good in vitro antimalarial activity against Plasmodium falciparum (3D7). PMID:23202850

  8. Potential of 2-Hydroxy-3-Phenylsulfanylmethyl-[1,4]-Naphthoquinones against Leishmania (L.) infantum: Biological Activity and Structure-Activity Relationships

    PubMed Central

    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. PMID:25171058

  9. Tabebuia avellanedae naphthoquinones: activity against methicillin-resistant staphylococcal strains, cytotoxic activity and in vivo dermal irritability analysis

    PubMed Central

    Pereira, Eliezer Menezes; Machado, Thelma de Barros; Leal, Ivana Correa Ramos; Jesus, Desyreé Murta; Damaso, Clarissa Rosa de Almeida; Pinto, Antonio Ventura; Giambiagi-deMarval, Marcia; Kuster, Ricardo Machado; dos Santos, Kátia Regina Netto

    2006-01-01

    Background Methicillin-resistant Staphylococcus aureus (MRSA) and coagulase-negative staphylococcus infections are a worldwide concern. Currently, these isolates have also shown resistance to vancomycin, the last therapy used in these cases. It has been observed that quinones and other related compounds exhibit antibacterial activity. This study evaluated the antibacterial activity, toxicity and in vivo dermal irritability of lapachol extracted from Tabebuia avellanedae and derivatives against methicillin-resistant staphylococcal isolates. In addition, its mechanism of action was also analyzed. Methods The compounds ?-lapachone, 3-hydroxy ? N lapachone and ?-lapachone were tested to determine the MIC values against methicillin-resistant S. aureus, S. epidermidis and S. haemolyticus strains, being the two last ones hetero-resistant to vancomycin. Experiments of protein synthesis analysis to investigate the naphthoquinones action were assessed. In vitro toxicity to eukaryotic BSC-40 African Green Monkey Kidney cell cultures and in vivo primary dermal irritability in healthy rabbits were also performed. Results The compounds tested showed antibacterial activity (MICs of 8, 4/8 and 64/128 ?g/mL to ?-lapachone, 3-hydroxy ? N lapachone and ?-lapachone, respectively), but no bactericidal activity was observed (MBC > 512 ?g/mL for all compounds). Although it has been observed toxic effect in eukaryotic cells, the compounds were shown to be atoxic when applied as topic preparations in healthy rabbits. No inhibition of proteins synthesis was observed. Conclusion Our results suggest that quinones could be used in topic preparations against wound infections caused by staphylococci, after major investigation of the pharmacological properties of the compounds. Studies about the use of these compounds on tumoral cells could be carried on, due to their effect in eukaryotic cells metabolism. PMID:16553949

  10. Synthesis and characterization of n-alkylamino derivatives of vitamin K3: Molecular structure of 2-propylamino-3-methyl-1,4-naphthoquinone and antibacterial activities

    NASA Astrophysics Data System (ADS)

    Chadar, Dattatray; Camilles, Maria; Patil, Rishikesh; Khan, Ayesha; Weyhermüller, Thomas; Salunke-Gawali, Sunita

    2015-04-01

    We would like to introduce eight analogues of n-alkylamino derivatives of vitamin K3 (2-methyl-1,4-naphthoquinone) viz, 2-(n-alkylamino)-3-methyl-1,4-naphthoquinone (where n-alkyl is methyl; LM-1, ethyl; LM-2, propyl; LM-3, butyl; LM-4, pentyl; LM-5, hexyl; LM-6, heptyl; LM-7, octyl; LM-8). All the above analogues have been successfully synthesized from vitamin K3 and characterized using different analytical techniques. Furthermore, in order to understand the mechanistic aspects of formation of LM-1 to LM-8 compounds, we could propose the mechanism. The FT-IR analysis of LM-1 to LM-8 indicate the presence of characteristic band of Nsbnd H group ?3287-3364 cm-1, the variation was attributed to extensive intramolecular hydrogen bonding interaction. The molecular structure of LM-3 compound has been confirmed by single crystal X-ray diffraction analysis. LM-3 compound crystallises in triclinic space group P1. There were four independent molecules in asymmetric unit cell and their molecular interactions observed via Nsbnd H⋯O, Csbnd H⋯O and ?-? stacking of quinonoid rings. Pharmacological potential of all compounds has been evaluated in terms of their antibacterial activities against Pseudomonas aeruginosa and Staphylococcus aureus. All the compounds were active against both the strains while LM-2 was found to be more effective with a minimum inhibition concentration of 0.3125 ?g/mL and 0.156 ?g/mL respectively.

  11. Trypanosoma cruzi mitochondrial swelling and membrane potential collapse as primary evidence of the mode of action of naphthoquinone analogues

    PubMed Central

    2013-01-01

    Background Naphthoquinones (NQs) are privileged structures in medicinal chemistry due to the biological effects associated with the induction of oxidative stress. The present study evaluated the activities of sixteen NQs derivatives on Trypanosoma cruzi. Results Fourteen NQs displayed higher activity against bloodstream trypomastigotes of T. cruzi than benznidazole. Further assays with NQ1, NQ8, NQ9 and NQ12 showed inhibition of the proliferation of axenic epimastigotes and intracelulluar amastigotes interiorized in macrophages and in heart muscle cells. NQ8 was the most active NQ against both proliferative forms of T. cruzi. In epimastigotes the four NQs induced mitochondrial swelling, vacuolization, and flagellar blebbing. The treatment with NQs also induced the appearance of large endoplasmic reticulum profiles surrounding different cellular structures and of myelin-like membranous contours, morphological characteristics of an autophagic process. At IC50 concentration, NQ8 totally disrupted the ??m of about 20% of the parasites, suggesting the induction of a sub-population with metabolically inactive mitochondria. On the other hand, NQ1, NQ9 or NQ12 led only to a discrete decrease of TMRE + labeling at IC50 values. NQ8 led also to an increase in the percentage of parasites labeled with DHE, indicative of ROS production, possibly the cause of the observed mitochondrial swelling. The other three NQs behaved similarly to untreated controls. Conclusions NQ1, NQ8, NQ9 and NQ12 induce an autophagic phenotype in T. cruzi epimastigoted, as already observed with others NQs. The absence of oxidative stress in NQ1-, NQ9- and NQ12-treated parasites could be due to the existence of more than one mechanism of action involved in their trypanocidal activity, leaving ROS generation suppressed by the detoxification system of the parasite. The strong redox effect of NQ8 could be associated to the presence of the acetyl group in its structure facilitating quinone reduction, as previously demonstrated by electrochemical analysis. Further experiments using biochemical and molecular approaches are needed to better characterize ROS participation in the mechanism of action of these NQs. PMID:24004461

  12. An assessment of the genotoxicity of 2-hydroxy-1,4-naphthoquinone, the natural dye ingredient of Henna.

    PubMed

    Kirkland, David; Marzin, Daniel

    2003-06-01

    2-Hydroxy-1,4-naphthoquinone (HNQ; Lawsone; CAS 83-72-7) is the principal natural dye ingredient contained in the leaves of Henna (Lawsonia inermis). Published genotoxicity studies on HNQ suggested it was a weak bacterial mutagen for Salmonella typhimurium strain TA98 or was more clearly mutagenic for strain TA 2637, both in the presence of metabolic activation. HNQ was unable to induce sex-linked recessive lethal mutations in Drosophila melanogaster. However, a small increase in micronucleus frequency was reported in the bone marrow of mice at a single mid-range dose level, 24h after intraperitoneal injection. In view of the wide use of Henna hair dyes it was deemed necessary to conduct a thorough investigation, under Good Laboratory Practice conditions, of the genotoxicity of HNQ. HNQ was non-mutagenic in bacterial (Ames test) or mammalian (V79 hprt) assays. It was borderline positive in a mouse lymphoma tk mutation assay and a chromosome aberration test (CHO cells), results that may reflect a similar clastogenic mechanism. Negative in vivo genotoxicity results were noted in the rat hepatocyte in vivo/in vitro UDS test, in peripheral lymphocytes (chromosome aberrations) of rats receiving repeated oral doses of HNQ at the MTD for 28 days, and in mouse and hamster bone marrow chromosome aberration tests. However small, but statistically significant increases in the incidence of bone marrow micronuclei were observed in two out of five tests at 72 h after dosing, but not at 24 or 48 h. There was evidence of haematotoxicity at 72 h, which may have been enhanced by the vehicle (DMSO) used in the positive tests. As erythropoiesis and administration of haematotoxic agents are known to induce small increases in the frequency of bone marrow micronuclei, typically at delayed sampling times, the data suggest that the positive 72 h response produced by HNQ is consistent with stimulation of haematopoiesis subsequent to haematological toxicity of HNQ, and not due to a DNA-reactive mechanism. Overall, the weight of evidence suggests that Henna and HNQ pose no genotoxic risk to the consumer. PMID:12787822

  13. Synthesis and anti-Trypanosoma cruzi activity of naphthoquinone-containing triazoles: electrochemical studies on the effects of the quinoidal moiety.

    PubMed

    Diogo, Emilay B T; Dias, Gleiston G; Rodrigues, Bernardo L; Guimarães, Tiago T; Valença, Wagner O; Camara, Celso A; de Oliveira, Ronaldo N; da Silva, Mauro G; Ferreira, Vitor F; de Paiva, Yen Galdino; Goulart, Marilia O F; Menna-Barreto, Rubem F S; de Castro, Solange L; da Silva Júnior, Eufrânio N

    2013-11-01

    In our continued search for novel trypanocidal compounds, twenty-six derivatives of para- and ortho-naphthoquinones coupled to 1,2,3-triazoles were synthesized. These compounds were evaluated against the infective bloodstream form of Trypanosoma cruzi, the etiological agent of Chagas disease. Compounds 17-24, 28-30 and 36-38 are described herein for the first time. Three of these novel compounds (28-30) were found to be more potent than the standard drug benznidazole, with IC50/24h values between 6.8 and 80.8?M. Analysis of the toxicity to heart muscle cells led to LC50/24h of <125, 63.1 and 281.6?M for 28, 29 and 30, respectively. Displaying a selectivity index of 34.3, compound 30 will be further evaluated in vivo. The electrochemical properties of selected compounds were evaluated in an attempt to find correlations with trypanocidal activity, and it was observed that more electrophilic quinones were generally more potent. PMID:24074878

  14. Synthesis and evaluation of 1,4-naphthoquinone ether derivatives as SmTGR inhibitors and new anti-schistosomal drugs.

    PubMed

    Johann, Laure; Belorgey, Didier; Huang, Hsin-Hung; Day, Latasha; Chessé, Matthieu; Becker, Katja; Williams, David L; Davioud-Charvet, Elisabeth

    2015-08-01

    Investigations regarding the chemistry and mechanism of action of 2-methyl-1,4-naphthoquinone (or menadione) derivatives revealed 3-phenoxymethyl menadiones as a novel anti-schistosomal chemical series. These newly synthesized compounds (1-7) and their difluoromethylmenadione counterparts (8, 9) were found to be potent and specific inhibitors of Schistosoma mansoni thioredoxin-glutathione reductase (SmTGR), which has been identified as a potential target for anti-schistosomal drugs. The compounds were also tested in enzymic assays using both human flavoenzymes, i.e. glutathione reductase (hGR) and selenium-dependent human thioredoxin reductase (hTrxR), to evaluate the specificity of the inhibition. Structure-activity relationships as well as physico- and electro-chemical studies showed a high potential for the 3-phenoxymethyl menadiones to inhibit SmTGR selectively compared to hGR and hTrxR enzymes, in particular those bearing an ?-fluorophenol methyl ether moiety, which improves anti-schistosomal action. Furthermore, the (substituted phenoxy)methyl menadione derivative (7) displayed time-dependent SmTGR inactivation, correlating with unproductive NADPH-dependent redox cycling of SmTGR, and potent anti-schistosomal action in worms cultured ex vivo. In contrast, the difluoromethylmenadione analog 9, which inactivates SmTGR through an irreversible non-consuming NADPH-dependent process, has little killing effect in worms cultured ex vivo. Despite ex vivo activity, none of the compounds tested was active in vivo, suggesting that the limited bioavailability may compromise compound activity. Therefore, future studies will be directed toward improving pharmacokinetic properties and bioavailability. PMID:26111549

  15. Experimental Chemotherapy for Chagas Disease: A Morphological, Biochemical, and Proteomic Overview of Potential Trypanosoma cruzi Targets of Amidines Derivatives and Naphthoquinones

    PubMed Central

    de Castro, Solange L.; Batista, Denise G. J.; Batista, Marcos M.; Batista, Wanderson; Daliry, Anissa; de Souza, Elen M.; Menna-Barreto, Rubem F. S.; Oliveira, Gabriel M.; Salomão, Kelly; Silva, Cristiane F.; Silva, Patricia B.; Soeiro, Maria de Nazaré C.

    2011-01-01

    Chagas disease (CD), caused by Trypanosoma cruzi, affects approximately eight million individuals in Latin America and is emerging in nonendemic areas due to the globalisation of immigration and nonvectorial transmission routes. Although CD represents an important public health problem, resulting in high morbidity and considerable mortality rates, few investments have been allocated towards developing novel anti-T. cruzi agents. The available therapy for CD is based on two nitro derivatives (benznidazole (Bz) and nifurtimox (Nf)) developed more than four decades ago. Both are far from ideal due to substantial secondary side effects, limited efficacy against different parasite isolates, long-term therapy, and their well-known poor activity in the late chronic phase. These drawbacks justify the urgent need to identify better drugs to treat chagasic patients. Although several classes of natural and synthetic compounds have been reported to act in vitro and in vivo on T. cruzi, since the introduction of Bz and Nf, only a few drugs, such as allopurinol and a few sterol inhibitors, have moved to clinical trials. This reflects, at least in part, the absence of well-established universal protocols to screen and compare drug activity. In addition, a large number of in vitro studies have been conducted using only epimastigotes and trypomastigotes instead of evaluating compounds' activities against intracellular amastigotes, which are the reproductive forms in the vertebrate host and are thus an important determinant in the selection and identification of effective compounds for further in vivo analysis. In addition, due to pharmacokinetics and absorption, distribution, metabolism, and excretion characteristics, several compounds that were promising in vitro have not been as effective as Nf or Bz in animal models of T. cruzi infection. In the last two decades, our team has collaborated with different medicinal chemistry groups to develop preclinical studies for CD and investigate the in vitro and in vivo efficacy, toxicity, selectivity, and parasite targets of different classes of natural and synthetic compounds. Some of these results will be briefly presented, focusing primarily on diamidines and related compounds and naphthoquinone derivatives that showed the most promising efficacy against T. cruzi. PMID:22091400

  16. LQB-118, a pterocarpanquinone structurally related to lapachol [2-hydroxy-3-(3-methyl-2-butenyl)-1,4-naphthoquinone]: a novel class of agent with high apoptotic effect in chronic myeloid leukemia cells.

    PubMed

    Maia, Raquel C; Vasconcelos, Flavia C; de Sá Bacelar, Thiago; Salustiano, Eduardo J; da Silva, Luis Felipe R; Pereira, Débora L; Moellman-Coelho, Arthur; Netto, Chaquip D; da Silva, Alcides J; Rumjanek, Vivian M; Costa, Paulo R R

    2011-12-01

    Despite the relevant therapeutic progresses obtained with imatinib, clinical resistance to this drug has emerged and reemerged after cytogenetic remission in a group of patients with chronic myeloid leukemia (CML). Therefore, novel treatment strategies are needed. In this study, we evaluated the anti-CML activity and mechanisms of action of LQB-118, a pterocarpanquinone structurally related to lapachol [2-hydroxy-3-(3-methyl-2-butenyl)-1,4-naphthoquinone]. LQB-118 treatment resulted in an important reduction of cell viability in cell lines derived from CML, both the vincristine-sensitive K562 cell line, and the resistant K562-Lucena (a cell line overexpressing P-glycoprotein). In agreement with these results, the induction of caspase-3 activation by this compound indicated that a significant rate of apoptosis was taking place. In these cell lines, apoptosis induced by LQB-118 was accompanied by a reduction of P-glycoprotein, survivin, and XIAP expression. Moreover, this effect was not restricted to cell lines as LQB-118 produced significant apoptosis rate in cells from CML patients exhibiting multifactorial drug resistance phenotype such as P-glycoprotein, MRP1 and p53 overexpression. The data suggest that LQB-118 has a potent anti-CML activity that can overcome multifactorial drug resistance mechanisms, making this compound a promising new anti-CML agent. PMID:20499132

  17. Charge–transfer reaction of 2,3-dichloro-1,4-naphthoquinone with crizotinib: Spectrophotometric study, computational molecular modeling and use in development of microwell assay for crizotinib

    PubMed Central

    Alzoman, Nourah Z.; Alshehri, Jamilah M.; Darwish, Ibrahim A.; Khalil, Nasr Y.; Abdel-Rahman, Hamdy M.

    2014-01-01

    The reaction of 2,3-dichloro-1,4-naphthoquinone (DCNQ) with crizotinib (CZT; a novel drug used for treatment of non-small cell lung cancer) was investigated in different solvents of varying dielectric constants and polarity indexes. The reaction produced a red-colored product. Spectrophotometric investigations confirmed that the reaction proceeded through charge–transfer (CT) complex formation. The molar absorptivity of the complex was found to be linearly correlated with the dielectric constant and polarity index of the solvent; the correlation coefficients were 0.9567 and 0.9069, respectively. The stoichiometric ratio of DCNQ:CZT was found to be 2:1 and the association constant of the complex was found to be 1.07 × 102 l/mol. The kinetics of the reaction was studied; the order of the reaction, rate and rate constant were determined. Computational molecular modeling for the complex between DCNQ and CZT was conducted, the sites of interaction on CZT molecule were determined, and the mechanism of the reaction was postulated. The reaction was employed as a basis in the development of a novel 96-microwell assay for CZT in a linear range of 4–500 ?g/ml. The assay limits of detection and quantitation were 2.06 and 6.23 ?g/ml, respectively. The assay was validated as per the guidelines of the International Conference on Harmonization (ICH) and successfully applied to the analysis of CZT in its bulk and capsules with good accuracy and precision. The assay has high throughput and consumes a minimum volume of organic solvents thus it reduces the exposures of the analysts to the toxic effects of organic solvents, and significantly reduces the analysis cost. PMID:25685046

  18. Thermodynamic properties of 1,4-benzoquinone (BQ), 1,4-hydroquinone (HQ), 1,4-naphthoquinone (NQ), 1,4-naphthohydroquinone (NHQ), and the complexes BQ-HQ 1:1, NQ-HQ 1:1, NQ-NHQ 2:1, and NQ-NHQ 1:1

    NASA Astrophysics Data System (ADS)

    de Kruif, C. G.; Smit, E. J.; Govers, H. A. J.

    1981-05-01

    Simultaneous torsion and mass loss effusion techniques are applied to measure vapor pressure as a function of temperature. The enthalpy of sublimation is derived from the temperature dependence of vapor pressure. Overall mean values for both techniques are as follows: 1,4-benzoquinone, ?H°s(261.50 K) = (68.0±0.5) kJ mol-1; 1,4-hydroquinone, ?H°s(342.37 K) = (103.9±1) kJ mol-1; 1,4-naphthoquinone, ?H°s(313.21 K) = (90.7±2) kJ mol-1; 1,4-naphthohydroquinone, ?H°s(381.09 K) = (119.0±1) kJ mol-1. The complexes evaporate incongruently. The enthalphies of sublimation of the first mentioned constituent when evaporated are found as follows: BQ-HQ 1:1, ?H°s(312.97 K) = (88.6±1) kJ mole-1; NQ-HQ 1:1, ?H°s(324.03 K) = (98.7±1) kJ mole-1; NQ-NHQ 2:1, ?H°s(328.49 K) = (88.7±3) kJ mol-1; NQ-NHQ 1:1, ?H°s(342.36 K) = (102.3±2) kJ mol-1. The temperatures given are midrange values at which the saturation vapor pressure of each substance is 0.4 Pa. From the measured vapor pressures and the enthalphies the sublimation of Gibbs energies and enthalpies of complexation are calculated: BQ-HQ 1:1, 295 K, ?G°compl = (-13.8±1) kJ mol-1, ?H°compl = (-20.6±1) kJ mol-1; NQ-HQ 1:1, 320 K, ?G°compl = (-3.2±2) kJ mol-1, ?H°compl = (-8.0±2) kJ mol-1; NQ-NHQ 2:1, 320 K, ?G°compl = (-12.9±1) kJ mol-1, ?H°compl = (-9.6±4) kJ mol-1; NQ-NHQ 1:1, 330 K, ?G°compl = (-8.6±1) kJ mol-1, ?H°compl = (-11.6±2) kJ mol-1.

  19. Modification of Phospholipid Bilayers Induced by Sulfurated Naphthoquinones

    PubMed Central

    Di Vitta, Claudio; Funari, Sérgio S.

    2013-01-01

    New thionaphthoquinones and their hydroxyl derivatives, bearing alkyl side chains that match the phospholipids POPC and POPE, were synthesized in order to investigate their interactions with lipids. It was observed that, in general, these additives destabilize the lipid bilayer and induce less organized structures with higher curvature, in particular the induction of an hexagonal phase on aqueous POPC mixtures. Moreover, cubic phases, not normally observed in the pure lipids when fully hydrated, were detected. Coexistence of lamellar phases was interpreted as a consequence of microsegregation of the components in the mixtures. These results are in line with previous observations on the effect of structurally similar (hydro)quinones in phase behavior of these lipids. PMID:23606970

  20. Synthesis and Biological Evaluation of Naphthoquinone Analogs as a Novel Class of Proteasome Inhibitors

    PubMed Central

    Lawrence, Harshani R.; Kazi, Aslamuzzaman; Luo, Yunting; Kendig, Robert; Ge, Yiyu; Jain, Sanjula; Daniel, Kenyon; Santiago, Daniel; Guida, Wayne C.; Sebti, Saïd M.

    2012-01-01

    Screening of the NCI Diversity Set-1 identified PI-083 (NSC-45382) a proteasome inhibitor selective for cancer over normal cells. Focused libraries of novel compounds based on PI-083 chloronaphthoquinone and sulfonamide moieties were synthesized to gain a better understanding of the structure activity relationship responsible for chymotrypsin-like proteasome inhibitory activity. This led to the demonstration that the chloronaphthoquinone and the sulfonamide moieties are critical for inhibitory activity. The pyridyl group in PI-083 can be replaced with other heterocyclic groups without significant loss of activity. Molecular modeling studies were also performed to explore the detailed interactions of PI-083 and its derivatives with the ?5 and ?6 subunits of the 20S proteasome. The refined model showed an H-bond interaction between the Asp-114 and the sulfonamide moiety of the PI-083 in the ?6 subunit. PMID:20621484

  1. Semisynthesis and antitumoral activity of 2-acetylfuranonaphthoquinone and other naphthoquinone derivatives from lapachol.

    PubMed

    Eyong, Kenneth O; Kumar, Ponminor S; Kuete, Victor; Folefoc, Gabriel N; Nkengfack, Ephriam A; Baskaran, Sundarababu

    2008-10-15

    Ozonolysis of lapachol (1), resulting in an unusual formation of a potent antitumor agent 2-acetylfuranonaphthoquinone (3) along with the expected aldehyde 6, is described. The reaction of lapachol (1) with CAN in dry acetonitrile leading to biologically active furanonaphthoquinones is also reported. The antitumoral activity of the tested compounds on human DU-145 prostate carcinoma cells was evaluated following XTT assay. The results revealed that 2-(1-methylethenyl)-2,3-dihydronaphtho[2,3-b]furan-4,9-dione (5), beta-lapachone (10) and dehydro-beta-lapachone diacetate (11) showed 100% inhibition at 25 microg/ml. All the tested samples showed dose-dependent activity. PMID:18829316

  2. In Vitro Induction of Erythrocyte Phosphatidylserine Translocation by the Natural Naphthoquinone Shikonin

    PubMed Central

    Lupescu, Adrian; Bissinger, Rosi; Jilani, Kashif; Lang, Florian

    2014-01-01

    Shikonin, the most important component of Lithospermum erythrorhizon, has previously been shown to exert antioxidant, anti-inflammatory, antithrombotic, antiviral, antimicrobial and anticancer effects. The anticancer effect has been attributed to the stimulation of suicidal cell death or apoptosis. Similar to the apoptosis of nucleated cells, erythrocytes may experience eryptosis, the suicidal erythrocyte death characterized by cell shrinkage and by phosphatidylserine translocation to the erythrocyte surface. Triggers of eryptosis include the increase of cytosolic Ca2+-activity ([Ca2+]i) and ceramide formation. The present study explored whether Shikonin stimulates eryptosis. To this end, Fluo 3 fluorescence was measured to quantify [Ca2+]i, forward scatter to estimate cell volume, annexin V binding to identify phosphatidylserine-exposing erythrocytes, hemoglobin release to determine hemolysis and antibodies to quantify ceramide abundance. As a result, a 48 h exposure of human erythrocytes to Shikonin (1 µM) significantly increased [Ca2+]i, increased ceramide abundance, decreased forward scatter and increased annexin V binding. The effect of Shikonin (1 µM) on annexin V binding was significantly blunted, but not abolished by the removal of extracellular Ca2+. In conclusion, Shikonin stimulates suicidal erythrocyte death or eryptosis, an effect at least partially due to the stimulation of Ca2+ entry and ceramide formation. PMID:24828755

  3. Potent and specific bactericidal effect of juglone (5-hydroxy-1,4-naphthoquinone) on the fire blight pathogen Erwinia amylovora.

    PubMed

    Fischer, Thilo Christopher; Gosch, Christian; Mirbeth, Beate; Gselmann, Markus; Thallmair, Veronika; Stich, Karl

    2012-12-12

    A screening of plant quinones for inhibiting effects on the bacterial fire blight pathogen Erwinia amylovora was performed. The most active compound, juglone from walnuts, has a potent and specific bactericidal effect on E. amylovora and minimal inhibitory concentrations of only 2.5-10 ?M, with stronger effects at lower, but still physiological, pH values. In vitro tests with juglone and inoculated flowers of apple (Malus domestica) showed an efficacy of 67% in preventing infection. In two years of field tests juglone had variable degrees of efficacy ranging from 40 to 82%, seemingly due to environmental conditions. A phytotoxic reaction to juglone, which is known for its allelopathic effect on plants, was restricted to browning of petals; later fruit russeting was not observed. Juglone is a promising candidate for the development of a new environmentally friendly plant protectant to replace the antibiotic streptomycin currently used in fire blight control. PMID:23163769

  4. Vasorelaxation induced by a new naphthoquinone-oxime is mediated by NO-sGC-cGMP pathway.

    PubMed

    Dantas, Bruna P V; Ribeiro, Thaís P; Assis, Valéria L; Furtado, Fabíola F; Assis, Kívia S; Alves, Jeziane S; Silva, Tania M S; Camara, Celso A; França-Silva, Maria S; Veras, Robson C; Medeiros, Isac A; Alencar, Jacicarlos L; Braga, Valdir A

    2014-01-01

    It has been established that oximes cause endothelium-independent relaxation in blood vessels. In the present study, the cardiovascular effects of the new oxime 3-hydroxy-4-(hydroxyimino)-2-(3-methylbut-2-enylnaphtalen-1(4H)-one (Oxime S1) derived from lapachol were evaluated. In normotensive rats, administration of Oxime S1 (10, 15, 20 and 30 mg/Kg, i.v.) produced dose-dependent reduction in blood pressure. In isolated aorta and superior mesenteric artery rings, Oxime S1 induced endothelium-independent and concentration-dependent relaxations (10(-8) M to 10(-4) M). In addition, Oxime S1-induced vasorelaxations were attenuated by hydroxocobalamin or methylene blue in aorta and by PTIO or ODQ in mesenteric artery rings, suggesting a role for the nitric oxide (NO) pathway. Additionally, Oxime S1 (30 and 100 µM) significantly increased NO concentrations (13.9 ± 1.6 nM and 17.9 ± 4.1 nM, respectively) measured by nitric oxide microsensors. Furthermore, pre-contraction with KCl (80 mM) prevented Oxime S1-derived vasorelaxation in endothelium-denuded aortic rings. Of note, combined treatment with potassium channel inhibitors also reduced Oxime S1-mediated vasorelaxation suggesting a role for potassium channels, more precisely Kir, Kv and KATP channels. We observed the involvement of BKCa channels in Oxime S1-induced relaxation in mesenteric artery rings. In conclusion, these data suggest that the Oxime S1 induces hypotension and vasorelaxation via NO pathway by activating soluble guanylate cyclase (sGC) and K+ channels. PMID:25006785

  5. Reversed-phase HPLC determination of chlorophyll a' and naphthoquinones in photosystem I of red algae: existence of two menaquinone-4 molecules in photosystem I of Cyanidium caldarium.

    PubMed

    Yoshida, Emi; Nakamura, Akimasa; Watanabe, Tadashi

    2003-07-01

    Chlorophyll (Chl) a', the C13(2)-epimer of Chl a, is one of the two Chl molecules constituting the primary electron donor (P700) of photosystem (PS) I of a thermophilic cyanobacterium Synechococcus elongatus. To examine whether PS I of other oxygenic photosynthetic organisms in general contain one Chl a' molecule in P700, the pigment composition of thylakoid membranes and PS I preparations isolated from red algae Porphyridium purpureum and Cyanidium caldarium was examined by reversed-phase HPLC with particular attention to Chl a' and phylloquinone (PhQ), the secondary electron acceptor of PS I. The two red algae contained one Chl a' molecule at the core part of PS I. In PS I of C. caldarium, two menaquinone-4 (MQ-4) molecules were detected in place of PhQ used by higher plants and cyanobacteria. The 1:2:1 stoichiometry among Chl a', PhQ (MQ-4) and P700 in PS I of the red algae indicates that one Chl a' molecule universally exists in PS I of oxygenic photosynthetic organisms, and two MQ-4 molecules are associated with PS I of C. caldarium. PMID:12880082

  6. Antigenotoxic, anti-photogenotoxic and antioxidant activities of natural naphthoquinone shikonin and acetylshikonin and Arnebia euchroma callus extracts evaluated by the umu-test and EPR method.

    PubMed

    Skrzypczak, Agata; Przystupa, Natalia; Zgadzaj, Anna; Parzonko, Andrzej; Syk?owska-Baranek, Katarzyna; Paradowska, Katarzyna; Na??cz-Jawecki, Grzegorz

    2015-12-25

    The aim of this study was to evaluate the antigenotoxic and antioxidant potential of shikonin (SH), acetylshikonin (ACS) and Arnebia euchroma callus extract (EXT). The antigenotoxic activity was investigated by the umu-test as the inhibition of the SOS system induction caused by genotoxic chemical agents - 4-nitroquinoline oxide and 2-aminoanthracene. Moreover the ability of SH, ACS and EXT to prevent photogenotoxicity triggered by chlorpromazine under UVA irradiation was measured. The cytotoxicity of EXT toward V79 Chinese hamster cell line was additionally assessed. Shikonin and acetylshikonin had no effect on 4-NQO induced genotoxicity whereas EXT demonstrated an unclear effect. The protection against 2AA induced genotoxicity was observed for all tested substances. The highest protection was demonstrated for EXT with inhibition of 66%. SH and ACS reduced 2AA genotoxicity with inhibition of about 60%. Under UVA the strongest and dose-dependent activity was observed for EXT. Acetylshikonin was a weak anti-photogenotoxin whereas shikonin had no clear effect. EXT was highly cytotoxic toward the V79 cell line - the cells' morphology was affected seriously and apoptosis was impacted. The antioxidant activity of SH, ACS and EXT was studied by means of electron paramagnetic resonance spectroscopy using 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical. All three samples exhibited radical scavenging properties. PMID:26434532

  7. Antimicrobial activities of active component isolated from Lawsonia inermis leaves and structure-activity relationships of its analogues against food-borne bacteria.

    PubMed

    Yang, Ji-Yeon; Lee, Hoi-Seon

    2015-04-01

    The antimicrobial activities of Lawsonia inermis leaf extract and 2-hydroxy-1,4-naphthoquinone analogues against food-borne bacteria. The antimicrobial activities of five fractions derived from the methanol extract of Lawsonia inermis leaves were evaluated against 7 food-borne bacteria. 2-Hydroxy-1,4-naphthoquinone was isolated by chromatographic analyses. 2-Hydroxy-1,4-naphthoquinone showed the strong activities against Bacillus cereus, Listeria monocytogenes, Salmonella enterica, Shigella sonnei, Staphylococcus epidermidis, and S. intermedius, but exerted no growth-inhibitory activities against S. typhimurium. The antimicrobial activities of the 2-hydroxy-1,4-naphthoquinone analogues were tested against 7 food-borne bacteria to establish structure-activity relationships. Hydroxyl (2-hydroxy-1,4-naphthoquinone and 5-hydroxy-1,4-naphthoquinone), methoxy (2-methoxy-1,4-naphthoquinone), and methyl (2-methyl-1,4-naphthoquinone, and 5-hydroxy-2-methyl-1,4-naphthoquinone) functional groups on the 1,4-naphthoquinone skeleton possessed potent activities, whereas bromo (2-bromo-1,4-naphthoquinone and 2,3-dibromo-1,4-naphthoquione) and chloro (2,3-dichloro-1,4-naphthoquinone) exhibited no activity against 7 food-borne bacteria. The L. inermis leaf extract and 2-hydroxy-1,4-naphthoquinone analogues should be useful as natural antimicrobial agents against food-borne bacteria. PMID:25829631

  8. DIFFERENTIATING MECHANISMS OF REACTIVE CHEMICAL TOXICITY IN ISOLATED TROUT HEPATOCYTES

    EPA Science Inventory

    The toxicity of four quinones, 2,3-dimethoxy-1,4-naphthoquinone (DMONQ), 2-methyl 1,4-naphthoquinone (MNQ ),1,4-naphthoquinone (NQ), and 1,4-benzoquinone (BQ), which redox cycle or arlyate in mammalian cells, was determined in isolated trout (Oncorhynchus mykiss) hepatocytes. Mor...

  9. ACTIVITY OF QUINONES ON COLLETOTRICHUM SPECIES

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The antifungal activity of 1,4-naphthoquinones, 1,2-naphthoquinones, 1,4-benzoquinones, anthraquinones, and other miscellaneous compounds from our natural products collection were tested by bioautography. Quinones demonstrated good to moderate antifungal activity against Colletotrichum spp. Collet...

  10. The Chemistry of Plant and Animal Dyes.

    ERIC Educational Resources Information Center

    Sequin-Frey, Margareta

    1981-01-01

    Provides a brief history of natural dyes. Chemical formulas are provided for flavonoids, luteolin, genistein, brazilin, tannins, terpenes, naphthoquinone, anthraquinone, and dyes with an alkaloid structure. Also discusses chemical background of different dye processes. (CS)

  11. 40 CFR Appendix Vii to Part 261 - Basis for Listing Hazardous Waste

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ...polycyclic aromatic hydrocarbons). K023 Phthalic anhydride, maleic anhydride. K024 Phthalic anhydride, 1,4-naphthoquinone. K025 ...K088 Cyanide (complexes). K093 Phthalic anhydride, maleic anhydride. K094...

  12. 40 CFR Appendix Vii to Part 261 - Basis for Listing Hazardous Waste

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ...polycyclic aromatic hydrocarbons). K023 Phthalic anhydride, maleic anhydride. K024 Phthalic anhydride, 1,4-naphthoquinone. K025 ...K088 Cyanide (complexes). K093 Phthalic anhydride, maleic anhydride. K094...

  13. 40 CFR Appendix Vii to Part 261 - Basis for Listing Hazardous Waste

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ...polycyclic aromatic hydrocarbons). K023 Phthalic anhydride, maleic anhydride. K024 Phthalic anhydride, 1,4-naphthoquinone. K025 ...K088 Cyanide (complexes). K093 Phthalic anhydride, maleic anhydride. K094...

  14. 40 CFR Appendix Vii to Part 261 - Basis for Listing Hazardous Waste

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ...polycyclic aromatic hydrocarbons). K023 Phthalic anhydride, maleic anhydride. K024 Phthalic anhydride, 1,4-naphthoquinone. K025 ...K088 Cyanide (complexes). K093 Phthalic anhydride, maleic anhydride. K094...

  15. 40 CFR Appendix Vii to Part 261 - Basis for Listing Hazardous Waste

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ...polycyclic aromatic hydrocarbons). K023 Phthalic anhydride, maleic anhydride. K024 Phthalic anhydride, 1,4-naphthoquinone. K025 ...K088 Cyanide (complexes). K093 Phthalic anhydride, maleic anhydride. K094...

  16. Atovaquone derivatives as potent cytotoxic and apoptosis inducing agents.

    PubMed

    Zhou, Jing; Duan, Lei; Chen, Huaming; Ren, Xiaomei; Zhang, Zhang; Zhou, Fengtao; Liu, Jinsong; Pei, Duanqing; Ding, Ke

    2009-09-01

    2-Piperazinyl naphthoquinones (2) and 2-piperidinyl naphthoquinones (3) were designed and synthesized as new cytotoxic and apoptosis inducing agents by utilizing the anti-parasite drug atovaquone as lead compound. Several compounds displayed significantly improved cytotoxic activities against a panel of cancer cell lines than that of atovaquone. These compounds also induced apoptosis through activating pro-apoptotic caspases 9 and 3. PMID:19632833

  17. In vitro Activation of heme oxygenase-2 by menadione and its analogs

    PubMed Central

    2014-01-01

    Background Previously, we reported that menadione activated rat, native heme oxygenase-2 (HO-2) and human recombinant heme oxygenase-2 selectively; it did not activate spleen, microsomal heme oxygenase-1. The purpose of this study was to explore some structure–activity relationships of this activation and the idea that redox properties may be an important aspect of menadione efficacy. Methods Heme oxygenase activity was determined in vitro using rat spleen and brain microsomes as the sources of heme oxygenase-1 and ?2, respectively, as well as recombinant, human heme oxygenase-2. Results Menadione analogs with bulky aliphatic groups at position-3, namely vitamins K1 and K2, were not able to activate HO-2. In contrast, several compounds with similar bulky but less lipophilic moieties at position-2 (and ?3) were able to activate HO-2 many fold; these compounds included polar, rigid, furan-containing naphthoquinones, furan-benzoxazine naphthoquinones, 2-(aminophenylphenyl)-3-piperidin-1-yl naphthoquinones. To explore the idea that redox properties might be involved in menadione efficacy, we tested analogs such as 1,4-dimethoxy-2-methylnaphthalene, pentafluoromenadione, monohalogenated naphthoquinones, ?-tetralone and 1,4-naphthoquinone. All of these compounds were inactive except for 1,4-naphthoquinone. Menadione activated full-length recombinant human heme oxygenase-2 (FL-hHO-2) as effectively as rat brain enzyme, but it did not activate rat spleen heme oxygenase. Conclusions These observations are consistent with the idea that naphthoquinones such as menadione bind to a receptor in HO-2 and activate the enzyme through a mechanism that may involve redox properties. PMID:24533775

  18. Cataractogenicity and bioactivation of naphthalene derivatives in lens culture and in vivo

    SciTech Connect

    Lubek, B.M.; Kubow, S.; Basu, P.K.; Wells, P.G. )

    1989-01-01

    The cataractogenicity of naphthalene derivatives was investigated in a lens culture system that included the lens with an intact capsule and epithelium. The in vivo cataractogenicity of naphthalene, 1000 or 2000 mg/kg ip, also was evaluated in New Zealand white and Chinchilla pigmented rabbits. A dose-related brunescence was observed in lenses incubated with 1,4-naphthoquinone in concentrations from 31.6 to 316 microM. With 316 microM naphthoquinone, lenses were totally opaque within 24 hr. No lenticular opacities were observed with 1-naphthol or 2-naphthol in incubations lasting up to 96 hr. The bioactivation of naphthalene derivatives to reactive free radical intermediates by lenses in organ culture was investigated by electron spin resonance spectrometry (ESR) using the spin trap alpha-phenyl-N-t-butylnitrone (PBN). Lenses were incubated with 316 microM naphthoquinone and 100 mM PBN for 0.25, 4 or 7 hr. A spin trapped radical product with unresolved peaks was observed with 0.25 and 7 hr incubation. No radicals were detected in the 4 hr incubation, nor in control cultures lacking either the lens, naphthoquinone or PBN. In the in vivo studies, naphthalene was cataractogenic in both albino and pigmented rabbits. The in vitro results indicate that naphthoquinone can be bioactivated by rabbit lens to a reactive free radical intermediate, which may contribute to cataractogenicity.

  19. Biologically Active Metabolites Produced by the Basidiomycete Quambalaria cyanescens

    PubMed Central

    Stod?lková, Eva; Císa?ová, Ivana; Kola?ík, Miroslav; Chudí?ková, Milada; Novák, Petr; Man, Petr; Kuzma, Marek; Pavl?, Barbora; ?erný, Jan; Flieger, Miroslav

    2015-01-01

    Four strains of the fungus Quambalaria cyanescens (Basidiomycota: Microstromatales), were used for the determination of secondary metabolites production and their antimicrobial and biological activities. A new naphthoquinone named quambalarine A, (S)-(+)-3-(5-ethyl-tetrahydrofuran-2-yliden)-5,7,8-trihydroxy-2-oxo-1,4-naphthoquinone (1), together with two known naphthoquinones, 3-hexanoyl-2,5,7,8-tetrahydroxy-1,4-naphthoquinone (named here as quambalarine B, 2) and mompain, 2,5,7,8-tetrahydroxy-1,4-naphthoquinone (3) were isolated. Their structures were determined by single-crystal X-ray diffraction crystallography, NMR and MS spectrometry. Quambalarine A (1) had a broad antifungal and antibacterial activity and is able inhibit growth of human pathogenic fungus Aspergillus fumigatus and fungi co-occurring with Q. cyanescens in bark beetle galleries including insect pathogenic species Beauveria bassiana. Quambalarine B (2) was active against several fungi and mompain mainly against bacteria. The biological activity against human-derived cell lines was selective towards mitochondria (2 and 3); after long-term incubation with 2, mitochondria were undetectable using a mitochondrial probe. A similar effect on mitochondria was observed also for environmental competitors of Q. cyanescens from the genus Geosmithia. PMID:25723150

  20. Directionality of electron transfer in cyanobacterial photosystem I at 298 and 77K.

    PubMed

    Makita, Hiroki; Hastings, Gary

    2015-06-01

    Electron transfer processes in cyanobacterial photosystem I particles from Synechocystis sp. PCC 6803 with a high potential naphthoquinone (2,3-dichloro-1,4-naphthoquinone) incorporated into the A1 binding site have been studied at 298 and 77K using time-resolved visible and infrared difference spectroscopy. The high potential naphthoquinone inhibits electron transfer past A1, and biphasic P700(+)A1(-) radical pair recombination is observed. The two phases are assigned to P700(+)A1B(-) and P700(+)A1A(-) recombination. Analyses of the transient absorption changes indicate that the ratio of A- and B-branch electron transfer is 95:5 at 77 K and 77:23 at 298 K. PMID:25962848

  1. Lactones and quinones from the tubers of Sinningia aggregata.

    PubMed

    Verdan, Maria Helena; Barison, Andersson; de Sá, Eduardo Lemos; Salvador, Marcos J; Poliquesi, Clarisse B; Eberlin, Marcos N; Stefanello, Maria Elida A

    2010-08-27

    Three new aromatic epsilon-lactones, aggregatins A (1), B (2), and C (3), a new naphthoquinone derivative, aggregatin D (4), and three known anthraquinones, 2-methylanthraquinone, 7-methoxy-2-methylanthraquinone, and 7-hydroxy-2-methylanthraquinone, were isolated from the tubers of Sinningia aggregata (Gesneriaceae). Compounds 1 and 4 and the anthraquinones showed marginal antimicrobial activity. PMID:20684540

  2. Microbial transformations of natural antitumor agents: oxidation of lapachol by Penicillium notatum.

    PubMed Central

    Otten, S; Rosazza, J P

    1978-01-01

    The naphthoquinone lapachol (1) is readily metabolized by several fungi and streptomycetes. Preparative-scale fermentations with Penicillium notatum (UI 1602) provided a major polar metabolite (4), which was isolated and identified as an intermediate of the Hooker oxidation. The metabolite was synthesized by reacting lapachol with hydrogen peroxide under alkaline conditions. PMID:637549

  3. Microbial transformations of natural antitumor agents: conversion of lapachol to dehydro-alpha-lapachone by Curvularia lunata.

    PubMed Central

    Otten, S; Rosazza, J P

    1979-01-01

    Microbial transformation of lapachol, a naturally occurring naphthoquinone, was carried out by Curvularia lunata (NRRL 2178). The fungus brings about oxidative cyclization of the substrate to dehydro-alpha-lapachone, which was isolated and characterized by nuclear magnetic resonance and mass spectral analyses; its structure was verified by chemical synthesis. The metabolite is a naturally occurring chromene possessing antibacterial and antitumor activities. PMID:574750

  4. Proc. Nati. Acad. Sci. USA Vol. 85, pp. 5374-5378, August 1988

    E-print Network

    Schnaufer, Achim

    (Trypanosoma cruzi/leishmaniasis/naphthoquinone/nitrofuran) GRAEME B. HENDERSON*t, PETER ULRICH*, ALAN H for biological activity against Trypano- soma cruzi trypomastigotes, many of the test compounds were trypanocidal cruzi, no generally effective chemotherapy currently exists for the millions of infected people (1

  5. Design and synthesis of propellane derivatives and oxa-bowls via ring-rearrangement metathesis as a key step

    PubMed Central

    Gunta, Rama

    2015-01-01

    Summary Various intricate propellane derivatives and oxa-bowls have been synthesized via a ring-rearrangement metathesis (RRM) as a key step starting from readily accessible starting materials such as p-benzoquinone, 1,4-naphthoquinone and 1,4-anthraquinone. PMID:26664592

  6. Comparative study of three Plumbago L. species (Plumbaginaceae) by microscopy, UPLC–UV and HPTLC analyses

    Technology Transfer Automated Retrieval System (TEKTRAN)

    This paper presents a comparative study of anatomy of leaves, stems and roots of three species of Plumbago, namely P. auriculata Lam., P. indica L. and P. zeylanica L. by light microscopy. The paper also provides qualitative and quantitative analysis of the naphthoquinone, plumbagin, a major constit...

  7. Quantum-chemical calculations and electron diffraction study of the equilibrium molecular structure of vitamin K3

    NASA Astrophysics Data System (ADS)

    Khaikin, L. S.; Tikhonov, D. S.; Grikina, O. E.; Rykov, A. N.; Stepanov, N. F.

    2014-05-01

    The equilibrium molecular structure of 2-methyl-1,4-naphthoquinone (vitamin K3) having C s symmetry is experimentally characterized for the first time by means of gas-phase electron diffraction using quantum-chemical calculations and data on the vibrational spectra of related compounds.

  8. Kinetic Phases in the Electron Transfer from P+ Associated Processes in Rhodobacter sphaeroides R-26 Reaction Centers

    E-print Network

    Gunner, Marilyn

    in Rhodobacter sphaeroides R-26 Reaction Centers Jiali Li, Dan Gilroy, David M. Tiede,§ and M. R. Gunner to form P+QAQB - was measured in Rhodobacter sphaeroides R-26 reaction centers (RCs) where the native primary quinone, ubiquinone-10 (UQA), was replaced by 2-methyl-3-phytyl-1,4-naphthoquinone (MQA

  9. Vitamin K

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Vitamin K was identified in the early 1930’s when it was shown to be essential for normal blood coagulation. Phylloquinone (2-methyl-3-phytyl-1,4-naphthoquinone) found in green plants is the major source of the vitamin. Large amounts of menaquinones with lengthy side chains are also synthesized in...

  10. DEFICIENCY IN PHYLLOQUINONE (VITAMIN K1) METHYLATION AFFECTS PRENYL QUINONE DISTRIBUTION PHOTOSYSTEM I ABUNDANCE AND ANTHOCYANIN ACCUMULATION IN THE ARABIDOPSIS AtmenG MUTANT

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Phylloquinone (vitamin K1) is synthesized in cyanobacteria and in chloroplasts of higher plants where it serves as electron carrier of photosystem I. The last step of phylloquinone synthesis in cyanobacteria is the methylation of 2-phytyl-1,4-naphthoquinone by the menG gene product. The gene encodin...

  11. Synthetic lapachol derivatives relax guinea-pig ileum by blockade of the voltage-gated calcium channels.

    PubMed

    Cavalcante, Fabiana de A; Monteiro, Fabio de S; Martins, Italo Rossi R; Barbosa, Ticiano P; Camara, Celso de A; Pinto, Angelo C; Vargas, Maria D; da Silva, Bagnólia A

    2010-01-01

    The present study was designed to further evaluate a possible spasmolytic activity of synthetic lapachol derivatives, norlapachol, alpha-norlapachone, beta-norlapachone and hydro-hydroxy-norlapachol (HH-norlapachol), on guinea-pig ileum. In guinea-pig ileum, except for norlapachol, all naphthoquinones inhibited the phasic contractions induced by carbachol or histamine. Even when the ileum was pre-contracted with KCl, carbachol or histamine, all naphthoquinones induced relaxation, suggesting that these naphthoquinones could be acting on the voltage-gated calcium channels (Ca(V)). As the tonic component this contraction is maintained mainly by the opening of the Ca(V), we hypothesized that these naphthoquinones might be acting on these channels. This hypothesis was confirmed by the observation that norlapachol (pD'2 = 4.99), alpha-norlapachone (pD'2 = 4.49), beta-norlapachone (pD'2 = 6.33), and HH-norlapachol (pD'2 = 4.53) antagonized the contractions induced by CaCl2 in depolarizing medium nominally without Ca2+. As beta-norlapachone was the most potent we decided to continue the study of its action mechanism. The fact that this naphthoquinone has inhibited the tonic contractions induced by S-(-)-Bay K8644 [EC50 = (1.6 +/- 0.30) x 10(-5) M] suggests that the Ca2+ channel involved belongs to the type L (Ca(V)1.2). In addition, in the functional level, the spasmolytic effect of beta-norlapachone does not involve participation of free radicals, since its curve of relaxation was unchanged in the presence of glutathione, an antioxidant agent. PMID:21138067

  12. Antibacterial activity of Tabebuia impetiginosa Martius ex DC (Taheebo) against Helicobacter pylori.

    PubMed

    Park, Byeoung-Soo; Lee, Hyun-Kyung; Lee, Sung-Eun; Piao, Xiang-Lan; Takeoka, Gary R; Wong, Rosalind Y; Ahn, Young-Joon; Kim, Jeong-Han

    2006-04-21

    The growth-inhibiting activity of Tabebuia impetiginosa Martius ex DC dried inner bark-derived constituents against Helicobacter pylori ATCC 43504 was examined using paper disc diffusion and minimum inhibitory concentration (MIC) bioassays. The activity of the isolated compounds was compared to that of the commercially available anti-Helicobacter pylori agents, amoxicillin, metronidazole, and tetracycline. The biologically active components of Tabebuia impetiginosa dried inner bark (taheebo) were characterized by spectroscopic analysis as 2-(hydroxymethyl)anthraquinone, anthraquinone-2-carboxylic acid, and 2-hydroxy-3-(3-methyl-2-butenyl)-1,4-naphthoquinone (lapachol). With the paper disc diffusion assay 2-(hydroxymethyl)anthraquinone exhibited strong activity against Helicobacter pylori ATCC 43504 at 0.01 mg/disc. Anthraquinone-2-carboxylic acid, lapachol and metronidazole were less effective, exhibiting moderate anti-Helicobacter pylori activity at 0.1 mg/disc. Amoxicillin and tetracycline were the most potent compounds tested, displaying very strong activity at 0.005 mg/disc. 2-(Hydroxymethyl)anthraquinone exhibited moderate activity at this dose. Tetracycline still had strong activity at 0.001 mg/disc while amoxicillin had little activity at this dose. In the MIC bioassay, 2-(hydroxymethyl)anthraquinone (2 microg/mL), anthraquinone-2-carboxylic acid (8 microg/mL), and lapachol (4 microg/mL) were more active than metronidazole (32 microg/mL) but less effective than amoxicillin (0.063 microg/mL) and tetracycline (0.5 microg/mL). The anti-Helicobacter pylori activity of seven 1,4-naphthoquinone derivatives (structurally related to lapachol), 1,4-naphthoquinone, 5,8-dihydroxy-1,4-naphthoquinone (naphthazarin), 2-methyl-1,4-naphthoquinone (menadione), 2-hydroxy-1,4-naphthoquinone (lawsone), 5-hydroxy-2-methyl-1,4-naphthoquinone (plumbagin), 5-hydroxy-1,4-naphthoquinone (juglone), and 2,3-dichloro-1,4-naphthoquinone (dichlone) was also evaluated using the paper disc assay. Menadione and plumbagin were the most potent compounds tested with the later still exhibiting very strong activity at 0.001 mg/disc. Menadione, juglone and tetracycline had strong activity at this low dose while the latter two compounds and amoxicillin had very strong activity at 0.005 mg/disc. Lawsone was unusual in that it had very strong activity at 0.1 and 0.05 mg/disc but weak activity at doses of 0.01 mg/disc and lower. Naphthazalin, lapachol and dichlone had similar activities while metronidazole had the lowest activity of all compounds tested. These results may be an indication of at least one of the pharmacological actions of taheebo. The Tabebuia impetiginosa dried inner bark-derived materials, particularly 2-(hydroxymethyl)anthraquinone, merit further study as potential Helicobacter pylori eradicating agents or lead compounds. PMID:16359837

  13. Toxicological assessment of beta-lapachone on organs from pregnant and non-pregnant rats.

    PubMed

    de Almeida, Edvaldo Rodrigues; Lucena, Flávia Raquel Santos; Silva, Camilla Vila Nova Soares; da Silva Costa-Junior, Wilson; Cavalcanti, Jouse Bezerra; Couto, Gerald Bosco Lindoso; da Silva, Luiz Lúcio Soares; da Mota, Diógenes Luís; da Silveira, Alex Benício; de Sousa Filho, Samuel Daniel; da Silva, Aldo Cezar Passilongo

    2009-09-01

    Naphthoquinones have been studied extensively due to their activity as topoisomerase inhibitors. These enzymes are critical to DNA replication in cells. beta-Lapachone (beta-lap) is an o-naphthoquinone chemically obtained from lapachol. This work results in a toxicological evaluation of beta-lap in Wistar rats observing the following parameters: teratology, histology, hematology and serum biochemistry. The data demonstrate teratogenic action at the doses used, as well as hematological alterations in the total leukocytes, monocytes and segmented. The biochemical data demonstrated an increase in gamma glutamyl transferase, alkaline phosphatase and glutamate pyruvate transaminase levels. Histological study showed significant alterations in the spleen, however, the liver and kidney did not present significant alterations. PMID:19197915

  14. Anti-diabetic activity of active fractions of Stereospermum tetragonum DC and isolation of active principles

    PubMed Central

    Bino Kingsley, Renjit; Mishra, Manisha; Brindha, Pemaiah; Subramoniam, Appian

    2013-01-01

    Objectives To identify the active principles, determine the anti-diabetes activity of fraction of Stereospermum tetragonum root. Materials and Methods The efficacy was evaluated in streptozotocin induced type 2 diabetic rats and the anti-hyperglycemic activity was studied by glucose tolerance test. The major active compounds were isolated by solvent fractionation and chromatographic techniques and characterized with spectral data. Results The active fraction of S. tetragonum showed presence of anti-diabetes mellitus activity in type-2 diabetic rats. It did not significantly influence insulin release from cultured islets. Two active principles (active at 2 mg/kg dose) were isolated and characterized with spectral data. One of them was identified as an iridoid type glycoside and the other one was a lapachol like compound (derivative of naphthoquinone). Conclusions Two active principles from the anti-diabetes fraction of S. tetragonum root were isolated and identified as an iridoid glycoside and a naphthoquinone derivative. PMID:24023445

  15. Synthesis and Spectroscopic Characterization of High-Spin Mononuclear Iron(II) p-Semiquinonate Complexes

    PubMed Central

    2015-01-01

    Two mononuclear iron(II) p-semiquinonate (pSQ) complexes have been generated via one-electron reduction of precursor complexes containing a substituted 1,4-naphthoquinone ligand. Detailed spectroscopic and computational analysis confirmed the presence of a coordinated pSQ radical ferromagnetically coupled to the high-spin FeII center. The complexes are intended to model electronic interactions between (semi)quinone and iron cofactors in biology. PMID:25393154

  16. Larvicidal activity of Cybistax antisyphilitica against Aedes aegypti larvae.

    PubMed

    Rodrigues, A M S; de Paula, J E; Roblot, F; Fournet, A; Espíndola, L S

    2005-12-01

    The larvicidal activity against Aedes aegypti larvae of a stem wood hexane extract of Cybistax antisyphilitica was evaluated. Bioassay-guided fractionation of the crude extract, monitored by larvicidal assay, led to the isolation of a natural quinone identified as 2-hydroxy-3-(3-methyl-2-butenyl)-1.4-naphthoquinone (lapachol). This compound was quite potent against A. aegypti larvae (LC50 26.3 microg/ml). PMID:16229968

  17. Growth inhibitory activity for cancer cell lines of lapachol and its natural and semi-synthetic derivatives.

    PubMed

    Fiorito, Serena; Epifano, Francesco; Bruyère, Céline; Mathieu, Véronique; Kiss, Robert; Genovese, Salvatore

    2014-01-15

    A series of 17 selected natural and semisynthetic 1,4-naphthoquinones were synthesized, and their growth inhibitory activity was evaluated in vitro. The compounds were tested on six human cancer cell lines using the MTT colorimetric assay. The data revealed that of the chemicals under study only lapachol, its acetate and 3-geranyllawsone displayed the highest activity, recording mean IC50 values ranging from 15 to 22 ?M. PMID:24374273

  18. Synthesis and pharmacological activity of diterpenylnaphthoquinone derivatives.

    PubMed

    Pertino, Mariano Walter; Theoduloz, Cristina; Palenzuela, Jose Antonio; Afonso, Maria del Mar; Yesilada, Erdem; Monsalve, Francisco; González, Paulo; Droguett, Daniel; Schmeda-Hirschmann, Guillermo

    2011-01-01

    New diterpenylquinones, combining a diterpene diacid and a naphthoquinone, were prepared from junicedric acid and lapachol. The new derivatives were assessed as gastroprotective agents by the HCl-EtOH-induced gastric lesions model in mice as well as for basal cytotoxicity on the following human cell lines: Normal lung fibroblasts (MRC-5), gastric epithelial adenocarcinoma (AGS), and hepatocellular carcinoma (Hep G2). Several of the new compounds were significantly active as antiulcer agents and showed selective cytotoxicity against AGS cells. PMID:21996716

  19. -GAB and pH Dependence of the Electron Transfer from P+ in Rhodobacter sphaeroides Reaction Centers

    E-print Network

    Gunner, Marilyn

    -G°AB and pH Dependence of the Electron Transfer from P+ QA - QB to P+ QAQB - in Rhodobacter+QA -QB and P+QAQB - states (-G°AB) and on the pH was measured using naphthoquinones with different RCs with ubiquinone as QA. The fast phase, 1, is pH independent from pH 6 to 11 while 2 slows above pH

  20. Airborne quinones induce cytotoxicity and DNA damage in human lung epithelial A549 cells: the role of reactive oxygen species.

    PubMed

    Shang, Yu; Zhang, Ling; Jiang, Yuting; Li, Yi; Lu, Ping

    2014-04-01

    Ambient particulate matter (PM) is associated with adverse health effects. Quinones present in PM are hypothesized to contribute to these harmful effects through the generation of reactive oxygen species (ROS). However, whether the ROS induced by quinones is involved in mediating DNA damage as well as other biological responses in pulmonary cells is less well known. In this study, the toxic effects of five typical airborne quinones, including 1,2-naphthoquinone, 2-methylanthraquinone, 9,10-phenanthrenequinone, 2-methyl-1,4-naphthoquinone, and acenaphthenequinone, on cytotoxicity, DNA damage, intracellular calcium homeostasis, and ROS generation, were studied in human lung epithelial A549 cells. An antioxidant N-acetylcysteine (NAC) was used to examine the involvement of ROS in adverse biological responses induced by quinones. The quinones caused a concentration-dependent viability decrease, cellular LDH release, DNA damage, and ROS production in A549 cells. 1,2-Naphthoquinone, but not the other four quinones, increased intracellular calcium (Ca(2+)) levels in a dose-dependent manner. These toxic effects were abolished by administration of NAC, suggesting that ROS played a key role in the observed toxic effects of quinones in A549 cells. These results emphasize the importance of quinones in PM on the adverse health effects of PMs, which has been underestimated in the past few years, and highlight the need, when evaluating the effects on health and exposure management, to always consider their qualitative chemical compositions in addition to the size and concentration of PMs. PMID:24480427

  1. Blood shizonticidal activities of phenazines and naphthoquinoidal compounds against Plasmodium falciparum in vitro and in mice malaria studies

    PubMed Central

    de Souza, Nicolli Bellotti; de Andrade, Isabel M; Carneiro, Paula F; Jardim, Guilherme AM; de Melo, Isadora MM; da Silva, Eufrânio N; Krettli, Antoniana Ursine

    2014-01-01

    Due to the recent advances of atovaquone, a naphthoquinone, through clinical trials as treatment for malarial infection, 19 quinone derivatives with previously reported structures were also evaluated for blood schizonticide activity against the malaria parasite Plasmodium falciparum. These compounds include 2-hydroxy-3-methylamino naphthoquinones (2-9), lapachol (10), nor-lapachol (11), iso-lapachol (12), phthiocol (13) and phenazines (12-20). Their cytotoxicities were also evaluated against human hepatoma and normal monkey kidney cell lines. Compounds 2 and 5 showed the highest activity against P. falciparum chloroquine-resistant blood-stage parasites (clone W2), indicated by their low inhibitory concentration for 50% (IC50) of parasite growth. The therapeutic potential of the active compounds was evaluated according to the selectivity index, which is a ratio of the cytotoxicity minimum lethal dose which eliminates 50% of cells and the in vitro IC50. Naphthoquinones 2 and 5, with activities similar to the reference antimalarial chloroquine, were also active against malaria in mice and suppressed parasitaemia by more than 60% in contrast to compound 11 which was inactive. Based on their in vitro and in vivo activities, compounds 2 and 5 are considered promising molecules for antimalarial treatment and warrant further study. PMID:25099332

  2. Novel rearranged abietane diterpenoids from the roots of Salvia sahendica.

    PubMed

    Jassbi, Amir Reza; Mehrdad, Morteza; Eghtesadi, Farrokh; Ebrahimi, Samad Nejad; Baldwin, Ian T

    2006-08-01

    Two naphthoquinone diterpenoids, 1 and 2, one tricyclic, and one tetracyclic rearranged abietane ('4,5-seco-10,5-friedo-abietane') diterpenoids, 3 and 4, respectively, together with horminone (5) have been isolated from the roots of Salvia sahendica. Compounds 2 and 3 are new, and the 13C-NMR assignment for compound 4 was modified using ' Heteronuclear Multiple-Bond Correlation' (HMBC) spectroscopic data. The structures of the compounds have been established by using different spectral data including 1D- and 2D-NMR, IR, UV, and MS. The elemental composition for the major peaks of 3 and 4 were determined by ' High-Resolution Electron Impact Mass Spectrometry' (HR-EI-MS). The relative configurations of the new compounds were determined by 1H-NMR and 'Rotating-Frame NOES' (ROESY) spectroscopy. Compounds 1, 2, and 5 showed antifungal activities when tested on Blakeslea trispora. Lapachol, a prelynated naphthoquinone, was used as a positive control. The biological activities of the related naphthoquinones and abietane diterpenoids were discussed. PMID:17193322

  3. Blood shizonticidal activities of phenazines and naphthoquinoidal compounds against Plasmodium falciparum in vitro and in mice malaria studies.

    PubMed

    de Souza, Nicolli Bellotti; de Andrade, Isabel M; Carneiro, Paula F; Jardim, Guilherme A M; de Melo, Isadora M M; da Silva Júnior, Eufrânio N; Krettli, Antoniana Ursine

    2014-08-01

    Due to the recent advances of atovaquone, a naphthoquinone, through clinical trials as treatment for malarial infection, 19 quinone derivatives with previously reported structures were also evaluated for blood schizonticide activity against the malaria parasite Plasmodium falciparum. These compounds include 2-hydroxy-3-methylamino naphthoquinones (2-9), lapachol (10), nor-lapachol (11), iso-lapachol (12), phthiocol (13) and phenazines (12-20). Their cytotoxicities were also evaluated against human hepatoma and normal monkey kidney cell lines. Compounds 2 and 5 showed the highest activity against P. falciparum chloroquine-resistant blood-stage parasites (clone W2), indicated by their low inhibitory concentration for 50% (IC50) of parasite growth. The therapeutic potential of the active compounds was evaluated according to the selectivity index, which is a ratio of the cytotoxicity minimum lethal dose which eliminates 50% of cells and the in vitro IC50. Naphthoquinones 2 and 5, with activities similar to the reference antimalarial chloroquine, were also active against malaria in mice and suppressed parasitaemia by more than 60% in contrast to compound 11 which was inactive. Based on their in vitro and in vivo activities, compounds 2 and 5 are considered promising molecules for antimalarial treatment and warrant further study. PMID:25099332

  4. Development of a test system for screening toxic substances: a comparison using organic substances

    SciTech Connect

    Thomas, C.L.

    1985-01-01

    The purpose of this research was to develop a test system for screening toxic substances by predicting their aquatic ecosystem effects. The system studied was a static, one liter microcosm with a diverse species assemblage. The microcosm was composed of biotic inoculum, chemically defined medium and sediment. The biotic inoculum contained primary producers, grazers, carnivores and decomposers. Three different types of sediment were studied: sand, clay, and clay plus sand. Four organic chemicals: phenol, triethylene glycol (TEG), quinoline and naphthoquinone were evaluated with this test system. The toxicities of TEG, quinoline and naphthoquinone were compared for each sediment type. Toxicity was evaluated in terms of the chemical's effects on primary productivity and heterotrophic activity though other effects are also noted. Naphthoquinone concentration exhibited no correlation between ecosystem property values and therefore, could not be ranked. Phenol exhibited the greatest toxicity to net production immediately after the toxicant addition. Quinoline was most toxic to net production over the longer time scale. TEG exhibited the least toxicity to net production, however, TEG exhibited higher toxicity to heterotrophic activity than either quinoline or phenol. Although the type of sediment used in the microcosms did not change the relative toxicities of the chemicals, the microcosms with clay sediment always were observed to exhibit lower net production and higher variability.

  5. Selected phytotoxins and organic extracts from endophytic fungus Edenia gomezpompae as light reaction of photosynthesis inhibitors.

    PubMed

    Macías-Rubalcava, Martha Lydia; Ruiz-Velasco Sobrino, María Emma; Meléndez-González, Claudio; King-Díaz, Beatriz; Lotina-Hennsen, Blas

    2014-09-01

    In a search for natural herbicides, we investigated the action mechanism of the naphthoquinone spiroketals, isolated from the endophytic fungus Edenia gomezpompae: preussomerins EG1 (1) and EG4 (2), and palmarumycins CP17 (3), and CP2 (4) on the photosynthesis light reactions. The naphthoquinone spiroketals 1-4 inhibited the ATP synthesis in freshly lysed spinach thylakoids from water to MV, and they also inhibited the non-cyclic electron transport in the basal, phosphorylating and uncoupled conditions from water to MV. Therefore, they act as Hill reaction inhibitors. The results suggested that naphthoquinone spiroketals 1-4 have two interactions and inhibition site on the PSII electron transport chain. The first one involves the water splitting enzyme inhibition; and, the second on the acceptor site of PSII in a similar way that herbicide Diuron, studied by polaroghaphy and corroborated by fluorescence of the chlorophyll a of PSII. The culture medium and mycelium organic extracts from four morphological variants of E. gomezpompae were phytotoxic, and the culture medium extracts were more potent than mycelium extracts. They also act as Hill reaction inhibitors. PMID:24911268

  6. Computational Optimization of Bioanalytical Parameters for the Evaluation of the Toxicity of the Phytomarker 1,4 Napthoquinone and its Metabolite 1,2,4-trihydroxynapththalene

    PubMed Central

    Gopal, Velmani; AL Rashid, Mohammad Harun; Majumder, Sayani; Maiti, Partha Pratim; Mandal, Subhash C

    2015-01-01

    Objectives: Lawsone (1,4 naphthoquinone) is a non redox cycling compound that can be catalyzed by DT diaphorase (DTD) into 1,2,4-trihydroxynaphthalene (THN), which can generate reactive oxygen species by auto oxidation. The purpose of this study was to evaluate the toxicity of the phytomarker 1,4 naphthoquinone and its metabolite THN by using the molecular docking program AutoDock 4. Methods: The 3D structure of ligands such as hydrogen peroxide (H2O2), nitric oxide synthase (NOS), catalase (CAT), glutathione (GSH), glutathione reductase (GR), glucose 6-phosphate dehydrogenase (G6PDH) and nicotinamide adenine dinucleotide phosphate hydrogen (NADPH) were drawn using hyperchem drawing tools and minimizing the energy of all pdb files with the help of hyperchem by MM+ followed by a semi-empirical (PM3) method. The docking process was studied with ligand molecules to identify suitable dockings at protein binding sites through annealing and genetic simulation algorithms. The program auto dock tools (ADT) was released as an extension suite to the python molecular viewer used to prepare proteins and ligands. Grids centered on active sites were obtained with spacings of 54 × 55 × 56, and a grid spacing of 0.503 was calculated. Comparisons of Global and Local Search Methods in Drug Docking were adopted to determine parameters; a maximum number of 250,000 energy evaluations, a maximum number of generations of 27,000, and mutation and crossover rates of 0.02 and 0.8 were used. The number of docking runs was set to 10. Results: Lawsone and THN can be considered to efficiently bind with NOS, CAT, GSH, GR, G6PDH and NADPH, which has been confirmed through hydrogen bond affinity with the respective amino acids. Conclusion: Naphthoquinone derivatives of lawsone, which can be metabolized into THN by a catalyst DTD, were examined. Lawsone and THN were found to be identically potent molecules for their affinities for selected proteins. PMID:26120483

  7. Measurement of Protein Tyrosine Phosphatase Activity in Single Cells by Capillary Electrophoresis

    PubMed Central

    Phillips, Ryan M.; Bair, Eric; Lawrence, David S.; Sims, Christopher E.; Allbritton, Nancy L.

    2013-01-01

    A fluorescent peptide substrate was used to measure dephosphorylation by protein tyrosine phosphatases (PTP) in cell lysates, and single cells and to investigate the effect of environmental toxins on PTP activity in these systems. Dephosphorylation of the substrate by PTPN1 and PTPN2 obeyed Michaelis-Menten kinetics, with KM values of 770 ± 250 nM and 290 ± 54 nM, respectively. Dose-response curves and IC50 values were determined for the inhibition of these two enzymes by the environmental toxins Zn2+ and 1,2-naphthoquinone, as well as pervanadate. In A431 cell lysates, the reporter was a poor substrate for peptidases (degradation rate of 100 ± 8.2 fmol min?1 mg?1) but an excellent substrate for phosphatases (dephosphorylation rate of 1.4 ± 0.3 nmol min?1 mg?1). Zn2+, 1,2-naphthoquinone and pervanadate inhibited dephosphorylation of the reporter in cell lysates with IC50 values of 470 nM, 35 ?M, and 100 nM, respectively. Dephosphorylation of the reporter following loading into living single cells occurred at rates of at least 2 pmol min?1 mg?1. When single cells were exposed to 1,2-naphthoquinone (50 ?M), Zn2+ (100 ?M), and pervandate (1 mM), dephosphorylation was inhibited with median values and first and third quartile values of 41 (Q1 = 0%, Q3 = 96%), 50 (Q1 = 46%, Q3 = 74%), and 53% (Q1 = 36%, Q3 = 77%), respectively, demonstrating both the impact of these toxic exposures on cell signaling and the heterogeneity of response between cells. This approach will provide a valuable tool for the study of PTP dynamics, particularly in small, heterogeneous populations such as human biopsy specimens. PMID:23682679

  8. Nanometric layers for direct, signal-on, selective, and sensitive electrochemical detection of oligonucleotides hybridization.

    PubMed

    March, Grégory; Noël, Vincent; Piro, Benoît; Reisberg, Steeve; Pham, Minh-Chau

    2008-11-26

    We report a signal-on, reagentless electrochemical DNA biosensor, based on an electroactive self-assembled naphthoquinone derivative (JUG(thio)) monolayer. This system achieves highly sensitive (approximately 300 pM) and selective signal-on detection. Before hybridization, the single strand can interact with JUG(thio) and slow down the redox reaction. When the complementary target is added, the formation of the double helix eliminates the single strand/JUG(thio) interactions and the JUG(thio) redox rate, and hence the current increase. PMID:18973298

  9. Magnetic Field Effect: An Efficient Tool To Investigate The Mechanism Of Reactions Using Laser Flash Photolysis Technique

    SciTech Connect

    Basu, Samita; Bose, Adity; Dey, Debarati

    2008-04-24

    Magnetic field effect combined with laser flash photolysis technique have been used to study the mechanism of interactions between two drug-like quinone molecules, Menadione (1,4-naphthoquinone, MQ) and 9, 10 Anthraquinone (AQ) with one of the DNA bases, Adenine in homogeneous acetonitrile/water and heterogeneous micellar media. A switchover in reaction mode from electron transfer to hydrogen abstraction is observed with MQ on changing the solvent from acetonitrile/water to micelle; whereas, AQ retains its mode of interaction towards Adenine as electron transfer in both the media due to its bulky structure compared to MQ.

  10. Microwave-assisted rapid cyclization of lapachol, a main constituent of Heterophragma adenophyllum.

    PubMed

    Singh, P; Natani, K; Jain, S; Arya, K; Dandia, A

    2006-02-01

    Cyclization reactions of lapachol (1) isolated from Heterophragma adenophyllum have been studied under microwave irradiation under different conditions using alumina (acidic, basic and neutral)/silica gel/montmorillonite (KSF and K-10) as solid support along with neat reaction using 2-3 drops of DMF giving naturally occurring dehydro-alpha-lapachone (2), alpha-lapachone (3), beta-lapachone (4) depending upon the nature of support and irradiation time. A novel naphthoquinone derivative adenophyllone (5) can be synthesized from lapachol using DMF under microwaves. PMID:16496478

  11. Analysis of Diazofluorene DNA Binding and Damaging Activity. DNA Cleavage by a Synthetic Monomeric Diazofluorene

    PubMed Central

    Woo, Christina M.; Ranjan, Nihar; Arya, Dev P.; Herzon, Seth B.

    2014-01-01

    The lomaiviticins and kinamycins are complex DNA damaging natural products that contain a diazofluorene functional group. Herein, we elucidate the influence of skeleton structure, ring and chain isomerization, D-ring oxidation state, and naphthoquinone substitution on DNA binding and damaging activity. We show that the electrophilicity of the diazofluorene appears to be the most significant determinant of DNA damaging activity. These studies identify the monomeric diazofluorene 11 as a potent DNA cleavage agent in tissue culture. The simpler structure of 11 relative to the natural products establishes it as a useful lead for translational studies. PMID:25044348

  12. Synthesis of benzo[f]isoindole-4,9-diones.

    PubMed

    Claessens, Sven; Jacobs, Jan; Van Aeken, Sam; Tehrani, Kourosch Abbaspour; De Kimpe, Norbert

    2008-10-01

    A synthesis of benzo[f]isoindole-4,9-diones 1 is presented starting from the reaction of 2,3-bis(bromomethyl)-1,4-dimethoxynaphthalene 15 with primary amines affording 2,3-bis(aminomethyl)-1,4-dimethoxynaphthalenes 14, which could be converted by CAN-mediated oxidation in one step to benzo[f]isoindole-4,9-diones 1. An alternative synthesis of benzo[f]isoindole-4,9-diones 1 starts from 2,3-bis(bromomethyl)-1,4-naphthoquinone 9 via 2,3-dihydrobenzo[f]isoindoles 10 which spontaneously oxidize. PMID:18774861

  13. Synergistic TRAIL sensitizers from Barleria alluaudii and Diospyros maritima.

    PubMed

    Whitson, Emily L; Sun, Han; Thomas, Cheryl L; Henrich, Curtis J; Sayers, Thomas J; McMahon, James B; Griesinger, Christian; McKee, Tawnya C

    2012-03-23

    Barleria alluaudii and Diospyros maritima were both investigated as part of an ongoing search for synergistic TRAIL (tumor necrosis factor-?-related apoptosis-inducing ligand) sensitizers. As a result of this study, two naphthoquinone epoxides, 2,3-epoxy-2,3-dihydrolapachol (1) and 2,3-epoxy-2,3-dihydro-8-hydroxylapachol (2), both not previously isolated from natural sources, and the known 2-methylanthraquinone (3) were identified from B. alluaudii. Time-dependent density functional theory (TD-DFT) calculations of electronic circular dichroism (ECD) spectra were utilized to establish the absolute configuration of 1 and 2. Additionally, five known naphthoquinone derivatives, maritinone (4), elliptinone (5), plumbagin (6), (+)-cis-isoshinanolone (7), and ethylidene-6,6'-biplumbagin (8), were isolated from D. maritima. Compounds 1, 2, and 4-6 showed varying levels of synergy with TRAIL. Maritinone (4) and elliptinone (5) showed the highest synergistic effect, with more than a 3-fold increase in activity observed with TRAIL than with compound alone. PMID:22313254

  14. Synergistic TRAIL sensitizers from Barleria alluaudii and Diospyros maritima#

    PubMed Central

    Whitson, Emily L.; Sun, Han; Thomas, Cheryl L.; Henrich, Curtis J.; Sayers, Thomas J.; McMahon, James B.; Griesinger, Christian; McKee, Tawnya C.

    2012-01-01

    Barleria alluaudii and Diospyros maritima were both investigated as part of an ongoing search for synergistic TRAIL (tumor necrosis factor-?-related apoptosis-inducing ligand) sensitizers. As a result of this study, two naphthoquinone epoxides, 2,3-epoxy-2,3-dihydrolapachol (1) and 2,3-epoxy-2,3-dihydro-8-hydroxylapachol (2), both not previously isolated from natural sources, and the known 2-methyl anthraquinone (3) were identified from B. alluaudii. Time-dependent density functional theory (TD-DFT) calculations of electronic circular dichroism (ECD) spectra were utilized to establish the absolute configuration of 1 and 2. Additionally, five known naphthoquinone derivatives, maritinone (4), elliptinone (5), plumbagin (6), (+)-cis-isoshinanolone (7), and ethylidene-6,6?-biplumbagin (8) were isolated from D. maritima. Compounds 1, 2, and 4–6 showed varying levels of synergy with TRAIL. Maritinone (4) and elliptinone (5) showed the highest synergistic effect, with more than a three-fold increase in activity observed with TRAIL than with compound alone. PMID:22313254

  15. Rates of Hydroxyl Radical Production from Transition Metals and Quinones in a Surrogate Lung Fluid.

    PubMed

    Charrier, Jessica G; Anastasio, Cort

    2015-08-01

    Hydroxyl radical ((•)OH) is the most reactive, and perhaps most detrimental to health, of the reactive oxygen species. (•)OH production in lungs following inhalation of particulate matter (PM) can result from redox-active chemicals, including iron and copper, but the relative importance of these species is unknown. This work investigates (•)OH production from iron, copper, and quinones, both individually and in mixtures at atmospherically relevant concentrations. Iron, copper, and three of the four quinones (1,2-naphthoquinone, phenanthrenequinone and 1,4-naphthoquinone) produce (•)OH. Mixtures of copper or quinones with iron synergistically produce (•)OH at a rate 20-130% higher than the sum of the rates of the individual redox-active species. We developed a regression equation from 20 mixtures to predict the rate of (•)OH production from the particle composition. For typical PM compositions, iron and copper account for most (•)OH production, whereas quinones are a minor source, although they can contribute if present at very high concentrations. This work shows that Cu contributes significantly to (•)OH production in ambient PM; other work has shown that Cu appears to be the primary driver of HOOH production and dithiothreitol (DTT) loss in ambient PM extracts. Taken together, these results indicate that copper appears to be the most important individual contributor to direct oxidant production from inhaled PM. PMID:26153923

  16. Single crystal X-ray structure of Lawsone anion: Evidence for coordination of alkali metal ions and formation of naphthosemiquinone radical in basic media

    NASA Astrophysics Data System (ADS)

    Salunke-Gawali, Sunita; Kathawate, Laxmi; Shinde, Yogesh; Puranik, Vedavati G.; Weyhermüller, Thomas

    2012-02-01

    2-hydroxy-1,4-naphthoquinone; Lawsone (Lw) is a natural compound found in henna leaves. The reaction of lawsone with 'Na' metal (Lw-1), CH3COONa (Lw-2), NaOH (Lw-3), KOH (Lw-4), K2CO3 (Lw-5) and Tris(hydroxymethyl)aminomethane (Lw-6) were studied. Red orange solids obtained for Lw-1 to Lw-6 are characterized by Elemental Analysis, FTIR, 1HNMR and EPR studies. The results reveal the coordination of alkali metals 'Na' and 'K' to lawsone anion. The single crystal X-ray structure of Lw-6 was solved and it crystallizes in triclinic space group P-1 with extensive hydrogen bonding network of Csbnd H⋯O, Nsbnd H⋯O and Osbnd H⋯O between cations and anions. Polycrystalline powder X-band EPR spectra of Lw-1 to Lw-5 shows signals ˜2.004 at 133 K, while Lw-6 is EPR silent. The naphthosemiquinone (NSQ-rad ) radical formed in Lw-2 to Lw-5, is due to disproportion reaction of catechol and naphthoquinone.

  17. Pigment Cell Differentiation in Sea Urchin Blastula-Derived Primary Cell Cultures

    PubMed Central

    Ageenko, Natalya V.; Kiselev, Konstantin V.; Dmitrenok, Pavel S.; Odintsova, Nelly A.

    2014-01-01

    The quinone pigments of sea urchins, specifically echinochrome and spinochromes, are known for their effective antioxidant, antibacterial, antifungal, and antitumor activities. We developed in vitro technology for inducing pigment differentiation in cell culture. The intensification of the pigment differentiation was accompanied by a simultaneous decrease in cell proliferation. The number of pigment cells was two-fold higher in the cells cultivated in the coelomic fluids of injured sea urchins than in those intact. The possible roles of the specific components of the coelomic fluids in the pigment differentiation process and the quantitative measurement of the production of naphthoquinone pigments during cultivation were examined by MALDI and electrospray ionization mass spectrometry. Echinochrome A and spinochrome E were produced by the cultivated cells of the sand dollar Scaphechinus mirabilis in all tested media, while only spinochromes were found in the cultivated cells of another sea urchin, Strongylocentrotus intermedius. The expression of genes associated with the induction of pigment differentiation was increased in cells cultivated in the presence of shikimic acid, a precursor of naphthoquinone pigments. Our results should contribute to the development of new techniques in marine biotechnology, including the generation of cell cultures producing complex bioactive compounds with therapeutic potential. PMID:24979272

  18. Combination of chiroptical, absorption and fluorescence spectroscopic methods reveals multiple, hydrophobicity-driven human serum albumin binding of the antimalarial atovaquone and related hydroxynaphthoquinone compounds.

    PubMed

    Zsila, Ferenc; Fitos, Ilona

    2010-11-01

    High-affinity human serum albumin (HSA) binding of the C3-substituted antimalarial 2-hydroxy-1,4-naphthoquinone derivative atovaquone (ATQ) has been demonstrated and studied by circular dichroism (CD), UV/VIS absorption, fluorescence spectroscopy and affinity chromatography methods. The analysis of induced CD data generated upon HSA binding of ATQ revealed two high-affinity binding sites (K(a) ? 2 × 10(6) M(-1)). CD interaction studies and displacement of specific fluorescent and radioactive marker ligands indicated the contribution of both principal drug binding sites of HSA to complexation of ATQ, and also suggested the possibility of simultaneous binding of ATQ and some other drugs (e.g. warfarin, phenylbutazone, diazepam). Comparison of UV/VIS spectra of ATQ measured in aqueous solutions indicated the prevalence of the anionic species formed by dissociation of the 2-hydroxyl group. HSA binding of related natural hydroxynaphthoquinones, lapachol and lawsone also induces similar CD spectra. The much weaker binding affinity of lawsone (K(a) ? 10(4) M(-1)) bearing no C3 substituent highlights the importance of hydrophobic interactions in the strong HSA binding of ATQ and lapachol. Since neither drug exhibited significant binding to serum ?(1)-acid glycoprotein, HSA must be the principal plasma protein for the binding and transportation of 2-hydroxy-1,4-naphthoquinone-type compounds which are ionized at physiological pH values. PMID:20737064

  19. Pyrone polyketides synthesized by a type III polyketide synthase from Drosophyllum lusitanicum.

    PubMed

    Jindaprasert, Aphacha; Springob, Karin; Schmidt, Jürgen; De-Eknamkul, Wanchai; Kutchan, Toni M

    2008-12-01

    To isolate cDNAs involved in the biosynthesis of acetate-derived naphthoquinones in Drosophyllum lusitanicum, an expressed sequence tag analysis was performed. RNA from callus cultures was used to create a cDNA library from which 2004 expressed sequence tags were generated. One cDNA with similarity to known type III polyketide synthases was isolated as full-length sequence and termed DluHKS. The translated polypeptide sequence of DluHKS showed 51-67% identity with other plant type III PKSs. Recombinant DluHKS expressed in Escherichia coli accepted acetyl-coenzyme A (CoA) as starter and carried out sequential decarboxylative condensations with malonyl-CoA yielding alpha-pyrones from three to six acetate units. However, naphthalenes, the expected products, were not isolated. Since the main compound produced by DluHKS is a hexaketide alpha-pyrone, and the naphthoquinones in D. lusitanicum are composed of six acetate units, we propose that the enzyme provides the backbone of these secondary metabolites. An involvement of accessory proteins in this biosynthetic pathway is discussed. PMID:18466932

  20. A mechanistic examination of redox cycling activity in carbonaceous particulate matter

    NASA Astrophysics Data System (ADS)

    McWhinney, Robert David

    Mechanistic aspects of carbonaceous aerosol toxicity were examined with respect to the ability of particles to catalyse reactive oxygen species-generating redox cycling reactions. To investigate the role of secondary organic material, we examined two systems. In the first, two-stroke engine exhaust particles were found to increase their ability to catalyse redox cycling in the presence of a reducing agent, dithiothreitol (DTT), when the exhaust was exposed to ozone. This occurred through deposition of redox-active secondary organic aerosol (SOA) onto the particle that was ten times more redox active per microgram than the primary engine particle. In the second system, naphthalene SOA formed highly redox active particles. Activity was strongly correlated to the amount of the 1,4- and 1,2-naphthoquinone measured in the particle phase. However, these species and the newly quantified naphthalene oxidation product 5-hydroxy-1,4-naphthoquinone accounted for only 30% of the observed DTT decay from the particles. Gas-particle partitioning coefficients suggest 1,4- and 1,2- naphthoquinone are not strong contributors to ambient particle redox activity at 25 °C. However, a large number of redox active species are unidentified. Some of these may be highly oxidised products of sufficiently low vapour pressure to be atmospherically relevant. DTT activity of diesel particles was found to be high per unit mass. The activity was found to be associated with the insoluble fraction as filtration of the particles nearly eliminated DTT decay. Neither methanol nor dichloromethane extracts of diesel particles exhibited redox activity, indicating that the redox active species are associated with the black carbon portion of the particles. Examination of particle concentration techniques found that use of water condensation to grow and concentrate particles introduced a large organic artefact to the particles. Experiments with concentrated inorganic particles suggest that the source of this artefact is from irreversible uptake of water-soluble volatile organic compounds. Overall, carbonaceous redox active species can be thought of as a continuum from small, water-soluble species to redox active functionalities on elemental carbon backbones. In addition to clearly defined, quantifiable species, future research may need to consider examining broader chemical classes or redox-active chemical functionalities to overcome the inherent complexity of these constituents.

  1. Nanosecond electron transfer kinetics in photosystem I following substitution of quinones for vitamin K1 as studied by time resolved EPR.

    PubMed

    Sieckman, I; van der Est, A; Bottin, H; Sétif, P; Stehlik, D

    1991-06-17

    Room temperature transient EPR spectra of photosystem I (PS I) particles from Synechocystis 6803 are presented. Native PS I samples and preparations depleted in the A1-acceptor site by solvent extraction and then reconstituted with the quinones (Q) vitamin K1 (VK1), duroquinone (DQ and DQd12) and naphthoquinone (NQ) have been studied. Sequential electron transfer to P700+A1- (FeS) and P700+A1 (FeS)- is recovered only with VK1. With DQ and NQ electron transfer is restored to form the radical pair P700+Q- as specified by a characteristic electron spin polarization (ESP)-pattern, but further electron transfer is either slowed down or blocked. A qualitative analysis of the K-band spectrum suggests that the orientation of reconstituted NQ in PS I is different from the native acceptor A1 = VK1. PMID:1647977

  2. Onosma L.: A review of phytochemistry and ethnopharmacology

    PubMed Central

    Kumar, Neeraj; Kumar, Rajnish; Kishore, Kamal

    2013-01-01

    The genus Onosma L. (Boraginaceae) includes about 150 species distributed world-wide in which only about 75 plants has been described for its morphology and less than 10 plants for their chemical constituents and clinical potential. The phytochemical reports of this genus revels that it comprise mainly aliphatic ketones, lipids, naphthazarins, alkaloids, phenolic compounds, naphthoquinones, flavones while most important are shikonins and onosmins. The plants are traditionally used as laxative, anthelmintic and for alexipharmic effects. The plants are also equally use in eye, blood diseases, bronchitis, abdominal pain, stangury, thirst, itch, lecoderma, fever, wounds, burns, piles and urinary calculi. The flowers of various plants are prescribed as stimulants, cardiotonic, in body swelling while leaves are used as purgative and in cutaneous eruptions. The roots are used for coloring food stuffs, oils and dying wool and in medicinal preparations. This review emphasizes the distribution, morphology, phytochemical constituents, ethnopharmacology, which may help in future research. PMID:24347922

  3. Contact Eczema Caused by True Teak (Tectona grandis)

    PubMed Central

    Krogh, H. K.

    1964-01-01

    A follow-up study of a previous epidemiological investigation in a furniture factory concerning allergic contact eczema caused by true teak (Tectona grandis) clearly shows that a good educational campaign associated with specific and general prophylactic measures are able to control occupational dermatoses. At the first investigation 20·5% of the workers had allergic contact eczema and/or severe itching whereas only 8·3% suffered from the same complaints on re-examination. The different prophylactic measures previously recommended had been taken. Patch tests with various teak extracts were made on 13 workers sensitized to teak; these showed that lapachol (a derivative of naphthoquinone) is one of the sensitizing agents in teak wood. Furthermore, allergic reactions were obtained in seven of these workers when Jacaranda wood dust containing lapachol was used as the test substance. PMID:14106137

  4. Naphthazarin protects against glutamate-induced neuronal death via activation of the Nrf2/ARE pathway

    SciTech Connect

    Son, Tae Gen; Kawamoto, Elisa M.; Yu, Qian-Sheng; Greig, Nigel H.; Mattson, Mark P.; Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD ; Camandola, Simonetta

    2013-04-19

    Highlights: •Naphthazarin activates the Nrf2/ARE pathway. •Naphthazarin induces Nrf2-driven genes in neurons and astrocytes. •Naphthazarin protects neurons against excitotoxicity. -- Abstract: Nuclear factor E2-related factor 2 (Nrf2)/antioxidant response element (ARE) pathway is an important cellular stress response pathway involved in neuroprotection. We previously screened several natural phytochemicals and identified plumbagin as a novel activator of the Nrf2/ARE pathway that can protect neurons against ischemic injury. Here we extended our studies to natural and synthetic derivatives of plumbagin. We found that 5,8-dimethoxy-1,4-naphthoquinone (naphthazarin) is a potent activator of the Nrf2/ARE pathway, up-regulates the expression of Nrf2-driven genes in primary neuronal and glial cultures, and protects neurons against glutamate-induced excitotoxicity.

  5. Pro-apoptotic activities of novel synthetic quinones in human cancer cell lines.

    PubMed

    Sagar, Sunil; Green, Ivan R

    2009-11-18

    Four novel quinonoid compounds are evaluated for their apoptotic potential against three cancer cell lines, i.e. MCF-7, HeLa and MG-63. APOPercentage assay was used for the screening of the compounds and it was established that the apoptotic potential of these compounds is cell line specific. The compound 2-(1',4'-benzoquinon-2'-yl)-5-hydroxy-7-methyl-1,4-naphthoquinone (S4) was found to be most active, which has a potential to kill approximately 99% of HeLa cancer cells in vitro after 72h at a concentration of 10microM. The compound's ability to induce specific markers of apoptosis in HeLa cells is further confirmed by DNA fragmentation and cell cycle assays. PMID:19481864

  6. Bioassay-guided isolation of urease and ?-chymotrypsin inhibitory constituents from the stems of Lawsonia alba Lam. (Henna).

    PubMed

    Uddin, Nizam; Siddiqui, Bina Shaheen; Begum, Sabira; Ali, Muhammad Imran; Marasini, Bishnu P; Khan, Ajmal; Choudhary, M Iqbal

    2013-01-01

    Seven constituents were isolated from the stems of Lawsonia alba Lam., following an activity-guided isolation, which include two new constituents, namely lawsorosemarinol (1) and lawsofructose (2), one known compound 2-(?-d-glucopyranosyloxy)-1, 4-naphthoquinone (3) and four compounds, 4-hydroxy coumarine (4), 3-(4-hyroxyphenyl)-triacontyl-(Z)-propenoate (5), 3-(4-hydroxy-3-methoxyphenyl)-triacontyl-(Z)-propenoate (6) and 7-hydroxy-4-methyl coumarin (7) first time isolated from Lawsonia alba. Their structure elucidation was based on spectroscopic data analyses. Compounds 3 and 7 showed a moderate inhibition of urease activity, while rest of them showed less than 50% inhibition. These compounds did not show any significant inhibition against ?-chymotrypsin. PMID:23103954

  7. Acetylshikonin Inhibits Human Pancreatic PANC-1 Cancer Cell Proliferation by Suppressing the NF-?B Activity

    PubMed Central

    Cho, Seok-Cheol; Choi, Bu Young

    2015-01-01

    Acetylshikonin, a natural naphthoquinone derivative compound, has been used for treatment of inflammation and cancer. In the present study, we have investigated whether acetylshikonin could regulate the NF-?B signaling pathway, thereby leading to suppression of tumorigenesis. We observed that acetylshikonin significantly reduced proliferation of several cancer cell lines, including human pancreatic PANC-1 cancer cells. In addition, acetylshikonin inhibited phorbol 12-myristate 13-acetate (PMA) or tumor necrosis-? (TNF-?)-induced NF-?B reporter activity. Proteome cytokine array and real-time RT-PCR results illustrated that acetylshikonin inhibition of PMA-induced production of cytokines was mediated at the transcriptional level and it was associated with suppression of NF-?B activity and matrix metalloprotenases. Finally, we observed that an exposure of acetylshikonin significantly inhibited the anchorage-independent growth of PANC-1 cells. Together, our results indicate that acetylshikonin could serve as a promising therapeutic agent for future treatment of pancreatic cancer. PMID:26336582

  8. Quinone reduction by Rhodothermus marinus succinate:menaquinone oxidoreductase is not stimulated by the membrane potential

    SciTech Connect

    Fernandes, Andreia S.; Konstantinov, Alexander A.; Teixeira, Miguel; Pereira, Manuela M. . E-mail: mpereira@itqb.unl.pt

    2005-05-06

    Succinate:quinone oxidoreductase (SQR), a di-haem enzyme purified from Rhodothermus marinus, reveals an HQNO-sensitive succinate:quinone oxidoreductase activity with several menaquinone analogues as electron acceptors that decreases with lowering the redox midpoint potential of the quinones. A turnover with the low-potential 2,3-dimethyl-1,4-naphthoquinone that is the closest analogue of menaquinone, although low, can be detected in liposome-reconstituted SQR. Reduction of the quinone is not stimulated by an imposed K{sup +}-diffusion membrane potential of a physiological sign (positive inside the vesicles). Nor does the imposed membrane potential increase the reduction level of the haems in R. marinus SQR poised with the succinate/fumarate redox couple. The data do not support a widely discussed hypothesis on the electrogenic transmembrane electron transfer from succinate to menaquinone catalysed by di-haem SQRs. The role of the membrane potential in regulation of the SQR activity is discussed.

  9. Synthesis of naphthofuranquinones with activity against Trypanosoma cruzi.

    PubMed

    Silva, Raphael S F; Costa, Elaine M; Trindade, Ursula L T; Teixeira, Daniel V; Pinto, Maria de Carmo F R; Santos, Gustavo L; Malta, Valeria R S; De Simone, Carlos Alberto; Pinto, Antonio Ventura; de Castro, Solange L

    2006-04-01

    Four new naphthofuranquinones, obtained from 2-hydroxy-3-allyl-naphthoquinone (1) and nor-lapachol (2), have their structures established by physical and X-ray analysis and their activity evaluated against Trypanosoma cruzi. Compounds 3 and 4 were obtained by addition of iodine to 1 followed by cyclization generating a furan ring. Compound 5 was obtained through the acid-catalyzed reaction by dissolution of 1 in sulfuric acid. Compound 6 was synthesized by addition of bromine and aniline to 2. The IC(50)/24 h for 3-6 in assays with T. cruzi trypomastigotes was between 157 and 640 microM, while the value for crystal violet was 536.0 +/- 3.0 microM. Compounds 3-5 also inhibited epimastigote proliferation. The trypanocidal activity of the new naphthofuranquinones endowed with redox properties reinforces a rational approach in the chemotherapy of Chagas' disease. PMID:16500733

  10. Reproductive toxicity of lapachol in adult male Wistar rats submitted to short-term treatment.

    PubMed

    de Cássia da Silveira E Sá, Rita; de Oliveira Guerra, Martha

    2007-07-01

    Lapachol is a therapeutic naphthoquinone, but little is known about its general and reproductive toxicity. In female rats, a high incidence of resorptions and fetal mortality has been reported. This work analyses the effect of the short-term administration of lapachol on vital and reproductive organs, and sperm production in Wistar rats. Adult animals were treated with 1 mL of lapachol hydroalcohol solution (100 mg/kg of body weight) for 5 days and killed 3 (T1) and 14 days (T2) after the end of treatment. Body and organ weights and sperm production were evaluated. The administration of lapachol significantly reduced the weight of the seminal vesicle (T1 animals). No significant alteration of gamete production, body weight and the weight of the other organs analysed were detected. The results suggest a reproductive toxicity effect of lapachol, indicating the seminal vesicle as a possible target organ. PMID:17421057

  11. Lapachol as an epithelial tumor inhibitor agent in Drosophila melanogaster heterozygote for tumor suppressor gene wts.

    PubMed

    Costa, W F; Oliveira, A B; Nepomuceno, J C

    2011-01-01

    The search for new and effective antitumor agents with fewer cytotoxic side effects on normal tissue has increasingly become important. Lapachol, a natural organic compound isolated from the lapacho tree (Tabebuia avellandedae), is chemically identified as belonging to the naphthoquinone group and is known for its anti-inflammatory, analgesic and antibiotic properties, although there are questions about its effectiveness for treating neoplasic cells. We evaluated the antitumoral effects of lapachol by testing for clones of epithelial tumors in Drosophila melanogaster. Seventy-two-hour old larvae bred from wts/TM3, Sb(1) females and mwh/mwh males, were treated with different concentrations of lapachol (20, 40 and 60 ?g/mL). Lapachol alone did not significantly increase the number of epithelial tumors. However, lapachol did significantly reduce the number of tumors provoked by doxorubicin. PMID:22194187

  12. Lapachol induces clastogenic effects in rats.

    PubMed

    Maistro, Edson Luis; Fernandes, Diego Mota; Pereira, Fernanda Maria; Andrade, Sergio Faloni

    2010-06-01

    Lapachol is a naturally occurring naphthoquinone derivative found in the heartwood of several plants, particularly those of the genus Tabebuia (Bignoneaceae). Despite its use as a therapeutic product with anti-inflammatory, analgesic, antipsoriatic, trypanocidal effects, among others, its in vivo mutagenic potential has still not been investigated. This paper reports the effects after a single oral administration of lapachol in the in vivo micronucleus (MN) and chromosome aberration (CA) assays. Both assays were performed using bone marrow cells from male Wistar rats. The animals were treated by oral gavage with hydroalcoholic solutions of lapachol at the doses of 122, 244 and 365 mg/kg, chosen on the basis of the LD(50) in male rats. The results show that the higher administered lapachol dose induced a significant increase in the frequency of micronucleated polychromatic erythrocytes (MNPCE) and CAs in rat bone marrow cells, indicating that lapachol shows clastogenic effects under the experimental conditions used. PMID:20112181

  13. Laser flash photolysis and magnetic-field-effect studies on interaction of thymine and thymidine with menadione: role of sugar in controlling reaction pattern

    NASA Astrophysics Data System (ADS)

    Bose, Adity; Dey, Debarati; Basu, Samita

    2008-04-01

    The magnetic field effect (MFE) in conjunction with laser flash photolysis has been used for the study of the interaction of one of the small drug like quinone molecules, 2-methyl, 1,4-naphthoquinone, commonly known as menadione (MQ), with one of the DNA bases, thymine (THN), and its corresponding nucleoside, thymidine (THDN), in acetonitrile (ACN) and sodium dodecylsulfate (SDS) micelles. It has been observed that THN undergoes electron transfer (ET) and hydrogen (H) abstraction with MQ, while THDN undergoes only H abstraction in both the media. However, our earlier studies showed that a purine base, adenine (ADN), and its nucleoside, 2'-deoxyadenosine (ADS), undergo ET in ACN and H abstraction in SDS. Here we have attempted to explain the differences in the reactions of these DNA bases with MQ. We also reveal the crucial role of a sugar unit in altering the behavior of purine and pyrimidine bases with respect to ET and H abstraction.

  14. Cross-dehydrogenative coupling of ?-C(sp(3))-H of ethers/alkanes with C(sp(2))-H of heteroarenes under metal-free conditions.

    PubMed

    Ambala, Srinivas; Thatikonda, Thanusha; Sharma, Shweta; Munagala, Gurunadham; Yempalla, Kushalava Reddy; Vishwakarma, Ram A; Singh, Parvinder Pal

    2015-12-14

    Here we have developed an effective metal-free dehydrogenative coupling method wherein ?-oxyalkyl and alkyl radicals were generated from various ethers and alkanes to undergo coupling with a variety of electron-deficient heteroarenes such as un/substituted iso-quinolones, quinolines, pyridines, pyrazines and pyrimidines. The persulfate-acetone-water system was optimized for the dehydrogenative coupling with cyclic ethers which gave moderate to excellent yields of ?-oxyalkyl containing heteroarenes. We have also optimized the conditions for coupling with cyclic alkanes and alicyclic ethers and demonstrated by conducting the reactions with a variety of electron-deficient heteroarenes. Further, the present method is also applicable to electron deficient arenes like naphthoquinones and moreover, it didn't require any external acid. PMID:26419479

  15. Chemical Composition of the Essential Oil of the Boreal Relict of Pyrola rotundifolia L. from Northern Kazakhstan.

    PubMed

    Kirillov, Vitaliy; Stikhareva, Tamara; Atazhanova, Gayane; Serafimovich, Mariya; Mukanov, Bolat; Adekenov, Sergazy; Mukasheva, Fariza; Yrymgali, Madi

    2015-10-01

    In Kazakhstan Pyrola rotundifolia L. is the plant-relict in the flora of insular pine forests of the region of low hillocks and declivities in Kazakhstan - a group of insular pine forests of Kokshetau, Bayanaul and Karkaralinsk. In this study, the essential oils from dried aerial parts of P. rotundifolia, collected in natural habitats of the State National Natural Park "Burabay" (Akmola oblast, Northern Kazakhstan), were extracted by hydrodistillation and analyzed by gas chromatography - mass spectrometry. The yield of the essential oil amounted to 0.057 % in relation to the mass of the air-dry raw material. The major components in dried plant oil were 2,6-dimethyl-1,4-naphthoquinone (12.99-93.49%) and dibutyl phthalate (4.42-40.48%), depending on the growth conditions. PMID:26369596

  16. Interactions between manganese oxides and multiple-ringed aromatic compounds

    SciTech Connect

    Whelan, G. ); Sims, R.C. . Dept. of Civil and Environmental Engineering)

    1992-08-01

    Objective is to determine whether Mn reductive dissolution can oxidize multiple-ringed aromatics, such as PAHs, in an oxic environment Research indicated that certain PAHs (eg, dihydrodiols and diones that form free-radical intermediates) are susceptible to oxidation and polymerization. Over 14 days, 83, 76, 54, 70, and 20% of the Mn was reduced by 2,3-, 1,3-, and 1,4-naphthalenediol, quinizarin, and 1,4-naphthoquinone, respectively. 100, 100, and 65% of the first three PAHs were oxidized, respectively. Aromatics with diol functional groups were more easily oxidized than those with only dione groups. Relatively insoluble compounds like quinizarin can be oxidized; insoluble ''humic-like'' material precipitated, indicating a polymerization-humification process. Results suggest that electron transfer/organic release from the oxide surface is the rate-limiting step.

  17. Interactions between manganese oxides and multiple-ringed aromatic compounds

    SciTech Connect

    Whelan, G.; Sims, R.C.

    1992-08-01

    Objective is to determine whether Mn reductive dissolution can oxidize multiple-ringed aromatics, such as PAHs, in an oxic environment? Research indicated that certain PAHs (eg, dihydrodiols and diones that form free-radical intermediates) are susceptible to oxidation and polymerization. Over 14 days, 83, 76, 54, 70, and 20% of the Mn was reduced by 2,3-, 1,3-, and 1,4-naphthalenediol, quinizarin, and 1,4-naphthoquinone, respectively. 100, 100, and 65% of the first three PAHs were oxidized, respectively. Aromatics with diol functional groups were more easily oxidized than those with only dione groups. Relatively insoluble compounds like quinizarin can be oxidized; insoluble ``humic-like`` material precipitated, indicating a polymerization-humification process. Results suggest that electron transfer/organic release from the oxide surface is the rate-limiting step.

  18. Antibacterial activity of plumbagin derivative-rich Plumbago indica root extracts and chemical stability.

    PubMed

    Kaewbumrung, Sermwut; Panichayupakaranant, Pharkphoom

    2014-01-01

    The extraction studies and a one-step purification of the crude extract of Plumbago indica using silica-gel vacuum chromatography provided a plumbagin derivative-rich P. indica root extract (PPE). The PPE was standardised to contain total plumbagin derivatives not less than 13% w/w. Antibacterial activities of the standardised PPE and three naphthoquinones, plumbagin, elliptinone and 3,3'-biplumbagin, against Propionibacterium acnes, Staphylococcus aureus and Staphylococcus epidermidis were evaluated by using the microdilution assay. The bactericidal activities of the PPE against these bacteria were much stronger than those of elliptinone and 3,3'-biplumbagin and almost equal to those of plumbagin. Stability of the PPE was determined under various conditions through a period of four months. The PPE was stable over a period of four months when stored as a dried powder but only in a well-closed container protected from light under 4 ± 2°C. PMID:24483166

  19. 1'-Butyl-2-methyl-1',2,2',3,4,9-hexa-hydro-spiro-[benzo[f]isoindole-1,3'-indole]-2',4,9-trione.

    PubMed

    Jagadeesan, G; Sethusankar, K; Bhaskar, G; Perumal, P T

    2012-07-01

    In the title compound, C(24)H(22)N(2)O(3), the indoline and pyrrole-fused naphtho-quinone units are both essentially planar [r.m.s. deviations = 0.042?(3) and 0.133?(3)?Å, respectively]. The pyrrole ring adopts a C-envelope conformation. The dihedral angle between the mean planes of the two five-membered rings is 89.94?(9)°. The O atoms deviate from the mean planes of the pyrrolidine and naphthalene rings by 0.0311?(2), 0.2570?(2) and 0.1669?(2)?Å. In the crystal, C-H?O inter-actions generate dimers with R(2) (2)(16) and R(2) (2)(18) graph-set motifs. The carbonyl O atom is involved in bifurcated hydrogen bonding. C-H?? inter-actions also occur. PMID:22798815

  20. A facile synthesis, anti-inflammatory and analgesic activity of isoxazolyl-2,3-dihydrospiro[benzo[f]isoindole-1,3'-indoline]-2',4,9-triones.

    PubMed

    Rajanarendar, E; Ramakrishna, S; Govardhan Reddy, K; Nagaraju, D; Reddy, Y N

    2013-07-01

    A new series of isoxazolyl-2,3-dihydrospiro[benzo[f]isoindole-1,3'-indoline]-2',4,9-triones (14) were synthesized by reaction of 4-amino-3-methyl-5-styrylisoxazole 10 with chloroacetic acid followed by a three component reaction with substituted isatins 12 and 1,4-naphthoquinone 13 using Ceric ammonium nitrate (CAN) catalyst under aerial oxidation condition. Structures of these compounds were established on the basis of IR, (1)H NMR, (13)C NMR and mass spectral data. The title compounds 14a-j were evaluated for their anti-inflammatory and analgesic activity. Compounds 14d, 14e and 14f exhibited potent anti-inflammatory and analgesic activity as that of standard drugs. PMID:23673015

  1. 1?-Butyl-2-methyl-1?,2,2?,3,4,9-hexa­hydro­spiro­[benzo[f]isoindole-1,3?-indole]-2?,4,9-trione

    PubMed Central

    Jagadeesan, G.; Sethusankar, K.; Bhaskar, G.; Perumal, P. T.

    2012-01-01

    In the title compound, C24H22N2O3, the indoline and pyrrole-fused naphtho­quinone units are both essentially planar [r.m.s. deviations = 0.042?(3) and 0.133?(3)?Å, respectively]. The pyrrole ring adopts a C-envelope conformation. The dihedral angle between the mean planes of the two five-membered rings is 89.94?(9)°. The O atoms deviate from the mean planes of the pyrrolidine and naphthalene rings by 0.0311?(2), 0.2570?(2) and 0.1669?(2)?Å. In the crystal, C—H?O inter­actions generate dimers with R 2 2(16) and R 2 2(18) graph-set motifs. The carbonyl O atom is involved in bifurcated hydrogen bonding. C—H?? inter­actions also occur. PMID:22798815

  2. Substitution of Redox Chemicals for Radiation in Phytochrome-Mediated Photomorphogenesis1

    PubMed Central

    Klein, Richard M.; Edsall, Pamela C.

    1966-01-01

    The reducing agents, potassium ferrocyanide, ?-mercaptoethylamine, cysteine, reduced DPN, ferrous sulfate, methyl viologen and ascorbic acid caused the expansion in darkness of disks of primary leaf tissue cut from dark-grown bean plants. The reducing agents interacted synergistically with low irradiances of red radiation and additively with high irradiance of red light. Exposure of disks treated with reducing agents to far red light repressed disk expansion and the decay in sensitivity to far red radiation showed the same time relations as sequential exposure to red and far red radiation. The oxidizing agents, 1,4-naphthoquinone, ferric sulfate, hydrogen peroxide, t-butyl hydroperoxide, cystine, and potassium ferricyanide repressed the expansion of leaf disks initiated by exposure to red radiation. The oxidizing agents interacted synergistically with low irradiances of far red light and additively with irradiances of far red light. PMID:16656360

  3. Anti-Tumor Effects of Novel 5-O-Acyl Plumbagins Based on the Inhibition of Mammalian DNA Replicative Polymerase Activity

    PubMed Central

    Kawamura, Moe; Kuriyama, Isoko; Maruo, Sayako; Kuramochi, Kouji; Tsubaki, Kazunori; Yoshida, Hiromi; Mizushina, Yoshiyuki

    2014-01-01

    We previously found that vitamin K3 (menadione, 2-methyl-1,4-naphthoquinone) inhibits the activity of human mitochondrial DNA polymerase ? (pol ?). In this study, we focused on plumbagin (5-hydroxy-2-methyl-1,4-naphthoquinone), and chemically synthesized novel plumbagins conjugated with C2:0 to C22:6 fatty acids (5-O-acyl plumbagins). These chemically modified plumbagins enhanced mammalian pol inhibition and their cytotoxic activity. Plumbagin conjugated with chains consisting of more than C18-unsaturated fatty acids strongly inhibited the activities of calf pol ? and human pol ?. Plumbagin conjugated with oleic acid (C18:1-acyl plumbagin) showed the strongest suppression of human colon carcinoma (HCT116) cell proliferation among the ten synthesized 5-O-acyl plumbagins. The inhibitory activity on pol ?, a DNA replicative pol, by these compounds showed high correlation with their cancer cell proliferation suppressive activity. C18:1-Acyl plumbagin selectively inhibited the activities of mammalian pol species, but did not influence the activities of other pols and DNA metabolic enzymes tested. This compound inhibited the proliferation of various human cancer cell lines, and was the cytotoxic inhibitor showing strongest inhibition towards HT-29 colon cancer cells (LD50?=?2.9 µM) among the nine cell lines tested. In an in vivo anti-tumor assay conducted on nude mice bearing solid tumors of HT-29 cells, C18:1-acyl plumbagin was shown to be a promising tumor suppressor. These data indicate that novel 5-O-acyl plumbagins act as anti-cancer agents based on mammalian DNA replicative pol ? inhibition. Moreover, the results suggest that acylation of plumbagin is an effective chemical modification to improve the anti-cancer activity of vitamin K3 derivatives, such as plumbagin. PMID:24520419

  4. Effect of Simultaneous Administration of Dihydroxyacetone on the Diffusion of Lawsone Through Various In Vitro Skin Models.

    PubMed

    Munt, Daniel J; Grana, Anne; Hulce, Martin; Fusaro, Ramon M; Dash, Alekha K

    2015-12-01

    Unprotected sunlight exposure is a risk factor for a variety of cutaneous cancers. Topically used dihydroxyacetone (DHA) creates, via Maillard reaction, chemically fixed keratin sunscreen in the stratum corneum with significant protection against UVA/Soret radiation. When used in conjunction with naphthoquinones a naphthoquinone-modified DHA Maillard reaction is produced that provides protection across the UVB/UVA/Soret spectra lasting up to 1 week, resisting sweating and contact removal. The aim of this study was to examine a simplified version of this formulation for effect on UV transmission and to determine if penetration levels merit toxicity concerns. Permeability was demonstrated for freshly prepared DHA (30 mg/mL) and lawsone (0.035 mg/mL) alone and in combination using a side-by-side diffusion apparatus at 37°C over 48 h across shed snake skin and dermatomed pig skin. These samples were then examined for effectiveness and safety. Concentrations were determined by HPLC and UPLC monitored from 250-500 nm. Lawsone flux significantly decreased across pig skin (20.8 (±4.8) and 0.09 (±0.1)?mg/cm(2) h without and with DHA, respectively) but did not change across shed snake skin in the presence of DHA. Significantly reduced lawsone concentration was noted in donor chambers of combined solutions. Damage was not observed in any skins. Darker coloration with greater UV absorbance was observed in skins exposed to the combined solution versus individual solutions. This study confirmed that combined DHA and lawsone provided effective blocking of ultraviolet light through products bound in keratinized tissue. DHA permeation levels in pig skin suggest further in vitro and in vivo study is required to determine the safety of this system. PMID:25986597

  5. Ex Vivo Chemical Cytometric Analysis of Protein Tyrosine Phosphatase Activity in Single Human Airway Epithelial Cells

    PubMed Central

    Phillips, Ryan M.; Dailey, Lisa A.; Bair, Eric; Samet, James M.; Allbritton, Nancy L.

    2014-01-01

    We describe a novel method for the measurement of protein tyrosine phosphatase (PTP) activity in single human airway epithelial cells (hAECs) using capillary electrophoresis. This technique involved the microinjection of a fluorescent phosphopeptide that is hydrolyzed specifically by PTPs. Analyses in BEAS-2B immortalized bronchial epithelial cells showed rapid PTP-mediated dephosphorylation of the substrate (2.2 pmol min?1 mg?1) that was blocked by pretreatment of the cells with the PTP inhibitors pervanadate, Zn2+, and 1,2-naphthoquinone (76%, 69%, 100% inhibition relative to PTP activity in untreated controls, respectively). These studies were then extended to a more physiologically relevant model system: primary hAECs cultured from bronchial brushings of living human subjects. In primary hAECs, dephosphorylation of the substrate occurred at a rate of 2.2 pmol min?1 mg?1, and was also effectively inhibited by pre-incubation of the cells with the inhibitors pervanadate, Zn2+, and 1,2- naphthoquinone (91%, 88%, and 87% median PTP inhibition, respectively). Reporter proteolysis in single BEAS-2B cells occurred at a median rate of 43 fmol min?1 mg?1 resulting in a mean half-life of 20 min. The reporter displayed a similar median half-life of 28 min in these single primary cells. Finally, single viable epithelial cells (which were assayed for PTP activity immediately after collection by bronchial brushing of a human volunteer) showed dephosphorylation rates ranging from 0.34–36 pmol min?1 mg?1 (n = 6). These results demonstrate the utility and applicability of this technique for the ex vivo quantification of PTP activity in small, heterogeneous, human cells and tissues. PMID:24380370

  6. Time-resolved visible and infrared difference spectroscopy for the study of photosystem I with different quinones incorporated into the A1 binding site.

    PubMed

    Makita, Hiroki; Zhao, Nan; Hastings, Gary

    2015-03-01

    Room (298 K) and low (77K) temperature time-resolved visible and infrared difference spectroscopy has been used to study photosystem I particles with phylloquinone (2-methyl-3-phytyl-1,4-naphthoquinone), menadione (2-methyl-1,4-naphthoquinone) and plastoquinone 9 (2,3-dimethyl-5-prenyl-l,4-benzoquinone), incorporated into the A1 binding site. Concentrated samples in short path-length (~5 ?m) sample cells are typically used in FTIR experiments. Measurements were undertaken using standard "dilute" samples at 298 K, and concentrated (~5×) samples at both 298 and 77K. No concentration induced alterations in the flash-induced absorption changes were observed. Concentrated samples in short path-length cells form a transparent film at 77K, and could therefore be studied spectroscopically at 77K without addition of a cryoprotectant. At 298 K, for photosystem I with plastoquinone 9/menadione/phylloquinone incorporated, P700+FA/B- radical pair recombination is characterized by a time constant of 3/14/80 ms, and forward electron transfer from A1A- to Fx by a time constant of 211/3.1/0.309 ?s, respectively. At 77K, for concentrated photosystem I with menadione/phylloquinone incorporated, P700+A1- radical pair recombination is characterized by a time constant of 240/340 ?s, with this process occurring in 58/39% of the PSI particles, respectively. The origin of these differences is discussed. Marcus electron transfer theory in combination with kinetic modeling is used to simulate the observed electron transfer time constants at 298 K. This simulation allows an estimate of the redox potential for the different quinones in the A1 binding site. PMID:25534606

  7. Direct charge recombination from D +Q AQ B- to DQ AQ B in bacterial reaction centers from Rhodobacter sphaeroides containing low potential quinone in the Q A site

    NASA Astrophysics Data System (ADS)

    Labahn, A.; Bruce, J. M.; Okamura, M. Y.; Feher, G.

    1995-08-01

    In native RCs from Rb. sphaeroides the recombination D +Q AQ B- ? DQ AQ B proceeds via an indirect path involving the intermediate state D +Q A-Q B. To observe the direct recombination rate, kBD, the energy difference between the D +Q A-Q B and D +Q AQ B- states has to be increased. This had been accomplished in mutant RCs (DN(L213)) by lowering the energy of the D +Q AQ B- state [A. Labahn, M.L. Paddock, P.H. McPherson, M.Y. Okamura and G. Feher, J. Phys. Chem. 98 (1994) 3417] or, as presented in this work, by arising the energy of the D +Q A-Q B state through substitution of Q 10 by the low potential quinones: (2,3,5-trimethyl-1,4-naphthoquinone, 2,3,6,7-tetramethyl-1,4-naphthoquinone, 2-chloro-9,10-anthraquinone) while retaining the native Q 10 in the Q B site. The recombination rates kBD in these hybrid RCs were fitted with the Marcus theory giving a reorganization energy, ?BD = 1.1 ± 0.1 eV and an electronic matrix element V( r) = (1.2 ± 0.5) × 10 -8 eV. The larger value of ?BD compared to ?AD (1.1 versus 0.6 eV) is consistent with the more polar environment of Q B- and is believed to be the main contributor to the large observed ratio of kAD/ kBD ? 100.

  8. Different cell death pathways induced by drugs in Trypanosoma cruzi: an ultrastructural study.

    PubMed

    Menna-Barreto, Rubem F S; Salomão, Kelly; Dantas, Andréia P; Santa-Rita, Ricardo M; Soares, Maurilio J; Barbosa, Helene S; de Castro, Solange L

    2009-02-01

    Electron microscopy has proven to be a reliable and essential tool to determine morphological alterations and target organelles in the investigation of new drugs for Chagas disease. In this review, we focused on evaluating different agents that induce death of Trypanosoma cruzi, i.e. lysophospholipids analogues, naphthoquinones and derivatives, cytoskeletal inhibitors and natural products. Apoptosis-like presents as morphological characteristics DNA fragmentation, membrane blebbing and apoptotic body formation. Autophagy involves autophagosome formation, with the appearance of membranes surrounding organelles and cytosolic structures. Necrosis causes the loss of osmotic balance, an increase of cytoplasmic vacuolization and plasma membrane disruption. Mitochondrion appears as a central checkpoint in both apoptosis and necrosis. Our evidences of ultrastructural changes to T. cruzi treated with the different classes of compounds point to dramatic mitochondrial alterations and similar autophagic phenotypes. Lysophospholipid analogues interfere in the lipid biosynthesis in epimastigotes, altering the amount of both phospholipids and sterols, and consequently the physical properties of the membrane. Naphthoquinone derivatives led to a strong DNA fragmentation in trypomastigotes and to the release of cysteine proteases from reservosomes to cytosol in epimastigotes, starting a proteolytic process which results in parasite death. The susceptibility of reservosomes was also observed in parasites treated with propolis, suggesting impairment of lipid metabolism, compromising membrane fluidity and leading to lysis. The cytoskeletal agents blocked mitosis of epimastigotes, arresting cell cycle and impairing the parasite proliferation. The variety of drug stimuli converge to the same pathway of death suggests an intense cross-talking between the three types of PCD in the protozoa. PMID:18849169

  9. Synthesis, characterization and molecular structures of homologated analogs of 2-bromo-3-(n-alkylamino)-1,4-napthoquinone

    NASA Astrophysics Data System (ADS)

    Salunke-Gawali, Sunita; Pawar, Omkar; Nikalje, Milind; Patil, Rishikesh; Weyhermüller, Thomas; Puranik, Vedavati G.; Badireenath Konkimalla, V.

    2014-01-01

    Four analogues of 2-bromo-3-(n-alkylamino)-1,4-napthoquinone (where n-alkyl is methyl in L-1Br, ethyl in L-2Br, propyl in L-3Br and butyl in L-4Br) are synthesized and characterized. A reaction mechanism is proposed for the formation of L-1Br to L-4Br from the starting material 2,3-dibromo-1,4-naphthoquinone. The ?NH frequency in the FT-IR spectra is affected by the intramolecular hydrogen bonding in L-1Br to L-4Br and is observed ˜3267 cm-1 in L-2Br. A shift of ˜25 cm-1 is observed in the ?CBr frequency in all the compounds as compared to 2,3-dibromo-1,4-naphthoquinone (627 cm-1). A broad charge transfer band is observed between 400 and 600 nm in the UV-Vis spectra, which imparts red colour to all the compounds. Molecular structures of L-2Br and L-3Br were studied by single crystal X-ray diffraction studies. Molecules of L-2Br crystallize in Pca21, whereas the molecule L-3Br crystallizes in the P-1 space group. Molecules of L-2Br forms a polymeric chain through NH⋯O interaction and forms beautiful butterfly like arrangement of molecules when viewed down the 'a' axis. Ladder like polymeric chain of molecules is observed in L-3Br via CH⋯O and NH⋯O interactions. Every alternating neighbouring chains of L-3Br, show ?-? stacking interactions between the quinonoid rings of the molecules, however this interaction is not observed in L-2Br.

  10. [Tobacco--once a medicinal plant. Does it contain substances with medicinal properties?].

    PubMed

    Budzianowski, Jaromir

    2013-01-01

    Tobacco and its use was discovered by Christopher Columbus in parallel with the discovery of America. Soon after, tobacco became a known medicinal plant in Europe. Its harmful effects were gradually discovered, especially those of tobacco smoke, and now it is considered a toxic plant. Tobacco leaf has a monograph in German "Hagers Enzyklopädie derArzneistoffe und Drogen", which describes its old, already not valid, medicinal use and clearly shows the toxic effects. Epidemiological studies indicate about 50% lower incidence of Parkinson's disease in smokers than in non-smokers. In turn, studies of the brains of smokers using positron emission tomography showed significantly decreased level of monoamine oxidase B--an enzyme which degrades dopamine--the neurotransmitter which the significant insufficiency of about 80-85%, is responsible for the symptoms of Parkinson's disease. From the tobacco leaves there were isolated MAO-B inhibitors--naphthoquinone--2,3,6-trimethyl-1,4-naphthoquinone and diterpenoid -trans,trans-farnesol, which occur also in tobacco smoke. In the last decade many papers have appeared on the neuroprotective activity of nicotine, the best known component of tobacco. through the effect of this compound on specific nicotinic cholinergic receptors (nAChRs), which interacts with nigrostriatal dopaminergic system as well as the possibility of using nicotine for the treatment of Parkinson's disease and other neurodegenerative diseases. Moreover, tobacco was also found to contain inhibitors of neuronal nitric oxide synthase (nNOS). Tobacco cannot be considered a medicinal plant, but some compounds occurring in that plant may find therapeutic use. PMID:24501813

  11. Plumbagin suppresses epithelial to mesenchymal transition and stemness via inhibiting Nrf2-mediated signaling pathway in human tongue squamous cell carcinoma cells

    PubMed Central

    Pan, Shu-Ting; Qin, Yiru; Zhou, Zhi-Wei; He, Zhi-Xu; Zhang, Xueji; Yang, Tianxin; Yang, Yin-Xue; Wang, Dong; Zhou, Shu-Feng; Qiu, Jia-Xuan

    2015-01-01

    Tongue squamous cell carcinoma (TSCC) is the most common malignancy in oral and maxillofacial tumors with highly metastatic characteristics. Plumbagin (5-hydroxy-2-methyl-1, 4-naphthoquinone; PLB), a natural naphthoquinone derived from the roots of Plumbaginaceae plants, exhibits various bioactivities, including anticancer effects. However, the potential molecular targets and underlying mechanisms of PLB in the treatment of TSCC remain elusive. This study employed stable isotope labeling by amino acids in cell culture (SILAC)-based quantitative proteomic approach to investigate the molecular interactome of PLB in human TSCC cell line SCC25 and elucidate the molecular mechanisms. The proteomic data indicated that PLB inhibited cell proliferation, activated death receptor-mediated apoptotic pathway, remodeled epithelial adherens junctions pathway, and manipulated nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated oxidative stress response signaling pathway in SCC25 cells with the involvement of a number of key functional proteins. Furthermore, we verified these protein targets using Western blotting assay. The verification results showed that PLB markedly induced cell cycle arrest at G2/M phase and extrinsic apoptosis, and inhibited epithelial to mesenchymal transition (EMT) and stemness in SCC25 cells. Of note, N-acetyl-l-cysteine (NAC) and l-glutathione (GSH) abolished the effects of PLB on cell cycle arrest, apoptosis induction, EMT inhibition, and stemness attenuation in SCC25 cells. Importantly, PLB suppressed the translocation of Nrf2 from cytosol to nucleus, resulting in an inhibition in the expression of downstream targets. Taken together, these results suggest that PLB may act as a promising anticancer compound via inhibiting Nrf2-mediated oxidative stress signaling pathway in SCC25 cells. This study provides a clue to fully identify the molecular targets and decipher the underlying mechanisms of PLB in the treatment of TSCC. PMID:26491260

  12. Chemoprevention of skin cancer: effect of Lawsonia inermis L. (Henna) leaf powder and its pigment artifact, lawsone in the Epstein- Barr virus early antigen activation assay and in two-stage mouse skin carcinogenesis models.

    PubMed

    Kapadia, Govind J; Rao, G Subba; Sridhar, Rajagopalan; Ichiishi, Eiichiro; Takasaki, Midori; Suzuki, Nobutaka; Konoshima, Takao; Iida, Akira; Tokuda, Harukuni

    2013-12-01

    In continuation of our studies with chemoprevention potential of plant-derived naphthoquinone derivatives, leaf powder of the medicinal plant Lawsonia inermis L, commonly known as 'henna', was evaluated by its inhibition of the Epstein-Barr virus early antigen (EBV-EA) activation induced by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) in Raji cells. Lawsone (2-hydroxy- 1,4-naphthoquinone), the reddish orange pigment artifact formed during the extraction or preparation of the dye from henna leaves and believed to be the active component, was also assessed in this in vitro assay. Both showed a profound inhibition (>88%) of EBV-EA activation. In the in vivo two-stage mouse skin carcinogenesis study using UV-B radiation for initiation and TPA for tumor promotion, oral feeding of henna (0.0025%) in drinking water ad libitum decreased tumor incidence by 66% and multiplicity by 40% when compared to the positive control at 10 weeks of treatment. Similarly, in the above mouse model, orally fed lawsone (0.0025%) decreased tumor incidence by 72% and multiplicity by 50%. The tumor inhibitory trend continued throughout the 20-week test period. Similar antitumor activities were observed when henna (0.5 mg/ml) was applied topically on the back skin in the UV-B initiated, TPA promoted and peroxynitrite initiated, TPA promoted mouse skin carcinogenesis models. Topically applied lawsone (0.015 mg/ml) also exhibited similar protection against tumor formation in the 7,12-dimtehylbenz(a)anthracene induced and TPA promoted skin cancer in mice. Also, there was a delay of 1 to 2 weeks in tumor appearance in both henna and lawsone treated groups compared to control in all three test models. This study ascertains the skin cancer chemopreventive activity of henna leaf powder and lawsone when administered by either oral (through drinking water) or topical (by application on the back skin) routes. Further, it emphasizes the need for the evaluation of these henna-derived green chemopreventive candidates in combination with currently used sunscreen agents for complementary anticancer potential against UV-induced skin carcinogenesis. PMID:23848207

  13. Active transport of Ca2+ in bacteria: bioenergetics and function.

    PubMed

    Devés, R; Brodie, A F

    1981-04-27

    The bioenergetics of Ca2+ transport in bacteria are discussed with special emphasis on the interrelationship between transport and other cellular functions such as substrate oxidation by the respiratory chain and oxidative phosphorylation. The unusual polarity of Ca2+ movement provides an exceptional tool to compare active transport and other ATP requiring or generating processes since this ion is actively taken up by everted vesicles in which the coupling-factor ATPase is exposed to the external medium. As inferred from studies with everted vesicles, the active extrusion of Ca2+ by whole cells can be accomplished by substrate driven respiration, hydrolysis of ATP or as in the case of Streptococcus faecalis by a nonhydrolytic unknown process which involves ATP directly. Substrate oxidation and the hydrolysis of ATP result in the generation of a pH gradient which can energize the Ca2+ uptake directly (Ca2+/H+ antiport) or via a secondary Na+ gradient (Ca2+/Na+ antiport). In contrast to exponentially growing cells sporulating Bacilli accumulate Ca2+ during the synthesis of dipicolinic acid. Studies involving Ca2+ transport provided evidence in support of the hypothesis that the Mg2+ ATPase from Escherichia coli not only provides the driving force for various cellular functions but exerts a regulatory role by controlling the permeability of the membrane to protons. The different specificity requirements of various naphthoquinone analogs in the restoration of transport or oxidative phosphorylation, after the natural menaquinone has been destroyed by irradiation, has indicated that a protonmotive force is sufficient to drive active transport. However, in addition to the driving force (protonmotive force) necessary to establish oxidative phosphorylation, a specific spatial orientation of the respiratory components, such as the naphthoquinones, is essential for the utilization of the proton gradient or membrane potential or both. Finally, evidence suggesting that intracellular Ca2+ levels might play a fundamental role in bacterial homeostasis is discussed, in particular the role of Ca2+ in the process of chemotaxis and in conferring bacteria heat stability. A vitamin K-dependent carboxylation reaction has been found in Escherichia coli which is similar to that reported in mammalian systems which results in gamma carboxylation of glutamate residues. Although all of the proteins containing gamma-carboxyglutamate described so far are involved in Ca2+ metabolism, the role of these proteins in Escherichia coli is unknown and remains to be elucidated. PMID:6113540

  14. Plumbagin induces G2/M arrest, apoptosis, and autophagy via p38 MAPK- and PI3K/Akt/mTOR-mediated pathways in human tongue squamous cell carcinoma cells

    PubMed Central

    Pan, Shu-Ting; Qin, Yiru; Zhou, Zhi-Wei; He, Zhi-Xu; Zhang, Xueji; Yang, Tianxin; Yang, Yin-Xue; Wang, Dong; Qiu, Jia-Xuan; Zhou, Shu-Feng

    2015-01-01

    Plumbagin (5-hydroxy-2-methyl-1,4-naphthoquinone; PLB), a naturally occurring naphthoquinone isolated from the roots of Plumbaginaceae plants, has been reported to possess anticancer activities in both in vitro and in vivo studies, but the effect of PLB on tongue squamous cell carcinoma (TSCC) is not fully understood. This study aimed to investigate the effects of PLB on cell cycle distribution, apoptosis, and autophagy, and the underlying mechanisms in the human TSCC cell line SCC25. The results have revealed that PLB exerted potent inducing effects on cell cycle arrest, apoptosis, and autophagy in SCC25 cells. PLB arrested SCC25 cells at the G2/M phase in a concentration- and time-dependent manner with a decrease in the expression level of cell division cycle protein 2 homolog (Cdc2) and cyclin B1 and increase in the expression level of p21 Waf1/Cip1, p27 Kip1, and p53 in SCC25 cells. PLB markedly induced apoptosis and autophagy in SCC25 cells. PLB decreased the expression of the anti-apoptotic proteins B-cell lymphoma 2 (Bcl-2) and B-cell lymphoma-extra large (Bcl-xl) while increasing the expression level of the pro-apoptotic protein Bcl-2-associated X protein (Bax) in SCC25 cells. Furthermore, PLB inhibited phosphatidylinositol 3 kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR), glycogen synthase kinase 3? (GSK3?), and p38 mitogen-activated protein kinase (p38 MAPK) pathways as indicated by the alteration in the ratio of phosphorylation level over total protein expression level, contributing to the autophagy inducing effect. In addition, we found that wortmannin (a PI3K inhibitor) and SB202190 (a selective inhibitor of p38 MAPK) strikingly enhanced PLB-induced autophagy in SCC25 cells, suggesting the involvement of PI3K- and p38 MAPK-mediated signaling pathways. Moreover, PLB induced intracellular reactive oxygen species (ROS) generation and this effect was attenuated by l-glutathione (GSH) and n-acetyl-l-cysteine (NAC). Taken together, these results indicate that PLB promotes cellular apoptosis and autophagy in TSCC cells involving p38 MAPK- and PI3K/Akt/mTOR-mediated pathways with contribution from the GSK3? and ROS-mediated pathways. PMID:25834400

  15. Vibrational spectroscopy of photosystem I.

    PubMed

    Hastings, Gary

    2015-01-01

    Fourier transform infrared difference spectroscopy (FTIR DS) has been widely used to study the structural details of electron transfer cofactors (and their binding sites) in many types of photosynthetic protein complexes. This review focuses in particular on work that has been done to investigate the A?cofactor in photosystem I photosynthetic reaction centers. A review of this subject area last appeared in 2006 [1], so only work undertaken since then will be covered here. Following light excitation of intact photosystem I particles the P700?A?(1) secondary radical pair state is formed within 100ps. This state decays within 300ns at room temperature, or 300?s at 77K. Given the short-lived nature of this state, it is not easily studied using "static" photo-accumulation FTIR difference techniques at either temperature. Time-resolved techniques are required. This article focuses on the use of time-resolved step-scan FTIR DS for the study of the P700?A?(1) state in intact photosystem I. Up until now, only our group has undertaken studies in this area. So, in this article, recent work undertaken in our lab is described, where we have used low-temperature (77K), microsecond time-resolved step-scan FTIR DS to study the P700?A?(1) state in photosystem I. In photosystem I a phylloquinone molecule occupies the A?binding site. However, different quinones can be incorporated into the A1 binding site, and here work is described for photosystem I particles with plastoquinone-9, 2-phytyl naphthoquinone and 2-methyl naphthoquinone incorporated into the A?binding site. Studies in which ¹?O isotope labeled phylloquinone has been incorporated into the A1 binding site are also discussed. To fully characterize PSI particles with different quinones incorporated into the A1 binding site nanosecond to millisecond visible absorption spectroscopy has been shown to be of considerable value, especially so when undertaken using identical samples under identical conditions to that used in time-resolved step-scan FTIR measurements. In this article the latest work that has been undertaken using both visible and infrared time resolved spectroscopies on the same sample will be described. Finally, vibrational spectroscopic data that has been obtained for phylloquinone in the A1 binding site in photosystem I is compared to corresponding data for ubiquinone in the QA binding site in purple bacterial reaction centers. This article is part of a Special Issue entitled: Vibrational spectroscopies and bioenergetic systems. PMID:25086273

  16. Fractionating ambient humic-like substances (HULIS) for their reactive oxygen species activity - Assessing the importance of quinones and atmospheric aging

    NASA Astrophysics Data System (ADS)

    Verma, Vishal; Wang, Ying; El-Afifi, Rawan; Fang, Ting; Rowland, Janessa; Russell, Armistead G.; Weber, Rodney J.

    2015-11-01

    In this paper, we present a technique to identify the redox-active components of fine organic aerosols by fractionating humic-like substances (HULIS). We applied this technique to a dithiothreitol (DTT) assay - a measure of the capability of PM to generate reactive oxygen species (ROS), and assessed the contribution of quinones to the DTT activity of ambient water-soluble PM. Filter samples from the Southeastern Center for Air Pollution & Epidemiology (SCAPE) were extracted in water and then passed-through a C-18 column to isolate the HULIS fraction by retention on the column. The HULIS was then eluted with a sequence of solvents of increasing polarity, i.e., hexane, dichloromethane (DCM) and then methanol. Each of these eluted fractions was analyzed for DTT activity. The methanol fraction was found to possess most of the DTT activity (>70%), while the hexane fraction had the least activity (<5%), suggesting that the ROS-active compounds of ambient water-soluble PM2.5 HULIS are mostly polar in nature. A number of quinones thought to contribute to ambient PM DTT activity were also tested. 1,4 Naphthoquinone (1,4 NQ), 1,2 Naphthoquinone (1,2 NQ), 9,10 Phenanthrenequinone (PQ), and 5-hydroxy-1,4 NQ were analyzed by the same protocol. The hexane fraction of two quinones (PQ, and 1,4 NQ) was the most-DTT active, while methanol was the least, confirming that PQ, 1,4 NQ, and 1,2 NQ (which could not be recovered from the column) do not contribute significantly to the water-soluble DTT activity of ambient PM2.5. However, an oxygenated derivative of 1,4 NQ, (5-hydroxy-1,4 NQ), which is also intrinsically more DTT-active than 1,4 NQ, was mostly (>60%) eluted in methanol. The results demonstrate the importance of atmospheric aging (oxidation) of organic aerosols in enhancing the ROS activity of ambient PM.

  17. Dihydrodiol dehydrogenase and polycyclic aromatic hydrocarbon metabolism

    SciTech Connect

    Smithgall, T.E.

    1986-01-01

    Carcinogenic activation of polycyclic aromatic hydrocarbons by microsomal monoxygenases proceeds through trans-dihydrodiol metabolites to diol-epoxide ultimate carcinogens. This thesis directly investigated the role of dihydrodiol dehydrogenase, a cytosolic NAD(P)-linked oxidoreductase, in the detoxification of polycyclic aromatic trans-dihydrodiols. A wide variety of non-K-region trans-dihydrodiols were synthesized and shown to be substrates for the homogeneous rat liver dehydrogenase, including several potent proximate carcinogens derived from 7,12-dimethylbenz(a)anthracene, 5-methylchrysene, and benzo(a)pyrene. Since microsomal activation of polycyclic aromatic hydrocarbons is highly stereospecific, the stereochemical course of enzymatic trans-dihydrodiol oxidation was monitored using circular dichroism spectropolarimetry. The major product formed from the dehydrogenase-catalyzed oxidation of the trans-1,2-dihydrodiol of naphthalene was characterized using UV, IR, NMR, and mass spectroscopy, and appears to be 4-hydroxy-1,2-naphthoquinone. Mass spectral analysis suggests that an analogous hydroxylated o-quinone is formed as the major product of benzo(a)pyrene-7,8-dihydrodiol oxidation. Enzymatic oxidation of trans-dihydrodiols was shown to be potently inhibited by all of the major classes of the nonsteroidal antiinflammatory drugs. Enhancement of trans-dihydrodiol proximate carcinogen oxidation may protect against possible adverse effects of the aspirin-like drugs, and help maintain the balance between activation and detoxification of polycyclic aromatic hydrocarbons.

  18. Effect of biogenic photochromic electron acceptors on chlorophyll fluorescence

    NASA Astrophysics Data System (ADS)

    Lobanov, A. V.; Klimenko, I. V.; Nevrova, O. V.; Zhuravleva, T. S.

    2014-05-01

    It is shown that the photophysical properties of chlorophyll a (Chl) depend on the nature and relative amounts of 2-methyl-1,4-naphthoquinone (MNQ) and nicotinamide adenine dinucleotide phosphate (NADP). Photoinduced charge separation occurs in aqueous ethanol solutions of Chl (1 × 10-5 M) and NADP (5 × 10-6-5 × 10-4 M), resulting in the dynamic quenching of Chl fluorescence. Coordination interaction between Chl and NADP is established at an NADP concentration of ?5 × 10-4 M. The nonlinear Stern-Volmer dependence in this range is due to the input from static quenching. It is shown that the quenching of Chl fluorescence in an MNQ solution at Chl and MNQ concentrations of 1 × 10-5 M and 6.7 × 10-5-1 × 10-4 M, respectively, is described by a linear dependence in the Stern-Volmer coordinates; no complex formation is observed for Chl and MNQ under these conditions, and electron transfer is of the dynamic type. Static or mixed-type energy transfer from MNQ to Chl dominates at elevated MNQ concentrations.

  19. Rhinacanthin C Inhibits Osteoclast Differentiation and Bone Resorption: Roles of TRAF6/TAK1/MAPKs/NF-?B/NFATc1 Signaling

    PubMed Central

    Tomomura, Mineko; Suzuki, Ryuichiro; Shirataki, Yoshiaki; Sakagami, Hiroshi; Tamura, Nobuaki; Tomomura, Akito

    2015-01-01

    Rhinacanthin C is a naphthoquinone ester with anti-inflammatory activity, found in Rhinacanthus nasutus (L) Kurz (Acanthaceae). We found that rhinacanthin C inhibited osteoclast differentiation stimulated by the receptor activator of nuclear factor-?B ligand (RANKL) in mouse bone marrow macrophage cultures, although the precise molecular mechanisms underlying this phenomenon are unclear. In this study, we investigated the inhibitory mechanisms of rhinacanthin C in osteoclastogenesis. Rhinacanthin C suppressed RANKL-induced nuclear factor of activated T cells c1 (NFATc1) expression. Phosphorylation of ERK, JNK, and NF-?B, but not p38, was inhibited by rhinacanthin C, which also inhibited RANKL-stimulated TRAF6-TAK1 complex formation. Thus, the anti-osteoclastogenic effect of rhinacanthin C is mediated by a cascade of inhibition of RANKL-induced TRAF6-TAK1 association followed by activation of MAPKs/NF-?B; this leads to suppression of c-Fos and NFATc1, which regulate transcription of genes associated with osteoclast differentiation. In vivo, rhinacanthin C also reduced RANKL-induced osteoclast formation and bone resorption in mouse calvaria. Rhinacanthin C also suppressed LPS-stimulated osteoclastogenesis and bone resorption in vitro and in vivo. Rhinacanthin C may provide a novel therapy for abnormal bone lysis that occurs during inflammatory bone resorption. PMID:26083531

  20. Screening of Potential anti-Trypanosoma cruzi Candidates: In Vitro and In Vivo Studies

    PubMed Central

    Soeiro, Maria de Nazaré C; de Castro, Solange Lisboa

    2011-01-01

    Chagas disease (CD), caused by the intracellular protozoan Trypanosoma cruzi, is a parasitic illness endemic in Latin America. In the centennial after CD discovery by Carlos Chagas (1909), although it still represents an important public health problem in these affected areas, the existing chemotherapy, based on benznidazole and nifurtimox (both introduced more than four decades ago), is far from being considered ideal due to substantial toxicity, variable effect on different parasite stocks and well-known poor activity on the chronic phase. CD is considered one of the major “neglected” diseases of the world, as commercial incentives are very limited to guarantee investments for developing and discovering novel drugs. In this context, our group has been pursuing, over the last years, the efficacy, selectivity, toxicity, cellular targets and mechanisms of action of new potential anti-T. cruzi candidates screened from an in-house compound library of different research groups in the area of medicinal chemistry. A brief review regarding these studies will be discussed, mainly related to the effect on T. cruzi of (i) diamidines and related compounds, (ii) natural naphthoquinone derivatives, and (iii) megazol derivatives. PMID:21629508

  1. Diversity of ABBA Prenyltransferases in Marine Streptomyces sp. CNQ-509: Promiscuous Enzymes for the Biosynthesis of Mixed Terpenoid Compounds

    PubMed Central

    Leipoldt, Franziska; Zeyhle, Philipp; Kulik, Andreas; Kalinowski, Jörn; Heide, Lutz; Kaysser, Leonard

    2015-01-01

    Terpenoids are arguably the largest and most diverse family of natural products, featuring prominently in e.g. signalling, self-defence, UV-protection and electron transfer. Prenyltransferases are essential players in terpenoid and hybrid isoprenoid biosynthesis that install isoprene units on target molecules and thereby often modulate their bioactivity. In our search for new prenyltransferase biocatalysts we focused on the marine-derived Streptomyces sp. CNQ-509, a particularly rich source of meroterpenoid chemistry. Sequencing and analysis of the genome of Streptomyces sp. CNQ-509 revealed seven putative phenol/phenazine-specific ABBA prenyltransferases, and one putative indole-specific ABBA prenyltransferase. To elucidate the substrate specificity of the ABBA prenyltransferases and to learn about their role in secondary metabolism, CnqP1 –CnqP8 were produced in Escherichia coli and incubated with various aromatic and isoprenoid substrates. Five of the eight prenyltransferases displayed enzymatic activity. The efficient conversion of dihydroxynaphthalene derivatives by CnqP3 (encoded by AA958_24325) and the co-location of AA958_24325 with genes characteristic for the biosynthesis of THN (tetrahydroxynaphthalene)-derived natural products indicates that the enzyme is involved in the formation of debromomarinone or other naphthoquinone-derived meroterpenoids. Moreover, CnqP3 showed high flexibility towards a range of aromatic and isoprenoid substrates and thus represents an interesting new tool for biocatalytic applications. PMID:26659564

  2. Development of quinone analogues as dynamin GTPase inhibitors.

    PubMed

    MacGregor, Kylie A; Abdel-Hamid, Mohammed K; Odell, Luke R; Chau, Ngoc; Whiting, Ainslie; Robinson, Phillip J; McCluskey, Adam

    2014-10-01

    Virtual screening of the ChemDiversity and ChemBridge compound databases against dynamin I (dynI) GTPase activity identified 2,5-bis-(benzylamino)-1,4-benzoquinone 1 as a 273 ± 106 ?M inhibitor. In silico lead optimization and focused library-led synthesis resulted in the development of four discrete benzoquinone/naphthoquinone based compound libraries comprising 54 compounds in total. Sixteen analogues were more potent than lead 1, with 2,5-bis-(4-hydroxyanilino)-1,4-benzoquinone (45) and 2,5-bis(4-carboxyanilino)-1,4-benzoquinone (49) the most active with IC50 values of 11.1 ± 3.6 and 10.6 ± 1.6 ?M respectively. Molecular modelling suggested a number of hydrogen bonding and hydrophobic interactions were involved in stabilization of 49 within the dynI GTP binding site. Six of the most active inhibitors were evaluated for potential inhibition of clathrin-mediated endocytosis (CME). Quinone 45 was the most effective CME inhibitor with an IC50(CME) of 36 ± 16 ?M. PMID:25084145

  3. Effects of several quinones on insulin aggregation.

    PubMed

    Gong, Hao; He, Zihao; Peng, Anlin; Zhang, Xin; Cheng, Biao; Sun, Yue; Zheng, Ling; Huang, Kun

    2014-01-01

    Protein misfolding and aggregation are associated with more than twenty diseases, such as neurodegenerative diseases and metabolic diseases. The amyloid oligomers and fibrils may induce cell membrane disruption and lead to cell apoptosis. A great number of studies have focused on discovery of amyloid inhibitors which may prevent or treat amyloidosis diseases. Polyphenols have been extensively studied as a class of amyloid inhibitors, with several polyphenols under clinical trials as anti-neurodegenerative drugs. As oxidative intermediates of natural polyphenols, quinones widely exist in medicinal plants or food. In this study, we used insulin as an amyloid model to test the anti-amyloid effects of four simple quinones and four natural anthraquinone derivatives from rhubarb, a traditional herbal medicine used for treating Alzheimer's disease. Our results demonstrated that all eight quinones show inhibitory effects to different extent on insulin oligomerization, especially for 1,4-benzoquinone and 1,4-naphthoquinone. Significantly attenuated oligomerization, reduced amount of amyloid fibrils and reduced hemolysis levels were found after quinones treatments, indicating quinones may inhibit insulin from forming toxic oligomeric species. The results suggest a potential action of native anthraquinone derivatives in preventing protein misfolding diseases, the quinone skeleton may thus be further explored for designing effective anti-amyloidosis compounds. PMID:25008537

  4. Decolorization of azo dyes by Geobacter metallireducens.

    PubMed

    Liu, Guangfei; Zhou, Jiti; Chen, Congcong; Wang, Jing; Jin, Ruofei; Lv, Hong

    2013-09-01

    Geobacter metallireducens was found to be capable of decolorizing several azo dyes with different structures to various extents. Pyruvate, ethanol, acetate, propionate, and benzoate could support 66.3?±?2.6-93.7?±?2.1 % decolorization of 0.1 mM acid red 27 (AR27) in 40 h. The dependence of the specific decolorization rate on AR27 concentration (25 to 800 ?M) followed Michaelis-Menten kinetics (K m?=?186.9?±?1.4 ??, V max?=?0.65?±?0.02 ?mol?mg protein(-1) h(-1)). Enhanced AR27 decolorization was observed with the increase of cell concentrations ranging from 7.5 to 45 mgL(-1). AR27 decolorization by G. metallireducens was retarded by the presence of goethite, which competed electrons with AR27 and was reduced to Fe(II). The addition of low concentrations of humic acid (1-100 mgL(-1)) or 2-hydroxy-1,4-naphthoquinone (0.5-50 ?M) could improve the decolorization performance of G. metallireducens. High-performance liquid chromatography analysis suggested reductive pathway to be responsible for decolorization. This was the first study on azo dye decolorization by Geobacter strain and might improve our understanding of natural attenuation and bioremediation of environments polluted by azo dyes. PMID:23132348

  5. Synthesis and molecular structure of a zinc complex of the vitamin K3 analogue phthiocol

    NASA Astrophysics Data System (ADS)

    Kathawate, Laxmi; Sproules, Stephen; Pawar, Omkar; Markad, Ganesh; Haram, Santosh; Puranik, Vedavati; Salunke-Gawali, Sunita

    2013-09-01

    The complex [Zn(phthiocol)2(H2O)2]; 1, where phthiocol is 2-hydroxy-3-methyl-1,4-naphthoquinone, has been synthesized and characterized by elemental analysis, FT-IR, 1H NMR, UV-vis spectroscopy, thermogravimetric (TG) analysis, electrochemical and single crystal X-ray diffraction studies. The ?CO stretch shifts to lower frequencies upon complexation of phthiocol to Zn2+. 1H NMR spectra show an upfield shift of the benzenoid ring protons in 1. There is a bathochromic shift of the LMCT band in the UV-vis spectra of 1. Single crystal X-ray structure of 1 show distorted octahedral geometry around Zn2+. Two phthiocol ligands are in plane with the metal, while water molecules are trans to this plane. Coordination of deprotonated phthiocol ligands is 'trans, trans' to Zn2+. Intra as well as intermolecular interactions are observed in 1. Molecules of 1 show three dimensional network through CH⋯O and OH⋯O interactions. Additional anodic peaks are observed in cyclic voltammogram of phthiocol ligand due to oxidation of reduced species formed during reduction. One-electron reduction of 1 is shown to be reversible and DFT studies define this redox event as ligand-centered.

  6. Activation of c-Jun N-terminal kinase and apoptosis in endothelial cells mediated by endogenous generation of hydrogen peroxide

    NASA Technical Reports Server (NTRS)

    Ramachandran, Anup; Moellering, Douglas; Go, Young-Mi; Shiva, Sruti; Levonen, Anna-Liisa; Jo, Hanjoong; Patel, Rakesh P.; Parthasarathy, Sampath; Darley-Usmar, Victor M.

    2002-01-01

    Reactive oxygen species have been implicated in the activation of signal transduction pathways. However, extracellular addition of oxidants such as hydrogen peroxide (H2O2) often requires concentrations that cannot be readily achieved under physiological conditions to activate biological responses such as apoptosis. Explanations for this discrepancy have included increased metabolism of H2O2 in the extracellular environment and compartmentalization within the cell. We have addressed this issue experimentally by examining the induction of apoptosis of endothelial cells induced by exogenous addition of H2O2 and by a redox cycling agent, 2,3-dimethoxy-1,4-naphthoquinone, that generates H2O2 in cells. Here we show that low nanomolar steady-state concentrations (0.1-0.5 nmol x min(-1) x 10(6) cells) of H2O2 generated intracellularly activate c-Jun N terminal kinase and initiate apoptosis in endothelial cells. A comparison with bolus hydrogen peroxide suggests that the low rate of intracellular formation of this reactive oxygen species results in a similar profile of activation for both c-Jun N terminal kinase and the initiation of apoptosis. However, a detailed analysis reveals important differences in both the duration and profile for activation of these signaling pathways.

  7. A portable optical human sweat sensor

    NASA Astrophysics Data System (ADS)

    Al-omari, Mahmoud; Liu, Gengchen; Mueller, Anja; Mock, Adam; Ghosh, Ruby N.; Smith, Kyle; Kaya, Tolga

    2014-11-01

    We describe the use of HNQ (2-hydroxy-1,4-naphthoquinone or Lawsone) as a potential sweat sensor material to detect the hydration levels of human beings. We have conducted optical measurements using both artificial and human sweat to validate our approach. We have determined that the dominant compound that affects HNQ absorbance in artificial sweat is sodium. The presence of lactate decreases the reactivity of HNQ while urea promotes more interactions of sodium and potassium ions with HNQ. The interactions between the hydroxyl group of HNQ and the artificial sweat components (salts, lactic acid, and urea) were investigated comprehensively. We have also proposed and developed a portable diode laser absorption sensor system that converts the absorbance at a particular wavelength range (at 455 ± 5 nm, where HNQ has an absorbance peak) into light intensity measurements via a photocell. The absorbance intensity values obtained from our portable sensor system agrees within 10.4% with measurements from a laboratory based ultraviolet-visible spectrometer. Findings of this research will provide significant information for researchers who are focusing on real-time, in-situ hydration level detection.

  8. Plumbagin suppresses dendritic cell functions and alleviates experimental autoimmune encephalomyelitis.

    PubMed

    Zhang, Kai; Ge, Zhenzhen; Da, Yurong; Wang, Dong; Liu, Ying; Xue, Zhenyi; Li, Yan; Li, Wen; Zhang, Lijuan; Wang, Huafeng; Zhang, Huan; Peng, Meiyu; Hao, Junwei; Yao, Zhi; Zhang, Rongxin

    2014-08-15

    Plumbagin (PL, 5-hydroxy-2-methyl-1,4-naphthoquinone) is a herbal compound derived from medicinal plants of the Droseraceae, Plumbaginaceae, Dioncophyllaceae, and Ancistrocladaceae families. Reports have shown that PL exerts immunomodulatory activity and may be a novel drug candidate for immune-related disease therapy. However, its effects on dendritic cells (DCs), the most potent antigen-presenting cells (APCs), remain unclear. In this study, we demonstrate that PL inhibits the differentiation, maturation, and function of human monocyte-derived DCs. PL can also restrict the expression of Th1- and Th17-polarizing cytokines in mDC. In addition, PL suppresses DCs both in vitro and in vivo, as demonstrated by its effects on the mouse DC line DC2.4 and mice with experimental autoimmune encephalomyelitis (EAE), respectively. Notably, PL ameliorated the clinical symptoms of EAE, including central nervous system (CNS) inflammation and demyelination. Our results demonstrate the immune suppressive and anti-inflammatory properties of PL via its effects on DCs and suggest that PL could be a potential treatment for DC-related autoimmune and inflammatory diseases. PMID:24953531

  9. Conjugated polymer and drug co-encapsulated nanoparticles for Chemo- and Photo-thermal Combination Therapy with two-photon regulated fast drug release

    NASA Astrophysics Data System (ADS)

    Yuan, Youyong; Wang, Zuyong; Cai, Pingqiang; Liu, Jie; Liao, Lun-De; Hong, Minghui; Chen, Xiaodong; Thakor, Nitish; Liu, Bin

    2015-02-01

    The spatial-temporal synchronization of photothermal therapy and chemotherapy is highly desirable for an efficient cancer treatment with synergistic effect. Herein, we developed a chemotherapeutic drug doxorubicin (DOX) and photothermal conjugated polymer (CP) co-loaded nanoplatform using a near-infrared (NIR) laser responsive amphiphilic brush copolymer as the encapsulation matrix. The obtained nanoparticles (NPs) exhibit good monodispersity and excellent stability, which can efficiently convert laser energy into thermal energy for photothermal therapy. Moreover, the hydrophobic polymer matrix bearing a number of 2-diazo-1,2-naphthoquinones (DNQ) moieties could be transformed to a hydrophilic one upon NIR two-photon laser irradiation, which leads to fast drug release. Furthermore, the surface modification of the NPs with cyclic arginine-glycine-aspartic acid (cRGD) tripeptide significantly enhances the accumulation of the NPs within integrin ?v?3 overexpressed cancer cells. The half-maximal inhibitory concentration (IC50) of the combination therapy is 13.7 ?g mL-1, while the IC50 for chemotherapy and photothermal therapy alone is 147.8 ?g mL-1 and 36.2 ?g mL-1, respectively. The combination index (C.I.) is 0.48 (<1), which indicates the synergistic effect for chemotherapy and PTT. These findings provide an excellent NIR laser regulated nanoplatform for combined cancer treatment with synergistic effect due to the synchronous chemo- and photo-thermal therapy.

  10. The Mechanism Underlying the Antibacterial Activity of Shikonin against Methicillin-Resistant Staphylococcus aureus

    PubMed Central

    Lee, Young-Seob; Lee, Dae-Young; Kim, Yeon Bok; Lee, Sang-Won; Cha, Seon-Woo; Park, Hong-Woo; Kim, Geum-Soog; Kwon, Dong-Yeul; Lee, Min-Ho; Han, Sin-Hee

    2015-01-01

    Shikonin (SKN), a highly liposoluble naphthoquinone pigment isolated from the roots of Lithospermum erythrorhizon, is known to exert antibacterial, wound-healing, anti-inflammatory, antithrombotic, and antitumor effects. The aim of this study was to examine SKN antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA). The SKN was analyzed in combination with membrane-permeabilizing agents Tris and Triton X-100, ATPase inhibitors sodium azide and N,N?-dicyclohexylcarbodiimide, and S. aureus-derived peptidoglycan; the effects on MRSA viability were evaluated by the broth microdilution method, time-kill test, and transmission electron microscopy. Addition of membrane-permeabilizing agents or ATPase inhibitors together with a low dose of SKN potentiated SKN anti-MRSA activity, as evidenced by the reduction of MRSA cell density by 75% compared to that observed when SKN was used alone; in contrast, addition of peptidoglycan blocked the antibacterial activity of SKN. The results indicate that the anti-MRSA effect of SKN is associated with its affinity to peptidoglycan, the permeability of the cytoplasmic membrane, and the activity of ATP-binding cassette (ABC) transporters. This study revealed the potential of SKN as an effective natural antibiotic and of its possible use to substantially reduce the use of existing antibiotic may also be important for understanding the mechanism underlying the antibacterial activity of natural compounds. PMID:26265924

  11. Discovery and Development of Natural Product-derived Chemotherapeutic Agents Based on a Medicinal Chemistry Approach?†

    PubMed Central

    Lee, Kuo-Hsiung

    2010-01-01

    Medicinal plants have long been an excellent source of pharmaceutical agents. Accordingly, the long term objectives of the author's research program are to discover and design new chemotherapeutic agents based on plant-derived compound leads by using a medicinal chemistry approach, which is a combination of chemistry and biology. Different examples of promising bioactive natural products and their synthetic analogs, including sesquiterpene lactones, quassinoids, naphthoquinones, phenylquinolones, dithiophenediones, neo-tanshinlactone, tylophorine, suksdorfin, DCK, and DCP, will be presented with respect to their discovery and preclinical development as potential clinical trial candidates. Research approaches include bioactivity- or mechanism of action-directed isolation and characterization of active compounds, rational drug design-based modification and analog synthesis, as well as structure-activity relationship and mechanism of action studies. Current clinical trials agents discovered by the Natural Products Research Laboratories, University of North Carolina, include bevirimat (dimethyl succinyl betulinic acid), which is now in Phase IIb trials for treating AIDS. Bevirimat is also the first in a new class of HIV drug candidates called “maturation inhibitors”. In addition, an etoposide analog, GL-331, progressed to anticancer Phase II clinical trials, and the curcumin analog JC-9 is in Phase II clinical trials for treating acne and in development for trials against prostate cancer. The discovery and development of these clinical trials candidates will also be discussed. PMID:20187635

  12. The first naphthosemiquinone complex of K+ with vitamin K3 analog: Experiment and density functional theory

    NASA Astrophysics Data System (ADS)

    Kathawate, Laxmi; Gejji, Shridhar P.; Yeole, Sachin D.; Verma, Prakash L.; Puranik, Vedavati G.; Salunke-Gawali, Sunita

    2015-05-01

    Synthesis and characterization of potassium complex of 2-hydroxy-3-methyl-1,4-naphthoquinone (phthiocol), the vitamin K3 analog, has been carried out using FT-IR, UV-Vis, 1H and 13C NMR, EPR, cyclic voltammetry and single crystal X-ray diffraction experiments combined with the density functional theory. It has been observed that naphthosemiquinone binds to two K+ ions extending the polymeric chain through bridging oxygens O(2) and O(3). The crystal network possesses hydrogen bonding interactions from coordinated water molecules showing water channels along the c-axis. 13C NMR spectra revealed that the complexation of phthiocol with potassium ion engenders deshielding of C(2) signals, which appear at ? = ?14.6 ppm whereas those of C(3) exhibit up-field signals near ? ? 6.9 ppm. These inferences are supported by the M06-2x based density functional theory. Electrochemical experiments further suggest that reduction of naphthosemiquinone results in only a cathodic peak from catechol. A triplet state arising from interactions between neighboring phthiocol anion lead to a half field signal at g = 4.1 in the polycrystalline X-band EPR spectra at 133 K.

  13. Plumbagin alters telomere dynamics, induces DNA damage and cell death in human brain tumour cells.

    PubMed

    Khaw, Aik Kia; Sameni, Safoura; Venkatesan, Shriram; Kalthur, Guruprasad; Hande, M Prakash

    2015-11-01

    Natural plant products may possess much potential in palliative therapy and supportive strategies of current cancer treatments with lesser cytotoxicity to normal cells compared to conventional chemotherapy. In the current study, anti-cancer properties of plumbagin, a plant-derived naphthoquinone, on brain cancer cells were determined. Plumbagin treatment resulted in the induction of DNA damage, cell cycle arrest and apoptosis, followed by suppression of the colony forming ability of the brain tumour cells. These effects were substantiated by upregulation of PTEN, TNFRSF1A and downregulation of E2F1 genes, along with a drop in MDM2, cyclin B1, survivin and BCL2 protein expression. Plumbagin induced elevated levels of caspase-3/7 activity as well. For the first time, we show here that plumbagin inhibits telomerase in brain tumour cells and results in telomere shortening following chronic long-term treatment. This observation implies considerable cytotoxicity of plumbagin towards cancer cells with higher telomerase activity. Collectively, our findings suggest plumbagin as a potential chemotherapeutic phytochemical in brain tumour treatment modalities. PMID:26520377

  14. Physicochemical characteristics, oxidative capacities and cytotoxicities of sulfate-coated, 1,4-NQ-coated and ozone-aged black carbon particles

    NASA Astrophysics Data System (ADS)

    Li, Qian; Shang, Jing; Liu, Jia; Xu, Weiwei; Feng, Xiang; Li, Rui; Zhu, Tong

    2015-02-01

    Black carbon (BC) particles play important roles in climate change, visibility impairment, atmospheric reaction process, and health effect. The aging processes of BC alter not only atmospheric composition, but also the physicochemical characteristics of BC itself, thus impacting the environment and health effects. Here, three types of BC including sulfate-coated, 1,4-naphthoquinone (1,4-NQ)-coated, and O3-aged BC are presented. The morphologies, structures, extraction components, the amount of water-soluble organic carbon (WSOC) and free radical intensities of the three types of BC particles are examined by transmission electron microscopy, diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS), ultraviolet-visible spectrophotometry, total organic carbon detector and electron paramagnetic resonance, respectively. Dithiothreitol (DTT) and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide assays are utilized to assess the changes in oxidative capacity and cytotoxicity towards murine alveolar macrophage cells. The orders of DTT activities and cytotoxicities of the particles are both arranged as follows: BC/1,4-NQ > BC/O3 > BC > BC/sulfate, mainly because 1,4-NQ owned high oxidative potential and cytotoxicity, while sulfate did not exhibit oxidative capacity and cytotoxicity. The insoluble components of particles contribute most of the total DTT activity, whereas either water or methanol extract is minor contributor. DTT activity was positively correlated with both WSOC content and free radical intensity, with the correlation between DTT activity and WSOC content was stronger than that between DTT activity and free radical intensity.

  15. Human Vitamin K 2,3-Epoxide Reductase Complex Subunit 1-like 1 (VKORC1L1) Mediates Vitamin K-dependent Intracellular Antioxidant Function*

    PubMed Central

    Westhofen, Philipp; Watzka, Matthias; Marinova, Milka; Hass, Moritz; Kirfel, Gregor; Müller, Jens; Bevans, Carville G.; Müller, Clemens R.; Oldenburg, Johannes

    2011-01-01

    Human vitamin K 2,3-epoxide reductase complex subunit 1-like 1 (VKORC1L1), expressed in HEK 293T cells and localized exclusively to membranes of the endoplasmic reticulum, was found to support both vitamin K 2,3-epoxide reductase (VKOR) and vitamin K reductase enzymatic activities. Michaelis-Menten kinetic parameters for dithiothreitol-driven VKOR activity were: Km (?m) = 4.15 (vitamin K1 epoxide) and 11.24 (vitamin K2 epoxide); Vmax (nmol·mg?1·hr?1) = 2.57 (vitamin K1 epoxide) and 13.46 (vitamin K2 epoxide). Oxidative stress induced by H2O2 applied to cultured cells up-regulated VKORC1L1 expression and VKOR activity. Cell viability under conditions of no induced oxidative stress was increased by the presence of vitamins K1 and K2 but not ubinquinone-10 and was specifically dependent on VKORC1L1 expression. Intracellular reactive oxygen species levels in cells treated with 2,3-dimethoxy-1,4-naphthoquinone were mitigated in a VKORC1L1 expression-dependent manner. Intracellular oxidative damage to membrane intrinsic proteins was inversely dependent on VKORC1L1 expression and the presence of vitamin K1. Taken together, our results suggest that VKORC1L1 is responsible for driving vitamin K-mediated intracellular antioxidation pathways critical to cell survival. PMID:21367861

  16. Photochemistry of a photosynthetic reaction center immobilized in lipidic cubic phases

    SciTech Connect

    Hochkoeppler, A.; Venturoli, G.; Zannoni, D.; Landau, E.M.; Luisi, P.L.; Feick, R.

    1995-04-20

    Photosynthetic reaction centers, isolated and purified from the facultative phototrophic bacterium Chloroflexus aurantiacus, were immobilized in optically transparent lipidic cubic phases composed of 42% (w/w) 1-palmitoyl-2-hydroxy-sn-glycero-3-phosphocholine and 58% (w/w) water. The immobilized photosynthetic protein retains its native properties, as indicated by visible and circular dichroic spectra. The ground state visible spectrum of the immobilized reaction centers is very similar to the corresponding spectrum in aqueous solution, indicating that the protein pigments are not extracted into the lipidic regions of the cubic phase. The secondary structure of the protein is maintained in the immobilized state, as determined by far-UV circular dichroism spectroscopy in the 200- to 250-nm range. Moreover, immobilized reaction centers retain their photochemical activity: a reversible photo-oxidation of the primary electron donor (P) is seen upon continuous illumination. Furthermore, the entrapment of reaction centers does not affect the kinetics of charge recombination between the photo-oxidized primary donor (P{sup +}) and the photoreduced primary quinone acceptor, generated by a short flash of light. Reaction centers devoided of the secondary quinone acceptor can be easily reconstituted in cubic phases by means of their coimmobilization with 1,4-naphthoquinone.

  17. The anatomy and chemistry of the colour bands of grasstree stems (Xanthorrhoea preissii) used for plant age and fire history determination.

    PubMed

    Colangelo, Wendy I; Lamont, Byron B; Jones, Anthea S; Ward, David J; Bombardieri, Sandro

    2002-05-01

    A new method of ageing and determining the fire history of grasstrees, based on colour bands running along the stem, has been developed. As part of our evaluation of the technique, we examined the structural and chemical basis of the colour differences. Exposed ends of the leaf bases are cream, brown and black, with the inner cortex, especially in the black leaf bases, being darker than the outer cortex. There was no structural difference between the three leaf base types. Tannin concentration increased from cream to brown to black leaf bases, and from the inner to outer cortex, and remained quite stable over many years. Both water-soluble and insoluble pigments contribute to the darkness of the black leaf bases. A hydrophobic naphthoquinone was present in the conducting tissues of the vascular bundles, and related naphthalene-derivatives were present in the surrounding tissues. We conclude that the colour differences between the leaf bases have a chemical basis that can be linked to environmental changes: tannin cells to phenological effects, and naphthalene-derivatives in the vascular core to the passage of fire. PMID:12099535

  18. The Combination of Vitamin K3 and Vitamin C Has Synergic Activity against Forms of Trypanosoma cruzi through a Redox Imbalance Process

    PubMed Central

    Cristina Desoti, Vânia; Lazarin-Bidóia, Danielle; Martins Ribeiro, Fabianne; Cardoso Martins, Solange; da Silva Rodrigues, Jean Henrique; Ueda-Nakamura, Tania; Vataru Nakamura, Celso; Farias Ximenes, Valdecir; de Oliveira Silva, Sueli

    2015-01-01

    Chagas’ disease is an infection that is caused by the protozoan Trypanosoma cruzi, affecting millions of people worldwide. Because of severe side effects and variable efficacy, the current treatments for Chagas’ disease are unsatisfactory, making the search for new chemotherapeutic agents essential. Previous studies have reported various biological activities of naphthoquinones, such as the trypanocidal and antitumor activity of vitamin K3. The combination of this vitamin with vitamin C exerted better effects against various cancer cells than when used alone. These effects have been attributed to an increase in reactive oxygen species generation. In the present study, we evaluated the activity of vitamin K3 and vitamin C, alone and in combination, against T. cruzi. The vitamin K3 + vitamin C combination exerted synergistic effects against three forms of T. cruzi, leading to morphological, ultrastructural, and functional changes by producing reactive species, decreasing reduced thiol groups, altering the cell cycle, causing lipid peroxidation, and forming autophagic vacuoles. Our hypothesis is that the vitamin K3 + vitamin C combination induces oxidative imbalance in T. cruzi, probably started by a redox cycling process that leads to parasite cell death. PMID:26641473

  19. Detection of relative [Na+] and [K+] levels in sweat with optical measurements

    NASA Astrophysics Data System (ADS)

    Al-omari, Mahmoud; Sel, Kivanc; Mueller, Anja; Edwards, Jeffery; Kaya, Tolga

    2014-05-01

    We describe the use of 2-hydroxy-1,4-naphthoquinone (HNQ, Lawsone) as a potential sweat electrolyte measurement marker. We use ultraviolet-visible absorbance measurements to determine the absorbance energy in a particular wavelength range (400 nm-500 nm). This novel approach allows us to eliminate the importance of the exact wavelength of the absorbance peak but find the integral of the range of interest. Although we numerically calculate the absorbance energy, it is imperative to use photodiodes to measure the intensity of the transmitted light that is fabricated particularly for the range of interest for future device implementations. We explored various mixing ratios of water and acetone to find the optimum solvent that would give the most sensitive and accurate relative electrolyte sensing. The pH value was also modified to see the effect on the absorbance energy and intensity. A representative group of subjects were used to collect sweat from the dehydration and hyperhydration cases. The results are convincing that HNQ solutions can be used as a wearable, continuous sweat sensor.

  20. CYP76AH1 catalyzes turnover of miltiradiene in tanshinones biosynthesis and enables heterologous production of ferruginol in yeasts

    PubMed Central

    Guo, Juan; Zhou, Yongjin J.; Hillwig, Matthew L.; Shen, Ye; Yang, Lei; Wang, Yajun; Zhang, Xianan; Liu, Wujun; Peters, Reuben J.; Chen, Xiaoya; Zhao, Zongbao K.; Huang, Luqi

    2013-01-01

    Cytochrome P450 enzymes (CYPs) play major roles in generating highly functionalized terpenoids, but identifying the exact biotransformation step(s) catalyzed by plant CYP in terpenoid biosynthesis is extremely challenging. Tanshinones are abietane-type norditerpenoid naphthoquinones that are the main lipophilic bioactive components of the Chinese medicinal herb danshen (Salvia miltiorrhiza). Whereas the diterpene synthases responsible for the conversion of (E,E,E)-geranylgeranyl diphosphate into the abietane miltiradiene, a potential precursor to tanshinones, have been recently described, molecular characterization of further transformation of miltiradiene remains unavailable. Here we report stable-isotope labeling results that demonstrate the intermediacy of miltiradiene in tanshinone biosynthesis. We further use a next-generation sequencing approach to identify six candidate CYP genes being coregulated with the diterpene synthase genes in both the rhizome and danshen hairy roots, and demonstrate that one of these, CYP76AH1, catalyzes a unique four-electron oxidation cascade on miltiradiene to produce ferruginol both in vitro and in vivo. We then build upon the previous establishment of miltiradiene production in Saccharomyces cerevisiae, with incorporation of CYP76AH1 and phyto-CYP reductase genes leading to heterologous production of ferruginol at 10.5 mg/L. As ferruginol has been found in many plants including danshen, the results and the approaches that were described here provide a solid foundation to further elucidate the biosynthesis of tanshinones and related diterpenoids. Moreover, these results should facilitate the construction of microbial cell factories for the production of phytoterpenoids. PMID:23812755

  1. Effects of Salvia officinalis and Thymus vulgaris on oxidant-induced DNA damage and antioxidant status in HepG2 cells.

    PubMed

    Kozics, Katarína; Klusová, Veronika; Sran?íková, Annamária; Mu?aji, Pavol; Slame?ová, Darina; Hunáková, Lubica; Kusznierewicz, Barbara; Horváthová, Eva

    2013-12-01

    Salvia officinalis (SO) and Thymus vulgaris (TV) are medicinal plants well known for their curative powers. However, the molecular mechanisms responsible for these abilities of sage and thyme have not been fully understood yet. In this study we investigated the composition and the quantitative estimation of plant extracts, the protective effects of plant extracts against hydrogen peroxide- and 2,3-dimethoxy-1,4-naphthoquinone-induced DNA damage, and levels of enzymatic and non-enzymatic antioxidants (superoxide dismutase, glutathione peroxidase, glutathione) in human HepG2 cells. To measure antioxidative activity of plant extracts we used three assays: 1,1-diphenyl-2-picrylhydrazyl (DPPH), ferric reducing antioxidant power (FRAP) and 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS). The results showed that the oxidant-induced DNA lesions were significantly reduced in cells pre-treated with the plant extracts studied. The observed DNA-protective activity could be explained by both elevation of GPx activity in cells pre-treated with SO and TV and antioxidant activity of SO and TV. PMID:23870948

  2. ?-Lapachone activity in synergy with conventional antimicrobials against methicillin resistant Staphylococcus aureus strains.

    PubMed

    Macedo, L; Fernandes, T; Silveira, L; Mesquita, A; Franchitti, A A; Ximenes, E A

    2013-12-15

    The aim of this study was to evaluate the antimicrobial activity of lapachol, ?-lapachone, ?-lapachone and six antimicrobials (ampicillin, amoxicillin/clavulanic acid, cefoxitin, gentamicin, ciprofloxacin and meropenem) against twelve strains of Staphylococcus aureus from which resistance phenotypes were previously determined by the disk diffusion method. Five S. aureus strains (LFBM 01, LFBM 26, LFBM 28, LFBM 31 and LFBM 33) showed resistance to all antimicrobial agents tested and were selected for the study of the interaction between ?-lapachone and antimicrobial agents, busing checkerboard method. The criteria used to evaluate the synergistic activity were defined by the Fractional Inhibitory Concentration Index (FICI). Among the naphthoquinones, ?-lapachone was the most effective against S. aureus strains. FICI values ranged from 0.07 to 0.5, suggesting a synergistic interaction against multidrug resistant S. aureus (MRSA) strains. An additive effect was observed with the combination ?-lapachone/ciprofloxacin against the LFBM 33 strain. The combination of ?-lapachone with cefoxitin showed no added benefit against LFBM 31 and LFBM 33 strains. This study demonstrated that, in general, ?-lapachone combined with beta lactams antimicrobials, fluoroquinolones and carbapenems acts synergistically inhibiting MRSA strains. PMID:24035227

  3. Biological evaluation of hydroxynaphthoquinones as anti-malarials

    PubMed Central

    2013-01-01

    Background The hydroxynaphthoquinones have been extensively investigated over the past 50 years for their anti-malarial activity. One member of this class, atovaquone, is combined with proguanil in Malarone®, an important drug for the treatment and prevention of malaria. Methods Anti-malarial activity was assessed in vitro for a series of 3-alkyl-2-hydroxy-1,4-naphthoquinones (N1-N5) evaluating the parasitaemia after 48 hours of incubation. Potential cytotoxicity in HEK293T cells was assessed using the MTT assay. Changes in mitochondrial membrane potential of Plasmodium were measured using the fluorescent dye Mitrotracker Red CMXROS. Results Four compounds demonstrated IC50s in the mid-micromolar range, and the most active compound, N3, had an IC50 of 443 nM. N3 disrupted mitochondrial membrane potential, and after 1 hour presented an IC50??mit of 16 ?M. In an in vitro cytotoxicity assay using HEK 293T cells N3 demonstrated no cytotoxicity at concentrations up to 16 ?M. Conclusions N3 was a potent inhibitor of mitochondrial electron transport, had nanomolar activity against cultured Plasmodium falciparum and showed minimal cytotoxicity. N3 may serve as a starting point for the design of new hydroxynaphthoquinone anti-malarials. PMID:23841934

  4. Fragmentation studies and electrospray ionization mass spectrometry of lapachol: protonated, deprotonated and cationized species.

    PubMed

    Vessecchi, Ricardo; Emery, Flavio S; Galembeck, Sérgio E; Lopes, Norberto P

    2010-07-30

    Electrospray ionization mass spectrometric analysis of lapachol (2-hydroxy-3-(3-methyl-2-butenyl)-1,4-naphthoquinone) was accomplished in order to elucidate the gas-phase dissociation reactions of this important biologically active natural product. The occurrence of protonated and cationized species in the positive mode and of deprotonated species in the negative mode was explored by means of collision-induced dissociation (CID) experiments. For the protonated molecule, the H(2)O and C(4)H(8) losses occur by two competitive channels. For the deprotonated molecule, the even-electron rule is not conserved, and the radicalar species are eliminated by formation of distonic anions. The fragmentation mechanism for each ion was suggested on the basis of computational thermochemistry. Atomic charges, relative energies, and frontier orbitals were employed aiming at a better understanding of the gas-phase reactivity of lapachol. Potential energy surfaces for fragmentation reactions were obtained by the B3LYP/6-31+G(d,p) model. PMID:20552691

  5. A new type of pterocarpanquinone that affects Toxoplasma gondii tachyzoites in vitro.

    PubMed

    Portes, Juliana de Araujo; Netto, Chaquip Daher; da Silva, Alcides José Monteiro; Costa, Paulo Roberto Ribeiro; DaMatta, Renato Augusto; dos Santos, Thiago Alves Teixeira; De Souza, Wanderley; Seabra, Sergio Henrique

    2012-05-25

    Toxoplasma gondii, the agent of Toxoplasmosis, is an obligate intracellular protozoan able to infect a wide range of vertebrate cells, including nonprofessional and professional phagocytes. Therefore, drugs must have intracellular activities in order to control this parasite. The most common therapy for Toxoplasmosis is the combination of sulfadiazine and pyrimethamine. This treatment is associated with adverse reactions, thus, the development of new drugs is necessary. In previous studies, naphthoquinone derivatives showed anti-cancer activity functioning as agents capable of acting on groups of DNA, preventing cancer cells duplication. These derivatives also display anti-parasitic activity against Plasmodium falciparum and Leishmania amazonensis. The derivative pterocarpanquinone tested in this work resulted from the molecular hybridization between pterocarpans and naphtoquinone that presents anti-tumoral and anti-parasitic activities of lapachol. The aim of this work was to determine if this derivative is able to change T. gondii growth within LLC-MK2 cells. The drug did not arrest host cell growth, but was able to decrease the infection index of T. gondii with an IC(50) of 2.5 ?M. Scanning and transmission electron microscopy analysis showed morphological changes of parasites including membrane damage. The parasite that survived tended to encyst as seen by Dolichos biflorus lectin staining and Bag-1 expression. These results suggest that pterocarpanquinones are drugs potentially important for the killing and encystment of T. gondii. PMID:22177332

  6. Cytotoxicity and In Vitro Antileishmanial Activity of Antimony (V), Bismuth (V), and Tin (IV) Complexes of Lapachol.

    PubMed

    Rocha, Marcele Neves; Nogueira, Paula Monalisa; Demicheli, Cynthia; de Oliveira, Ludmila Gonçalvez; da Silva, Meiriane Mariano; Frézard, Frédéric; Melo, Maria Norma; Soares, Rodrigo Pedro

    2013-01-01

    Leishmania amazonensis is the etiologic agent of the cutaneous and diffuse leishmaniasis often associated with drug resistance. Lapachol [2-hydroxy-3-(3'-methyl-2-butenyl)-1,4-naphthoquinone] displays a wide range of antimicrobial properties against many pathogens. In this study, using the classic microscopic in vitro model, we have analyzed the effects of a series of lapachol and chlorides complexes with antimony (V), bismuth (V), and tin (IV) against L. amazonensis. All seven compounds exhibited antileishmanial activity, but most of the antimony (V) and bismuth (V) complexes were toxic against human HepG2 cells and murine macrophages. The best IC50 values (0.17 ± 0.03 and 0.10 ± 0.11??g/mL) were observed for Tin (IV) complexes (3) [(Lp)(Ph3Sn)] and (6) (Ph3SnCl2), respectively. Their selective indexes (SIs) were 70.65 and 120.35 for HepG2 cells, respectively. However, while analyzing murine macrophages, the SI decreased. Those compounds were moderately toxic for HepG2 cells and toxic for murine macrophages, still underlying the need of chemical modification in this class of compounds. PMID:23781165

  7. Synthesis and anti-Trypanosoma cruzi activity of derivatives from nor-lapachones and lapachones.

    PubMed

    da Silva Júnior, Eufrânio N; de Souza, Maria Cecília B V; Fernandes, Michelle C; Menna-Barreto, Rubem F S; Pinto, Maria do Carmo F R; de Assis Lopes, Francisco; de Simone, Carlos Alberto; Andrade, Carlos Kleber Z; Pinto, Antônio V; Ferreira, Vitor F; de Castro, Solange L

    2008-05-01

    New naphthoquinone derivatives were synthesized and assayed against bloodstream trypomastigote forms of Trypanosoma cruzi, the etiological agent of Chagas' disease. The compounds were rationalized based on hybrid drugs and appear as important compounds against this parasite. From nor-lapachol were prepared five substituted ortho-naphthofuranquinones, a non-substituted para-naphthofuranquinone, a new oxyrane and an azide and from alpha-lapachone a new non-substituted para-naphthofuranquinone. Other five substituted ortho-naphthofuranquinones recently designed as cytotoxic, were also evaluated. The most active compounds were the ortho naphthofuranquinones 3-(4-methoxyphenylamino)-2,3-dihydro-2,2-dimethylnaphtho[1,2-b]furan-4,5-dione and 3-(3-nitrophenylamino)-2,3-dihydro-2,2-dimethylnaphtho[1,2-b]furan-4,5-dione with trypanocidal activity higher than that of benznidazole, the standard drug. The compounds were rationalized based on hybrid drugs and appear as important compounds against T. cruzi. The trypanocidal activity of these substances endowed with redox properties representing a good starting point for a medicinal chemistry program aiming the chemotherapy of Chagas' disease. PMID:18378461

  8. Screening for small molecule modulators of Hsp70 chaperone activity using protein aggregation suppression assays: inhibition of the plasmodial chaperone PfHsp70-1.

    PubMed

    Cockburn, Ingrid L; Pesce, Eva-Rachele; Pryzborski, Jude M; Davies-Coleman, Michael T; Clark, Peter G K; Keyzers, Robert A; Stephens, Linda L; Blatch, Gregory L

    2011-05-01

    Plasmodium falciparum heat shock protein 70 (PfHsp70-1) is thought to play an essential role in parasite survival and virulence in the human host, making it a potential antimalarial drug target. A malate dehydrogenase based aggregation suppression assay was adapted for the screening of small molecule modulators of Hsp70. A number of small molecules of natural (marine prenylated alkaloids and terrestrial plant naphthoquinones) and related synthetic origin were screened for their effects on the protein aggregation suppression activity of purified recombinant PfHsp70-1. Five compounds (malonganenone A-C, lapachol and bromo-?-lapachona) were found to inhibit the chaperone activity of PfHsp70-1 in a concentration dependent manner, with lapachol preferentially inhibiting PfHsp70-1 compared to another control Hsp70. Using growth inhibition assays on P. falciparum infected erythrocytes, all of the compounds, except for malonganenone B, were found to inhibit parasite growth with IC(50) values in the low micromolar range. Overall, this study has identified two novel classes of small molecule inhibitors of PfHsp70-1, one representing a new class of antiplasmodial compounds (malonganenones). In addition to demonstrating the validity of PfHsp70-1 as a possible drug target, the compounds reported in this study will be potentially useful as molecular probes for fundamental studies on Hsp70 chaperone function. PMID:21426241

  9. Cytotoxicity and In Vitro Antileishmanial Activity of Antimony (V), Bismuth (V), and Tin (IV) Complexes of Lapachol

    PubMed Central

    Rocha, Marcele Neves; Nogueira, Paula Monalisa; Demicheli, Cynthia; de Oliveira, Ludmila Gonçalvez; da Silva, Meiriane Mariano; Frézard, Frédéric; Melo, Maria Norma; Soares, Rodrigo Pedro

    2013-01-01

    Leishmania amazonensis is the etiologic agent of the cutaneous and diffuse leishmaniasis often associated with drug resistance. Lapachol [2-hydroxy-3-(3?-methyl-2-butenyl)-1,4-naphthoquinone] displays a wide range of antimicrobial properties against many pathogens. In this study, using the classic microscopic in vitro model, we have analyzed the effects of a series of lapachol and chlorides complexes with antimony (V), bismuth (V), and tin (IV) against L. amazonensis. All seven compounds exhibited antileishmanial activity, but most of the antimony (V) and bismuth (V) complexes were toxic against human HepG2 cells and murine macrophages. The best IC50 values (0.17 ± 0.03 and 0.10 ± 0.11??g/mL) were observed for Tin (IV) complexes (3) [(Lp)(Ph3Sn)] and (6) (Ph3SnCl2), respectively. Their selective indexes (SIs) were 70.65 and 120.35 for HepG2 cells, respectively. However, while analyzing murine macrophages, the SI decreased. Those compounds were moderately toxic for HepG2 cells and toxic for murine macrophages, still underlying the need of chemical modification in this class of compounds. PMID:23781165

  10. PLS-Prediction and Confirmation of Hydrojuglone Glucoside as the Antitrypanosomal Constituent of Juglans Spp.

    PubMed

    Ellendorff, Therese; Brun, Reto; Kaiser, Marcel; Sendker, Jandirk; Schmidt, Thomas J

    2015-01-01

    Naphthoquinones (NQs) occur naturally in a large variety of plants. Several NQs are highly active against protozoans, amongst them the causative pathogens of neglected tropical diseases such as human African trypanosomiasis (sleeping sickness), Chagas disease and leishmaniasis. Prominent NQ-producing plants can be found among Juglans spp. (Juglandaceae) with juglone derivatives as known constituents. In this study, 36 highly variable extracts were prepared from different plant parts of J. regia, J. cinerea and J. nigra. For all extracts, antiprotozoal activity was determined against the protozoans Trypanosoma cruzi, T. brucei rhodesiense and Leishmania donovani. In addition, an LC-MS fingerprint was recorded for each extract. With each extract's fingerprint and the data on in vitro growth inhibitory activity against T. brucei rhodesiense a Partial Least Squares (PLS) regression model was calculated in order to obtain an indication of compounds responsible for the differences in bioactivity between the 36 extracts. By means of PLS, hydrojuglone glucoside was predicted as an active compound against T. brucei and consequently isolated and tested in vitro. In fact, the pure compound showed activity against T. brucei at a significantly lower cytotoxicity towards mammalian cells than established antiprotozoal NQs such as lapachol. PMID:26035104

  11. Modulatory effects of Tabebuia impetiginosa (Lamiales, Bignoniaceae) on doxorubicin-induced somatic mutation and recombination in Drosophila melanogaster.

    PubMed

    de Sousa, Neila C; de Rezende, Alexandre A A; da Silva, Regildo M G; Guterres, Zaira R; Graf, Ulrich; Kerr, Warwick E; Spanó, Mário A

    2009-04-01

    The wing Somatic Mutation and Recombination Test (SMART) in D. melanogaster was used to study genotoxicity of the medicinal plant Tabebuia impetiginosa. Lapachol (naphthoquinone) and ?-lapachone (quinone) are the two main chemical constituents of T. impetiginosa. These compounds have several biological properties. They induce apoptosis by generating oxygen-reactive species, thereby inhibiting topoisomerases (I and II) or inducing other enzymes dependent on NAD(P)H:quinone oxidoreductase 1, thus affecting cell cycle checkpoints. The SMART was used in the standard (ST) version, which has normal levels of cytochrome P450 (CYP) enzymes, to check the direct action of this compound, and in the high bioactivation (HB) version, which has a high constitutive level of CYP enzymes, to check for indirect action in three different T. impetiginosa concentrations (10%, 20% or 40% w/w). It was observed that T. impetiginosa alone did not modify the spontaneous frequencies of mutant spots in either cross. The negative results observed prompted us to study this phytotherapeuticum in association with the reference mutagen doxorubicin (DXR). In co-treated series, T. impetiginosa was toxic in both crosses at higher concentration, whereas in the HB cross, it induced a considerable potentiating effect (from ~24.0 to ~95.0%) on DXR genotoxity. Therefore, further research is needed to determine the possible risks associated with the exposure of living organisms to this complex mixture. PMID:21637695

  12. Structural elucidation of the metabolites of lapachol in rats by liquid chromatography-tandem mass spectrometry.

    PubMed

    Bai, Lu; Han, Ying; Yao, Jinfeng; Li, Xiaorong; Li, Yuhang; Xu, Pinxiang; Xue, Ming

    2014-01-01

    Lapachol is a natural naphthoquinone compound derived from Bignoniaceae (Tabebuia sp.) that possesses a range of significant biological activities. Nine phase I and four phase II metabolites of lapachol in rat bile were firstly elucidated and identified using a sensitive LC-ESI-MS(n) method. The molecular structures of the metabolites have been presented on the basis of the characteristics of their precursor and product ions, as well as their fragmentation mechanisms and chromatographic retention times. The results indicated that the phase I metabolites were predominantly biotransformed by the hydroxylation, semiquinone hydrogenation at the oxygen position or a side chain rearrangement. The phase II metabolites were identified as the glucuronidated conjugates which showed a characteristic neutral loss of 176Da. Based on the results of this research, we have proposed the metabolic pathways for lapachol in rats. This work has provided novel information for the in vivo lapachol metabolism which could be used to develop a novel drug candidate, as well as a better understanding of the safety and efficacy of the drug. PMID:24316523

  13. Multitarget drug design strategy: quinone-tacrine hybrids designed to block amyloid-? aggregation and to exert anticholinesterase and antioxidant effects.

    PubMed

    Nepovimova, Eugenie; Uliassi, Elisa; Korabecny, Jan; Peña-Altamira, Luis Emiliano; Samez, Sarah; Pesaresi, Alessandro; Garcia, Gregory E; Bartolini, Manuela; Andrisano, Vincenza; Bergamini, Christian; Fato, Romana; Lamba, Doriano; Roberti, Marinella; Kuca, Kamil; Monti, Barbara; Bolognesi, Maria Laura

    2014-10-23

    We report the identification of multitarget anti-Alzheimer compounds designed by combining a naphthoquinone function and a tacrine fragment. In vitro, 15 compounds displayed excellent acetylcholinesterase (AChE) inhibitory potencies and interesting capabilities to block amyloid-? (A?) aggregation. The X-ray analysis of one of those compounds in complex with AChE allowed rationalizing the outstanding activity data (IC50 = 0.72 nM). Two of the compounds showed negligible toxicity in immortalized mouse cortical neurons Neuro2A and primary rat cerebellar granule neurons. However, only one of them was less hepatotoxic than tacrine in HepG2 cells. In T67 cells, both compounds showed antioxidant activity, following NQO1 induction. Furthermore, in Neuro2A, they were able to completely revert the decrease in viability induced by A?. Importantly, they crossed the blood-brain barrier, as demonstrated in ex vivo experiments with rats. When ex vivo results were combined with in vitro studies, these two compounds emerged to be promising multitarget lead candidates worthy of further pursuit. PMID:25259726

  14. Conjugated polymer and drug co-encapsulated nanoparticles for chemo- and photo-thermal combination therapy with two-photon regulated fast drug release.

    PubMed

    Yuan, Youyong; Wang, Zuyong; Cai, Pingqiang; Liu, Jie; Liao, Lun-De; Hong, Minghui; Chen, Xiaodong; Thakor, Nitish; Liu, Bin

    2015-02-21

    The spatial-temporal synchronization of photothermal therapy and chemotherapy is highly desirable for an efficient cancer treatment with synergistic effect. Herein, we developed a chemotherapeutic drug doxorubicin (DOX) and photothermal conjugated polymer (CP) co-loaded nanoplatform using a near-infrared (NIR) laser responsive amphiphilic brush copolymer as the encapsulation matrix. The obtained nanoparticles (NPs) exhibit good monodispersity and excellent stability, which can efficiently convert laser energy into thermal energy for photothermal therapy. Moreover, the hydrophobic polymer matrix bearing a number of 2-diazo-1,2-naphthoquinones (DNQ) moieties could be transformed to a hydrophilic one upon NIR two-photon laser irradiation, which leads to fast drug release. Furthermore, the surface modification of the NPs with cyclic arginine-glycine-aspartic acid (cRGD) tripeptide significantly enhances the accumulation of the NPs within integrin ?v?3 overexpressed cancer cells. The half-maximal inhibitory concentration (IC50) of the combination therapy is 13.7 ?g mL(-1), while the IC50 for chemotherapy and photothermal therapy alone is 147.8 ?g mL(-1) and 36.2 ?g mL(-1), respectively. The combination index (C.I.) is 0.48 (<1), which indicates the synergistic effect for chemotherapy and PTT. These findings provide an excellent NIR laser regulated nanoplatform for combined cancer treatment with synergistic effect due to the synchronous chemo- and photo-thermal therapy. PMID:25608113

  15. Organic acids enhanced decoloration of azo dye in gas phase surface discharge plasma system.

    PubMed

    Wang, Tiecheng; Qu, Guangzhou; Ren, Jingyu; Sun, Qiuhong; Liang, Dongli; Hu, Shibin

    2016-01-25

    A gas phase surface discharge plasma combined with organic acids system was developed to enhance active species mass transfer and dye-containing wastewater treatment efficacy, with Acid Orange II (AO7) as the model pollutant. The effects of discharge voltage and various organic acid additives (acetic acid, lactic acid and nonoic acid) on AO7 decoloration efficiency were evaluated. The experimental results showed that an AO7 decoloration efficiency of approximately 69.0% was obtained within 4min of discharge plasma treatment without organic acid addition, which was improved to 82.8%, 83.5% and 88.6% within the same treatment time with the addition of acetic acid, lactic acid and nonoic acid, respectively. The enhancement effects on AO7 decoloration efficiency could be attributed to the decrease in aqueous surface tension, improvement in bubble distribution and shape, and increase in ozone equivalent concentration. The AO7 wastewater was biodegradable after discharge plasma treatment with the addition of organic acid. AO7 decomposition intermediates were analyzed by UV-vis spectrometry and GC-MS; 2-naphthol, 1,4-benzoquinone, phthalic anhydride, coumarin, 1,2-naphthoquinone, and 2-formyl-benzoic acid were detected. A possible pathway for AO7 decomposition in this system was proposed. PMID:26444488

  16. [Partially hydrogenated aryl-1,2/1,4-anthraquinone derivatives, 5-lipoxygenase inhibitors with arotinoid structure].

    PubMed

    Wurm, G; Probst, R; Schwandt, S

    2001-07-01

    The combination of 5-LOX inhibition and retinoid activity in one molecule could be an interesting pharmacological tool to influence psoriasis. Thus we synthesized compounds with arotinoid structure by anellation of the 5-LOX inhibitors 1 and 2 with 1,1,4,4-tetramethylcyclohexane. A key step was the CuCl-MeCN-O2 oxidation of tetrahydroanthracenol 13 to the corresponding 1,2-anthraquinone 14 which could be converted to the analogous 2-hydroxy-1,4-anthraquinone 19 by Thiele-Winter reaction followed by oxidation. The halogenated quinones 9 and 21 were arylated with 2,6-di-tertbutylphenol and demethylated or hydrolyzed to the target compounds 3 and 4 which were tested in comparison with the non-anellated 5-LOX inhibitors 1 and 2 for LOX inhibition in activated human granulocytes and for antioxidative activity by the method of Popov with the chemiluminometer Photochem. The results are discussed in relation to the corresponding logP values. The 1,2-quinones 1 and 3 are more potent 5-LOX inhibitors than their 1,4-analogues 2 and 4, the tetrahydroanthraquinon derivatives 3 and 4 are less potent than the naphthoquinones 1 and 2. All compounds are devoid of any activity in cell differentiation as compared to retinoic acid as indicated by the NBT test with HL-60 leukemia cells. PMID:11487969

  17. Shikonin inhibits TNF-?-induced growth and invasion of rat aortic vascular smooth muscle cells.

    PubMed

    Zhang, Xuemin; Hu, Wenyu; Wu, Fang; Yuan, Xue; Hu, Jian

    2015-08-01

    Shikonin is a naphthoquinone compound extracted from the Chinese herb purple gromwell. Shikonin has broad antibacterial, anti-inflammatory, and antitumor activities. The tumor necrosis factor-? (TNF-?)-induced proliferation and invasion of vascular smooth muscle cells (VSMCs) is an important factor that contributes to atherosclerosis. The effects of shikonin on the proliferation and apoptosis of VSMCs have been reported; however, the function of shikonin on TNF-?-mediated growth and invasion of VSMCs during atherosclerosis remains unclear. In this study, we used Western blot, flow cytometry, real-time quantitative PCR, and enzyme-linked immunosorbent assay to investigate the effect of shikonin on the TNF-?-induced growth and invasion of VSMCs and to determine the underlying mechanism. Our results showed that shikonin inhibits the TNF-?-mediated growth and invasion. Further study revealed that shikonin regulates the activation of nuclear factor kappa B and phosphatidyl inositol 3-kinase signaling pathways; modulates the expression of cyclin D1, cyclin E, B-cell lymphoma 2, and Bax; activates caspase-3 and caspase-9; induces cell cycle arrest; and promotes the apoptosis of VSMCs. Together, our results indicate that shikonin may become a promising agent for the treatment of atherosclerosis and they also establish foundation for the development of anti-atherosclerosis drugs. PMID:26042337

  18. Biotechnological approaches to the production of shikonins: a critical review with recent updates.

    PubMed

    Malik, Sonia; Bhushan, Shashi; Sharma, Madhu; Ahuja, Paramvir Singh

    2016-04-01

    Shikonins are commercially important secondary compounds, known for array of biological activities such as antimicrobial, insecticidal, antitumor, antioxidants, etc. These compounds are usually colored and therefore have application in food, textiles and cosmetics. Shikonin and its derivatives, which are commercially most important of the naphthoquinone pigments, are distributed among members of the family Boraginaceae. These include different species of Lithospermum, Arnebia, Alkanna, Anchusa, Echium and Onosma. The growing demand for plant-based natural products has made this group of compounds one of the enthralling targets for their in vitro production. The aim of this review is to highlight the recent progress in production of shikonins by various biotechnological means. Different methods of increasing the levels of shikonins in plant cells such as selection of cell lines, optimization of culture conditions, elicitation, in situ product removal, genetic transformation and metabolic engineering are discussed. The experience of different researchers working worldwide on this aspect is also considered. Further, to meet market demand, the needs for continuous and reliable production systems, as well as future prospects, are included. PMID:25319455

  19. Identification of ?-Lapachone Analogs as Novel MALT1 Inhibitors To Treat an Aggressive Subtype of Diffuse Large B-Cell Lymphoma.

    PubMed

    Lim, Sang Min; Jeong, Yujeong; Lee, Suhyun; Im, Honggu; Tae, Hyun Seop; Kim, Byung Gyu; Park, Hee Dong; Park, Jonghoon; Hong, Sungwoo

    2015-11-12

    The treatment of activated B cell-like DLBCL (ABC-DLBCL) is one of the urgent unmet medical needs because it is the most resistant DLBCL subtype to current therapies eagerly awaiting effective therapeutic strategies. Recently, the paracaspase MALT1 has emerged as a promising therapeutic target for the treatment of ABC-DLBCL. Herein, we report a new class of MALT1 inhibitors developed by high-throughput screening and structure-based drug design. The original hit, 4-amino-1,2-naphthoquinone series inhibited MALT1 activity but suffered from poor cellular activity. The extensive pharmacophore search led to the discovery of structurally similar ?-lapachone that is a direct inhibitor of MALT1 and possesses favorable physicochemical properties. Molecular simulation studies suggested the possibility of the formation of a covalent bond between MALT1 and ?-lapachone, which was corroborated by experimental wash-out studies. Inspired by this, we explored the structure-activity relationships by incorporating electron-withdrawing substituents at C8 position of ?-lapachone. These MALT1 inhibitors exhibited potent antiproliferative activity to OCI-LY3 cell line and inhibited the cleavage of CYLD mediated MALT1. PMID:26496175

  20. Shikonin Induces Apoptosis, Necrosis, and Premature Senescence of Human A549 Lung Cancer Cells through Upregulation of p53 Expression

    PubMed Central

    Yeh, Yueh-Chiao; Liu, Tsun-Jui; Lai, Hui-Chin

    2015-01-01

    Shikonin, a natural naphthoquinone pigment isolated from Lithospermum erythrorhizon, has been reported to suppress growth of various cancer cells. This study was aimed to investigate whether this chemical could also inhibit cell growth of lung cancer cells and, if so, works via what molecular mechanism. To fulfill this, A549 lung cancer cells were treated with shikonin and then subjected to microscopic, biochemical, flow cytometric, and molecular analyses. Compared with the controls, shikonin significantly induced cell apoptosis and reduced proliferation in a dose-dependent manner. Specially, lower concentrations of shikonin (1–2.5??g/mL) cause viability reduction; apoptosis and cellular senescence induction is associated with upregulated expressions of cell cycle- and apoptotic signaling-regulatory proteins, while higher concentrations (5–10??g/mL) precipitate both apoptosis and necrosis. Treatment of cells with pifithrin-?, a specific inhibitor of p53, suppressed shikonin-induced apoptosis and premature senescence, suggesting the role of p53 in mediating the actions of shikonin on regulation of lung cancer cell proliferation. These results indicate the potential and dose-related cytotoxic actions of shikonin on A549 lung cancer cells via p53-mediated cell fate pathways and raise shikonin a promising adjuvant chemotherapeutic agent for treatment of lung cancer in clinical practice. PMID:25737737

  1. Effect of nitrogen source on end products of naphthalene degradation

    SciTech Connect

    Aranha, H.G.; Brown, L.R.

    1981-07-01

    Soil cultures, enrichment cultures, and pure culture isolates produced substantial quantities of salicylic acid from naphthalene in a mineral salts medium containing NH/sub 4/Cl as the nitrogen source. However, when KNO/sub 3/ was substituted for NH/sub 4/Cl, these same cultures failed to accumulate detectable quantities of salicylic acid but did not turn the medium yellow. When an isolate identified as a Pseudomonas species was used, viable cell numbers were much greater in the medium containing KNO/sub 3/ but up to 94% of the naphthalene was utilized in both media. The differences between nitrogen sources could not be accounted for by pH alone since results obtained using buffered media were similar. Growth with NH/sub 4/NO/sub 3/ displayed a pattern similar to that obtained when NH/sub 4/Cl was used. The yellow coloration in the medium containing KNO/sub 3/ was apparently due to more than one compound, none of which were 1,2-naphthoquinone or acidic in nature, as suggested by other investigators. Further attempts to identify the yellow compounds by high-pressure liquid chromatography, infrared analysis, and gas chromatography-mass spectrometry have been unsuccessful thus far.

  2. Mitochondrial p53 phosphorylation induces Bak-mediated and caspase-independent cell death

    PubMed Central

    Luo, Na; Nie, Chunlai; Zhao, Xinyu; Yuan, Zhu; Liu, Xinyu; Wei, Yuquan

    2015-01-01

    Chemoresistance in cancer has previously been attributed to gene mutations or deficiency. Caspase mutations or Bax deficiency can lead to resistance to cancer drugs. We recently demonstrated that Bak initiates a caspase/Bax-independent cell death pathway. We show that Plumbagin (PL) (5-hydroxy-2-methyl-1,4-napthoquinone), a medicinal plant-derived naphthoquinone that is known to have anti-tumor activity in a variety of models, induces caspase-independent cell death in HCT116 Bax knockout (KO) or MCF-7 Bax knockdown (KD) cells that express wild-type (WT) Bak. The re-expression of Bax in HCT116 Bax KO cells fails to enhance the PL-induced cell death. Additionally, Bak knockdown by shRNA efficiently attenuates PL-induced cell death. These results suggest that PL-induced cell death depends primarily on Bak, not Bax, in these cells. Further experimentation demonstrated that p53 Ser15 phosphorylation and mitochondrial translocation mediated Bak activation and subsequent cell death. Knockdown of p53 or a p53 Ser15 mutant significantly inhibited p53 mitochondrial translocation and cell death. Furthermore, we found that Akt mediated p53 phosphorylation and the subsequent mitochondrial accumulation. Taken together, our data elaborate the role of Bak in caspase/Bax-independent cell death and suggest that PL may be an effective agent for overcoming chemoresistance in cancer cells with dysfunctional caspases. PMID:25980443

  3. Nitrosative and oxidative stress induced heme oxygenase-1 accumulation in rat mesangial cells.

    PubMed

    Sandau, K; Pfeilschifter, J; Brüne, B

    1998-01-19

    The formation of nitric oxide (NO.) and superoxide (O2-) promotes rat mesangial cell death. Apoptotic death is characterized by DNA fragmentation, caspase-3 activation and concomitant poly(ADPribose) polymerase cleavage, as well as accumulation of the tumor suppressor protein p53. In close association with apoptotic parameters we noticed upregulation of heme oxygenase by the NO donor S-nitrosoglutathione (GSNO) and the redox cycler 2,3-dimethoxy-1,4-naphthoquinone (DMNQ) in a time- and concentration-dependent manner. In response to the NO. donor, heme oxygenase-1 expression was more easily obtained than initiation of apoptosis. Radical (NO./O2-) cogeneration abrogated DNA fragmentation, suppressed caspase activation and lowered p53 accumulation, thereby promoting cell survival of mesangial cells. In contrast, heme oxygenase-1 expression remained elevated under conditions of GSNO/DMNQ coadministration. Conclusively, heme oxygenase-1 is a stress marker for both nitrosative and oxidative stress. Accumulation of heme oxygenase-1 is found under conditions of both, apoptotic cell death and cell survival, thereby questioning a specific cytoprotective role of heme oxygenase-1 under conditions of NO. and/or O2- formation in rat mesangial cells. PMID:9544795

  4. Shikonin inhibits adipogenic differentiation via regulation of mir-34a-FKBP1B.

    PubMed

    Jang, Young Jin; Jung, Chang Hwa; Ahn, Jiyun; Gwon, So Young; Ha, Tae Youl

    2015-11-27

    Shikonin is a naturally occurring naphthoquinone pigment and a major constituent present in Lithospermum erythrorhizon. Since microRNAs (miRNAs) are one of the key post-transcriptional regulators of adipogenesis, their manipulation represents a potential new strategy to inhibit adipogenesis. Our aim was to investigate shikonin-dependent inhibition of adipogenesis with an emphasis on miRNA-related processes. Mir-34a increased during induced adipogenesis, and this was suppressed in the presence of shikonin. mRNA expression of FKBP1B, a suggested target of mir-34a according to bioinformatics studies, decreased during adipogenesis, but was recovered by shikonin treatment, which reversely correlated with mir-34a expression. A mir-34a inhibitor suppressed MDI-induced adipogenesis by blocking PPAR? and C/EBP? expression, while suppression of mir-34a recovered MDI-induced down-regulation of FKBP1B expression. A mir-34a mimic decreased FKBP1B mRNA expression in 3T3-L1 preadipocytes. We also observed that mir-34a bound directly to the 3'-untranslated region of FKBP1B. Finally, FKBP1B overexpression attenuated MDI-induced adipogenesis, PPAR?, and C/EBP? expression. These results suggest that mir-34a regulates adipogenesis by targeting FKBP1B expression. Our findings reveal that shikonin prevents adipogenesis by blocking the mir-34a-FKBP1B pathway which represents a promising potential target for preventing obesity. PMID:26471303

  5. Plumbagin inhibits tumour angiogenesis and tumour growth through the Ras signalling pathway following activation of the VEGF receptor-2

    PubMed Central

    Lai, Li; Liu, Junchen; Zhai, Dong; Lin, Qingxiang; He, Lijun; Dong, Yanmin; Zhang, Jing; Lu, Binbin; Chen, Yihua; Yi, Zhengfang; Liu, Mingyao

    2012-01-01

    BACKGROUND AND PURPOSE Angiogenesis-based therapy is an effective anti-tumour strategy and previous reports have shown some beneficial effects of a naturally occurring bioactive compound plumbagin (5-hydroxy-2-methyl-1, 4-naphthoquinone). Here, we sought to determine the biological effects of plumbagin on signalling mechanisms during tumour angiogenesis. EXPERIMENTAL APPROACH The effects of plumbagin were evaluated in various in vitro assays which utilised human umbilical vein endothelial cells (HUVEC) proliferation, migration and tube formation. Plumbagin was also evaluated in vivo using chicken embryo chorioallantoic membrane (CAM) and mouse corneal micropocket models., Human colon carcinoma and prostate cancer xenograft mouse models were used to evaluate the effects of plumbagin on angiogenesis. Immunofluorescence, GST pull-down and Western blotting were employed to explore the underlying mechanisms of VEGF receptor (VEGFR)2-mediated Ras signalling pathways. KEY RESULTS Plumbagin not only inhibited endothelial cell proliferation, migration and tube formation but also suppressed chicken chorioallantoic membrane neovascularzation and VEGF-induced mouse corneal angiogenesis. Moreover, plumbagin suppressed tumour angiogenesis and tumour growth in human colon carcinoma and prostate cancer xenograft mouse models. At a molecular level, plumbagin blocked the Ras/Rac/cofilin and Ras/MEK signalling pathways mediated by VEGFR2 in HUVECs. CONCLUSIONS AND IMPLICATIONS Plumbagin inhibited tumour angiogenesis and tumour growth by interference with the VEGFR2-mediated Ras signalling pathway in endothelial cells. Our findings demonstrate a molecular basis for the effects of plumbagin and suggest that this compound might have therapeutic ant-tumour effects. PMID:21658027

  6. Dissimilar effects of ?-lapachone- and hydroxyurea-induced DNA replication stress in root meristem cells of Allium cepa.

    PubMed

    Zabka, Aneta; Trzaskoma, Pawe?; Maszewski, Janusz

    2013-12-01

    Two anticancer drugs, ?-lapachone (?-lap, a naphthoquinone) and hydroxyurea (HU, an inhibitor of ribonucleotide reductase), differently affect nuclear morphology and cell cycle control mechanisms in root meristem cells of Allium cepa. The 18 h treatment with 100 ?M ?-lap results in a lowered number of M-phase cells, increased occurrence of mitotic abnormalities, including over-condensation of chromosomes, their enhanced stickiness, formation of anaphase bridges, micronucleation and reduced mitotic spindles. Following prolonged incubations using high doses of ?-lap, cell nuclei reveal dark-red fluorescence evenly distributed in chromatin surrounding the unstained regions of nucleoli. Both drugs generate H2O2 and induce DNA double strand breaks, which is correlated with ?-phoshorylation of H2AX histones. However, the extent of H2AX phosphorylation (including the frequency of ?-H2AX foci and the relative number cells creating phospho-H2AX domains) is considerably reduced in root meristem cells treated jointly with the ?-lap/HU mixture. Furthermore, various effects of caffeine (an inhibitor of ATM/ATR cell cycle checkpoint kinases) on ?-lap- and HU-induced ?-phoshorylation of H2AX histones and the protective activity of HU against ?-lap suggest that their genotoxic activities are largely dissimilar. ?-Lap treatment results in the induction of apoptosis-like programmed cell death, while HU treatment leads to cell adaptation to replication stress and promotion of abnormal nuclear divisions with biphasic interphase/mitotic states of chromatin condensation. PMID:24184448

  7. Shikonin causes apoptosis by up-regulating p73 and down-regulating ICBP90 in human cancer cells.

    PubMed

    Jang, Soon Young; Hong, Darong; Jeong, Seo Young; Kim, Jong-Ho

    2015-09-11

    Shikonin, a natural naphthoquinone isolated from the Chinese traditional medicine Zi Cao (purple gromwell), is known to suppress the growth of several cancer cell types. In this study, we evaluated the pro-apoptotic effects of shikonin on MCF-7 and HeLa cells, and investigated the underlying mechanism. Shikonin-induced apoptosis was associated with activation of caspase-3, poly(ADP-ribose) polymerase (PARP) cleavage, up-regulation of p73, and down-regulation of BCL-2. Shikonin also induced up-regulation of the tumor suppressor gene, p16(INK4A). Increasing transcriptional activity of p16(INK4A) by shikonin treatment, we observed in luciferase promoter assay, reflects reduced promoter binding by down-regulation of ICBP90 (inverted CCAAT box binding protein, 90 kDa), which are involved in down-regulation of its partner, DNMT1 (DNA methyltransferase 1). On the basis of these results, we conclude that shikonin causes apoptosis via a p73-related, caspase-3-dependent pathway. PMID:26235879

  8. A solid device based on doped hybrid composites for controlling the dosage of the biocide N-(3-aminopropyl)-N-dodecyl-1,3-propanediamine in industrial formulations.

    PubMed

    Argente-García, A; Muñoz-Ortuño, M; Molins-Legua, C; Moliner-Martínez, Y; Campíns-Falcó, P

    2016-01-15

    A colorimetric composite device is proposed to determine the widely used biocide N-(3-aminopropyl)-N-dodecyl-1,3-propanediamine (ADP).This sensing device is based on a film of 1,2-Naphthoquinone-4-sulfonate (NQS) embedded into polydimethylsiloxane-tetraethylortosilicate-SiO2 nanoparticles composite (PDMS-TEOS-SiO2NPs). Semiquantitative analysis can be performed by visual inspection. Digitalized image or diffuse reflectance (DR) measurements can be carried out for quantitative analysis. Satisfactory detection limit (0.018%, w/v) and relative standard deviations <12% were achieved. The proposed device has been applied for the determination of ADP in detergent industrial formulations with recovery values between 80% and 112%. The method has been successfully validated, showing its high potential to control and monitor this compound because the device is easy to prepare and use, robust, portable, stable over time and cost effective. This device allows a green, simple and rapid approach for the analysis of samples without pretreatment and does not require highly trained personnel. These advantages give the proposed kit good prospects for implementation in several industries. PMID:26592589

  9. Analysis of atmospheric concentrations of quinones and polycyclic aromatic hydrocarbons in vapour and particulate phases

    NASA Astrophysics Data System (ADS)

    Delgado-Saborit, Juana Maria; Alam, Mohammed S.; Godri Pollitt, Krystal J.; Stark, Christopher; Harrison, Roy M.

    2013-10-01

    Polycyclic aromatic hydrocarbons (PAH) are often measured in studies of atmospheric chemistry or health effects of air pollution, due to their known human carcinogenicity. In recent years, PAH quinone derivatives have also become a focus of interest, primarily because they can contribute to oxidative stress. This work reports concentrations of 17 PAH and 15 quinones measured in air samples collected at a trafficked roadside. Data are presented for four compounds not previously reported in ambient air: 2-methyl-1,4-naphthoquinone, 2,6-di-tert-butyl-1,4-benzoquinone, methyl-1,4-benzoquinone and 2,3-dimethylanthraquinone, and a large vapour phase component is measured, not analysed in most earlier studies. Analyses are reported also for SRM 1649a and 1649b, including many compounds (8 for SRM 1649a and 12 for SRM 1649b) for which concentrations have not previously been reported. This work assesses the vapour/particle phase distribution of PAHs and quinones in relation to their molecular weight, vapour pressure, polarity and Henry's Law constant, finding that both molecular weight and vapour pressure (which are correlated) are good predictors of the partitioning.

  10. Buparvaquone is active against Neospora caninum in vitro and in experimentally infected mice

    PubMed Central

    Müller, Joachim; Aguado-Martinez, Adriana; Manser, Vera; Balmer, Vreni; Winzer, Pablo; Ritler, Dominic; Hostettler, Isabel; Arranz-Solís, David; Ortega-Mora, Luis; Hemphill, Andrew

    2015-01-01

    The naphthoquinone buparvaquone is currently the only drug used against theileriosis. Here, the effects of buparvaquone were investigated in vitro and in an experimental mouse model for Neospora caninum infection. In 4-day proliferation assays, buparvaquone efficiently inhibited N.?caninum tachyzoite replication (IC50?=?4.9?nM; IC100?=?100?nM). However, in the long term tachyzoites adapted and resumed proliferation in the presence of 100?nM buparvaquone after 20 days of cultivation. Parasiticidal activity was noted after 9 days of culture in 0.5?µM or 6 days in 1?µM buparvaquone. TEM of N.?caninum infected fibroblasts treated with 1?µM buparvaquone showed that the drug acted rather slowly, and ultrastructural changes were evident only after 3–5 days of treatment, including severe alterations in the parasite cytoplasm, changes in the composition of the parasitophorous vacuole matrix and a diminished integrity of the vacuole membrane. Treatment of N.?caninum infected mice with buparvaquone (100?mg/kg) either by intraperitoneal injection or gavage prevented neosporosis symptoms in 4 out of 6 mice in the intraperitoneally treated group, and in 6 out of 7 mice in the group receiving oral treatment. In the corresponding controls, all 6 mice injected intraperitoneally with corn oil alone died of acute neosporosis, and 4 out of 6 mice died in the orally treated control group. Assessment of infection intensities in the treatment groups showed that, compared to the drug treated groups, the controls showed a significantly higher parasite load in the lungs while cerebral parasite load was higher in the buparvaquone-treated groups. Thus, although buparvaquone did not eliminate the parasites infecting the CNS, the drug represents an interesting lead with the potential to eliminate, or at least diminish, fetal infection during pregnancy. PMID:25941626

  11. Potential of herbs in skin protection from ultraviolet radiation

    PubMed Central

    Kora?, Radava R.; Khambholja, Kapil M.

    2011-01-01

    Herbs have been used in medicines and cosmetics from centuries. Their potential to treat different skin diseases, to adorn and improve the skin appearance is well-known. As ultraviolet (UV) radiation can cause sunburns, wrinkles, lower immunity against infections, premature aging, and cancer, there is permanent need for protection from UV radiation and prevention from their side effects. Herbs and herbal preparations have a high potential due to their antioxidant activity, primarily. Antioxidants such as vitamins (vitamin C, vitamin E), flavonoids, and phenolic acids play the main role in fighting against free radical species that are the main cause of numerous negative skin changes. Although isolated plant compounds have a high potential in protection of the skin, whole herbs extracts showed better potential due to their complex composition. Many studies showed that green and black tea (polyphenols) ameliorate adverse skin reactions following UV exposure. The gel from aloe is believed to stimulate skin and assist in new cell growth. Spectrophotometer testing indicates that as a concentrated extract of Krameria triandra it absorbs 25 to 30% of the amount of UV radiation typically absorbed by octyl methoxycinnamate. Sesame oil resists 30% of UV rays, while coconut, peanut, olive, and cottonseed oils block out about 20%. A “sclerojuglonic” compound which is forming from naphthoquinone and keratin is the reaction product that provides UV protection. Traditional use of plant in medication or beautification is the basis for researches and making new trends in cosmetics. This review covers all essential aspects of potential of herbs as radioprotective agents and its future prospects. PMID:22279374

  12. Deuterium-Labeled Phylloquinone Has Tissue-Specific Conversion to Menaquinone-4 among Fischer 344 Male Rats12

    PubMed Central

    Al Rajabi, Ala; Booth, Sarah L.; Peterson, James W.; Choi, Sang Woon; Suttie, John W.; Shea, M. Kyla; Miao, Benchun; Grusak, Michael A.; Fu, Xueyan

    2012-01-01

    Phylloquinone (PK) is converted into menaquinone-4 (MK-4) via side chain removal-addition. Stable isotope use is an effective approach to identify the tissue location of this conversion, which is currently unknown. Following a 14-d PK-deficient diet, male Fischer 344 rats (8 mo; n = 15) were fed 1.6 mg deuterium-labeled PK (L-PK) per kg diet for 0 (control), 1 d (PK-1d), and 7 d (PK-7d). Both L-PK and deuterium-labeled MK-4 (L-MK-4) were detected in tissues in PK-1d and PK-7d, although the results varied. Whereas some tissues had an overall increase in MK-4 in response to L-PK, total brain, testes, and fat MK-4 concentrations did not. In contrast, L-MK-4 concentrations increased in all 3 tissues. The deuterium label was found only on the L-MK-4 naphthoquinone ring, confirming the need for side chain removal for the formation of MK-4. Labeled menadione (MD) was detected in urine and serum in PK-1d and PK-7d, confirming its role as an intermediate. A Caco-2 cell monolayer model was used to study the role of the enterocytes in the conversion process. Neither MK-4 nor MD was detected in Caco-2 cells treated with PK. However, when Caco-2 cells were treated with MD, MK-4 was formed. Similarly, MK-4 was formed in response to MD-treated 293T kidney cells, but not HuH7 liver cells. These data demonstrate that MK-4 is the predominant form of vitamin K in multiple tissues, but there appears to be a tissue-specific regulation for the conversion of PK to MK-4. PMID:22437559

  13. Enhancement of DMNQ-induced hepatocyte toxicity by cytochrome P450 inhibition

    SciTech Connect

    Ishihara, Yasuhiro; Shiba, Dai; Shimamoto, Norio . E-mail: n-shimamoto@kph.bunri-u.ac.jp

    2006-07-15

    Two mechanisms have been proposed to explain quinone cytotoxicity: oxidative stress via the redox cycle and the arylation of intracellular nucleophiles. As the redox cycle is catalyzed by NADPH cytochrome P450 reductase, cytochrome P450 systems are expected to be related to the cytotoxicity induced by redox-cycling quinones. Thus, we investigated the relationship between cytochrome P450 systems and quinone toxicity for rat primary hepatocytes using an arylator, 1,4-benzoquinone (BQ), and a redox cycler, 2,3-dimethoxy-1,4-naphthoquinone (DMNQ). The hepatocyte toxicity of both BQ and DMNQ increased in a time- and dose-dependent manner. Pretreatment with cytochrome P450 inhibitors, such as SKF-525A (SKF), ketoconazole and 2-methy-1,2-di-3-pyridyl-1-propanone, enhanced the hepatocyte toxicity induced by DMNQ but did not affect BQ-induced hepatocyte toxicity. The production of superoxide anion and the levels of glutathione disulfide and thiobarbituric-acid-reactive substances were increased by treatment with DMNQ, and SKF pretreatment further enhanced their increases. In addition, NADPH oxidation in microsomes was increased by treatment with DMNQ and further augmented by pretreatment with SKF, and a NADPH cytochrome P450 reductase inhibitor, diphenyleneiodonium chloride completely suppressed NADPH oxidations increased by treatment with either DMNQ- or DMNQ + SKF. Pretreatment with antioxidants, such as {alpha}-tocopherol, reduced glutathione, N-acetyl cysteine or an iron ion chelator deferoxamine, totally suppressed DMNQ- and DMNQ + SKF-induced hepatocyte toxicity. These results indicate that the hepatocyte toxicity of redox-cycling quinones is enhanced under cytochrome P450 inhibition, and that this enhancement is caused by the potentiation of oxidative stress.

  14. Novel Vitamin K analogs suppress seizures in zebrafish and mouse models of epilepsy.

    PubMed

    Rahn, J J; Bestman, J E; Josey, B J; Inks, E S; Stackley, K D; Rogers, C E; Chou, C J; Chan, S S L

    2014-02-14

    Epilepsy is a debilitating disease affecting 1-2% of the world's population. Despite this high prevalence, 30% of patients suffering from epilepsy are not successfully managed by current medication suggesting a critical need for new anti-epileptic drugs (AEDs). In an effort to discover new therapeutics for the management of epilepsy, we began our study by screening drugs that, like some currently used AEDs, inhibit histone deacetylases (HDACs) using a well-established larval zebrafish model. In this model, 7-day post fertilization (dpf) larvae are treated with the widely used seizure-inducing compound pentylenetetrazol (PTZ) which stimulates a rapid increase in swimming behavior previously determined to be a measurable manifestation of seizures. In our first screen, we tested a number of different HDAC inhibitors and found that one, 2-benzamido-1 4-naphthoquinone (NQN1), significantly decreased swim activity to levels equal to that of valproic acid, 2-n-propylpentanoic acid (VPA). We continued to screen structurally related compounds including Vitamin K3 (VK3) and a number of novel Vitamin K (VK) analogs. We found that VK3 was a robust inhibitor of the PTZ-induced swim activity, as were several of our novel compounds. Three of these compounds were subsequently tested on mouse seizure models at the National Institute of Neurological Disorders and Stroke (NINDS) Anticonvulsant Screening Program. Compound 2h reduced seizures particularly well in the minimal clonic seizure (6Hz) and corneal-kindled mouse models of epilepsy, with no observable toxicity. As VK3 affects mitochondrial function, we tested the effects of our compounds on mitochondrial respiration and ATP production in a mouse hippocampal cell line. We demonstrate that these compounds affect ATP metabolism and increase total cellular ATP. Our data indicate the potential utility of these and other VK analogs for the prevention of seizures and suggest the potential mechanism for this protection may lie in the ability of these compounds to affect energy production. PMID:24291671

  15. Isolation of cellular membranes from lignin-producing tissues of Norway spruce and analysis of redox enzymes.

    PubMed

    Kärkönen, Anna; Meisrimler, Claudia-Nicole; Takahashi, Junko; Väisänen, Enni; Laitinen, Teresa; Jiménez Barboza, Luis Alexis; Holmström, Sami; Salonvaara, Sadette; Wienkoop, Stefanie; Fagerstedt, Kurt V; Lüthje, Sabine

    2014-12-01

    There are no earlier reports with successful isolation of plasma membranes from lignin-forming tissues of conifers. A method to isolate cellular membranes from extracellular lignin-producing tissue-cultured cells and developing xylem of Norway spruce was optimized. Modifications to the homogenization buffer were needed to obtain membranes from these phenolics-rich tissues. Membranes were separated by aqueous polymer two-phase partitioning. Chlorophyll a determination, marker enzyme assays and western blot analyses using antibodies for each membrane type showed that mitochondrial, chloroplastic and to a certain extent also ER and Golgi membranes were efficiently diminished from the upper phase, but tonoplast and plasma membranes distributed evenly between the upper and lower phases. Redox enzymes present in the partially purified membrane fractions were assayed in order to reveal the origin of H(2)O(2) needed for lignification. The membranes of spruce contained enzymes able to generate superoxide in the presence of NAD(P)H. Besides members of the flavodoxin and flavodoxin-like family proteins, cytochrome b5, cytochrome P450 and several stress responsive proteins were identified by nitroblue tetrazolium staining of isoelectric focusing gels and by mass spectrometry. Naphthoquinones juglone and menadione increased superoxide production in activity-stained gels. Some juglone-activated enzymes were preferentially using NADH. With NADH, menadione activated only some of the enzymes that juglone did, whereas with NADPH the activation patterns were identical. Duroquinone, a benzoquinone, did not affect superoxide production. Superoxide dismutase, ascorbate peroxidase, catalase and an acidic class III peroxidase isoenzyme were detected in partially purified spruce membranes. The possible locations and functions of these enzymes are discussed. PMID:24730578

  16. Molecular structures and biological evaluation of 2-chloro-3-(n-alkylamino)-1,4-napthoquinone derivatives as potent antifungal agents

    NASA Astrophysics Data System (ADS)

    Pawar, Omkar; Patekar, Ashwini; Khan, Ayesha; Kathawate, Laxmi; Haram, Santosh; Markad, Ganesh; Puranik, Vedavati; Salunke-Gawali, Sunita

    2014-02-01

    Derivatives of 2-chloro-3-(n-alkylamino)-1,4-naphthoquinone {n-alkyl: methyl; L-1, ethyl; L-2, propyl; L-3 and butyl; L-4} have been synthesized and characterized by elemental analysis, FT-IR, 1H NMR, UV-visible spectroscopy, LC-MS and single crystal X-ray diffraction studies. Antifungal activity of L-1 to L-4 has been evaluated against Candida tropicalis, Candida albicans and Cladosporium herbarum. The intramolecular hydrogen bonding affects the N-H vibrational frequency in L-2 (3273 cm-1). The single crystal X-ray structure reveal that L-1 and L-3 crystallizes in triclinic P-1, whereas L-2 crystallizes in orthorhombic Pca21 space group. An extensive intra and intermolecular hydrogen bonding interactions were observed in L-1 to L-3 which leads to molecular association. Intramolecular N-H⋯O hydrogen bonding were observed in L-1 to L-3. Moreover ?-? stacking interactions were observed between the quinonoid rings of L-1 and L-3, however no such interactions were observed in L-2. An electrochemical study showed molecular association of L-1 to L-4 in DMSO solution. Compounds L-1 to L-4 were found to be potent antifungal agents against all the three strains, especially against C. tropicalis. Amongst these promising antifungal candidates, L-1 showed better activity compared to the clinically administered antifungal drug Amphotericin B and Nitrofurantoin with MIC = 1.25 ?g ml-1 and MIC = 0.025 ?g ml-1 respectively against C. albicans. Structure and activity relationship (SAR) study suggest a Log P value of ˜2.0 and the cyclic voltammetry studies reveals additional chemical processes for L-1, which exhibits maximum activity against all fungal strains.

  17. Posttranslational Regulation of Human DNA Polymerase ?.

    PubMed

    McIntyre, Justyna; McLenigan, Mary P; Frank, Ekaterina G; Dai, Xiaoxia; Yang, Wei; Wang, Yinsheng; Woodgate, Roger

    2015-11-01

    Human DNA polymerases (pols) ? and ? are Y-family DNA polymerase paralogs that facilitate translesion synthesis past damaged DNA. Both pol? and pol? can be monoubiquitinated in vivo. Pol? has been shown to be ubiquitinated at one primary site. When this site is unavailable, three nearby lysines may become ubiquitinated. In contrast, mass spectrometry analysis of monoubiquitinated pol? revealed that it is ubiquitinated at over 27 unique sites. Many of these sites are localized in different functional domains of the protein, including the catalytic polymerase domain, the proliferating cell nuclear antigen-interacting region, the Rev1-interacting region, and its ubiquitin binding motifs UBM1 and UBM2. Pol? monoubiquitination remains unchanged after cells are exposed to DNA-damaging agents such as UV light (generating UV photoproducts), ethyl methanesulfonate (generating alkylation damage), mitomycin C (generating interstrand cross-links), or potassium bromate (generating direct oxidative DNA damage). However, when exposed to naphthoquinones, such as menadione and plumbagin, which cause indirect oxidative damage through mitochondrial dysfunction, pol? becomes transiently polyubiquitinated via Lys(11)- and Lys(48)-linked chains of ubiquitin and subsequently targeted for degradation. Polyubiquitination does not occur as a direct result of the perturbation of the redox cycle as no polyubiquitination was observed after treatment with rotenone or antimycin A, which both inhibit mitochondrial electron transport. Interestingly, polyubiquitination was observed after the inhibition of the lysine acetyltransferase KATB3/p300. We hypothesize that the formation of polyubiquitination chains attached to pol? occurs via the interplay between lysine acetylation and ubiquitination of ubiquitin itself at Lys(11) and Lys(48) rather than oxidative damage per se. PMID:26370087

  18. Secondary Metabolites from Plants Inhibiting ABC Transporters and Reversing Resistance of Cancer Cells and Microbes to Cytotoxic and Antimicrobial Agents

    PubMed Central

    Wink, Michael; Ashour, Mohamed L.; El-Readi, Mahmoud Zaki

    2012-01-01

    Fungal, bacterial, and cancer cells can develop resistance against antifungal, antibacterial, or anticancer agents. Mechanisms of resistance are complex and often multifactorial. Mechanisms include: (1) Activation of ATP-binding cassette (ABC) transporters, such as P-gp, which pump out lipophilic compounds that have entered a cell, (2) Activation of cytochrome p450 oxidases which can oxidize lipophilic agents to make them more hydrophilic and accessible for conjugation reaction with glucuronic acid, sulfate, or amino acids, and (3) Activation of glutathione transferase, which can conjugate xenobiotics. This review summarizes the evidence that secondary metabolites (SM) of plants, such as alkaloids, phenolics, and terpenoids can interfere with ABC transporters in cancer cells, parasites, bacteria, and fungi. Among the active natural products several lipophilic terpenoids [monoterpenes, diterpenes, triterpenes (including saponins), steroids (including cardiac glycosides), and tetraterpenes] but also some alkaloids (isoquinoline, protoberberine, quinoline, indole, monoterpene indole, and steroidal alkaloids) function probably as competitive inhibitors of P-gp, multiple resistance-associated protein 1, and Breast cancer resistance protein in cancer cells, or efflux pumps in bacteria (NorA) and fungi. More polar phenolics (phenolic acids, flavonoids, catechins, chalcones, xanthones, stilbenes, anthocyanins, tannins, anthraquinones, and naphthoquinones) directly inhibit proteins forming several hydrogen and ionic bonds and thus disturbing the 3D structure of the transporters. The natural products may be interesting in medicine or agriculture as they can enhance the activity of active chemotherapeutics or pesticides or even reverse multidrug resistance, at least partially, of adapted and resistant cells. If these SM are applied in combination with a cytotoxic or antimicrobial agent, they may reverse resistance in a synergistic fashion. PMID:22536197

  19. Protein Sulfenylation: A Novel Readout of Environmental Oxidant Stress.

    PubMed

    Wages, Phillip A; Lavrich, Katelyn S; Zhang, Zhenfa; Cheng, Wan-Yun; Corteselli, Elizabeth; Gold, Avram; Bromberg, Philip; Simmons, Steven O; Samet, James M

    2015-12-21

    Oxidative stress is a commonly cited mechanism of toxicity of environmental agents. Ubiquitous environmental chemicals such as the diesel exhaust component 1,2-naphthoquinone (1,2-NQ) induce oxidative stress by redox cycling, which generates hydrogen peroxide (H2O2). Cysteinyl thiolate residues on regulatory proteins are subjected to oxidative modification by H2O2 in physiological contexts and are also toxicological targets of oxidant stress induced by environmental contaminants. We investigated whether exposure to environmentally relevant concentrations of 1,2-NQ can induce H2O2-dependent oxidation of cysteinyl thiols in regulatory proteins as a readout of oxidant stress in human airway epithelial cells. BEAS-2B cells were exposed to 0-1000 ?M 1,2-NQ for 0-30 min, and levels of H2O2 were measured by ratiometric spectrofluorometry of HyPer. H2O2-dependent protein sulfenylation was measured using immunohistochemistry, immunoblotting, and isotopic mass spectrometry. Catalase overexpression was used to investigate the relationship between H2O2 generation and protein sulfenylation in cells exposed to 1,2-NQ. Multiple experimental approaches showed that exposure to 1,2-NQ at concentrations as low as 3 ?M induces H2O2-dependent protein sulfenylation in BEAS-2B cells. Moreover, the time of onset and duration of 1,2-NQ-induced sulfenylation of the regulatory proteins GAPDH and PTP1B showed significant differences. Oxidative modification of regulatory cysteinyl thiols in human lung cells exposed to relevant concentrations of an ambient air contaminant represents a novel marker of oxidative environmental stress. PMID:26605980

  20. Development of Enantioselective Synthetic Routes to (–)-Kinamycin F and (–)-Lomaiviticin Aglycon

    PubMed Central

    Woo, Christina M.; Gholap, Shivajirao L.; Lu, Liang; Kaneko, Miho; Li, Zhenwu; Ravikumar, P. C.; Herzon, Seth B.

    2012-01-01

    The development of enantioselective synthetic routes to (–)-kinamycin F (9) and (–)-lomaiviticin aglycon (6) is described. The diazotetrahydrobenzo[b]fluorene (diazofluorene) functional group of the targets was prepared by fluoride-mediated coupling of a ?-trimethylsilylmethyl-?,?-unsaturated ketone (38) with an oxidized naphthoquinone (19), palladium-catalyzed cyclization (39?37), and diazo transfer (37?53). The D-ring precursors 60 and 68 were prepared from m-cresol and 3-ethylphenol, respectively. Coupling of the ?-trimethylsilylmethyl-?,?-unsaturated ketone 60 with the juglone derivative 61, cyclization, and diazo transfer, provided the advanced diazofluorene 63, which was elaborated to (–)-kinamycin F (9) in three steps. The diazofluorene 87 was converted to the C2-symmetric lomaiviticin aglycon precursor 91 by enoxysilane formation and oxidative dimerization with manganese tris(hexafluoroacetylacetonate) (94, 26%). The stereochemical outcome is attributed to the steric bias engendered by the mesityl acetal of 87 and contact ion pairing of the intermediates. The coupling product 91 was deprotected (tert-butylhydrogen peroxide, trifluoroacetic acid–dichloromethane) to form the chain isomer of lomaiviticin aglycon 98, which cyclizes to (–)-lomaiviticin aglycon (6, 39–41% overall). The scope of the fluoride-mediated coupling process is delineated (nine products, average yield = 72%, Table 2); a related enoxysilane quinonylation reaction is also described (10 products, average yield = 77%, Table 1). We establish that dimeric diazofluorenes undergo hydrodediazotization 3-fold faster then related monomeric diazofluorenes (Table 6). The simple diazofluorene 103 is a potent inhibitor of ovarian cancer stem cells (IC50 = 500 nM). PMID:23030272

  1. Synthesis and characterization of 2-(n-alkylamino)-1,4-napthoquinone: Molecular structures of ethyl and hexyl derivatives

    NASA Astrophysics Data System (ADS)

    Patil, Rishikesh; Chadar, Dattatray; Chaudhari, Dinkar; Peter, Justin; Nikalje, Milind; Weyhermüller, Thomas; Salunke-Gawali, Sunita

    2014-10-01

    We would like to introduce seven analogues of 2-(n-alkylamino)-1,4-napthoquinone (where n-alkyl is methyl in LH-1, ethyl in LH-2, propyl in LH-3, butyl in LH-4, pentyl in LH-5, hexyl in LH-6 and heptyl in LH-7). All the said analogues have been successfully synthesized from 1,4-naphthoquinone and well characterised using different spectroscopic techniques. Furthermore, in order to understand the mechanistic aspects of formation of LH-1-LH-7 compounds we could propose the mechanism. The FT-IR spectroscopic analysis of LH-1-LH-7 compounds indicating that the presence of characteristic band of Nsbnd H group at ?3340 cm-1. This band could assigned to existence of intramolecular hydrogen bonding interactions. The 13C-NMR spectroscopic technique has been used to study structural feature of LH-1-LH-7 compounds via HSQC, COSY and DEPT experiments. Finally, the structural aspects of the LH-2-LH-6 compounds have been confirmed by single crystal X-ray diffraction studies. We could observed that LH-2 compound crystallises in monoclinic space group P21/c, whereas LH-6 crystallises in triclinic P-1 space group. The molecule of LH-2 and LH-6 compounds forms dimers via Nsbnd H⋯O hydrogen bonding interaction while polymeric chains of dimers have been seen via Csbnd H⋯O hydrogen bonding. It is very interesting to note that the molecules of LH-6 possessing a ?-? stacking interaction between C⋯N of the neighbouring chains.

  2. Tanshinone IIA inhibits viral oncogene expression leading to apoptosis and inhibition of cervical cancer.

    PubMed

    Munagala, Radha; Aqil, Farrukh; Jeyabalan, Jeyaprakash; Gupta, Ramesh C

    2015-01-28

    Human papilloma virus (HPV) is the well-established etiological factor of cervical cancer. E6 and E7 oncoproteins expressed by HPV are known to inactivate tumor suppressor proteins p53 and pRb, respectively. Tanshinone IIA (Tan IIA) is a diterpenoid naphthoquinone found in the traditional Chinese medicine Danshen (Salvia sp.). Tan IIA has been shown to possess anti-tumor activity against several cancer types. In this study we show that Tan IIA potently inhibited proliferation of the human cervical cancer CaSki, SiHa, HeLa and C33a cells. Mechanistically in HPV positive CaSki cells, Tan IIA was found to (i) downregulate expression of HPV E6 and E7 genes and modulate associated proteins E6AP and E2F1, (ii) cause S phase cell cycle arrest, (iii) induce accumulation of p53 and alter expression of p53-dependent targets, (iv) modulate pRb and related proteins, and (v) cause p53-mediated apoptosis by moderating Bcl2, Bax, caspase-3, and PARP cleavage expressions. In vivo, Tan IIA resulted in over 66% reduction in tumor volume of cervical cancer xenograft in athymic nude mice. Tan IIA treated tumor tissues had lower expression of proliferation marker PCNA and changes in apoptosis targets were in agreement with in vitro studies, further confirming reduced proliferation and involvement of multiple targets behind anti-cancer effects. This is the first demonstration of Tan IIA to possess significant anti-viral activity by repressing HPV oncogenes leading to inhibition of cervical cancer. Together, our data suggest that Tan IIA can be exploited as a potent therapeutic agent for the prevention and treatment of cervical and other HPV-related cancers. PMID:25304375

  3. Phytochemical screening and anti-inflammatory activity of Cnidoscolus quercifolius (Euphorbiaceae) in mice

    PubMed Central

    de Araújo Gomes, Leandra Macedo; de Andrade, Thayne Mayra; Silva, Juliane Cabral; de Lima, Julianeli Tolentino; Quintans-Junior, Lucindo José; da Silva Almeida, Jackson Roberto Guedes

    2014-01-01

    Background: Cnidoscolus quercifolius is a species popularly known as favela and faveleira, and belonging to the Caatinga biome (semi-arid vegetation, Brazil), where is used in folk medicine as an anti-inflammatory. Objective: The aim was to evaluate the anti-inflammatory effect of the ethanolic extract from barks (Cqb-EtOH) and leaves (Cql-EtOH) of C. quercifolius in mice using experimental models of inflammation. Materials and Methods: The preliminary phytochemical analysis of the ethanolic extract was performed. The activity was evaluated by paw edema induced by carrageenan and leukocytes migration to the peritoneal cavity induced by carrageenan methods. Results: A preliminary analysis of Cqb-EtOH revealed that it contained coumarins, flavonoids, monoterpenes/diterpenes and naphthoquinones, while the Cql-EtOH showed positive reaction to coumarins, anthracene derivatives, flavonoids, lignans and triterpenes/steroids. Cqb-EtOH and Cql-EtOH (100, 200 and 400 mg/kg) inhibited significantly (P < 0.01) the increase in the edema volume after administration of carrageenan. In the peritonitis test, acute pretreatment with Cqb-EtOH and Cql-EtOH (100, 200 and 400 mg/kg) inhibited the leukocyte migration. Conclusions: It can be concluded that extracts from the barks and leaves of C. quercifolius have anti-inflammatory activity, which supports the popular use of this plant to treat inflammation. Thus, extracts has significant anti-inflammatory properties, which are related probably to inhibition of release of mediators of the inflammatory process. PMID:25276074

  4. Toxicological effects of polycyclic aromatic hydrocarbons and their derivatives on respiratory cells

    NASA Astrophysics Data System (ADS)

    Koike, Eiko; Yanagisawa, Rie; Takano, Hirohisa

    2014-11-01

    Polycyclic aromatic hydrocarbons (PAHs) are found in ambient aerosols and particulate matter. Experimental studies have shown that PAHs and related chemicals can induce toxicological effects. The present study aimed to investigate the effects of PAHs and their derivatives on the respiratory and immune systems and the underlying mechanisms. The human bronchial epithelial cell line BEAS-2B was exposed to PAHs and their derivatives, and the cytotoxicity and proinflammatory protein expression were then investigated. A cytotoxic effect was observed in BEAS-2B exposed to PAH derivatives such as naphthoquinone (NQ), phenanthrenequinone (PQ), 1-nitropyrene (1-NP), and 1-aminopyrene (1-AP). In addition, 1,2-NQ and 9,10-PQ showed more effective cytotoxicity than 1,4-NQ and 1,4-PQ, respectively. Pyrene showed a weak cytotoxic effect. On the other hand, naphthalene and phenanthrene showed no significant effects. Pyrene, 1-NP, and 1-AP also increased intercellular adhesion molecule-1 expression and interleukin-6 production in BEAS-2B. The increase was partly suppressed by protein kinase inhibitors such as the epidermal growth factor receptor-selective tyrosine kinase inhibitor and nuclear receptor antagonists such as the thyroid hormone receptor antagonist. The present study suggests that the toxicological effects of chemicals may be related to the different activities resulting from their structures, such as numbers of benzene rings and functional groups. Furthermore, the chemical-induced increase in proinflammatory protein expression in bronchial epithelial cells was possibly a result of the activation of protein kinase pathways and nuclear receptors. The increase may partly contribute to the adverse health effects of atmospheric PAHs.

  5. Plumbagin shows anticancer activity in human osteosarcoma (MG-63) cells via the inhibition of S-Phase checkpoints and down-regulation of c-myc

    PubMed Central

    Yan, Chao-Hua; Li, Feng; Ma, Yuan-Chen

    2015-01-01

    Objective: Plumbagin, a naphthoquinone constituent of Plumbago zeylanica L. (Plumbaginaceae), has been extensively studied for its pharmacological activities and reported to show a good anti-cancer activity in different human cancer cell lines. It is known to exhibit proapoptotic, antiangiogenic and antimetastatic effects in cancer cells. Plumbagin is also known to inhibit NF-?B, JNK (Hsu), PKC?, and STAT-3. However, the anti-proliferatory activity and their core molecular mechanisms have been poorly determined. Methods: Human osteosarcoma (MG-63) cells were exposed to plumbagin and the anti-proliferative activity was evaluated by MTT assay. The mechanism of action for the growth inhibitory activity of plumbagin on MG-63 cells was evaluated using flow cytometry for cell cycle distribution, and western blot for assessment of accumulation and phosphorylation of potential target proteins. Furthermore, morphology of MG-63 cells was assessed after treatment with Plumbagin. Results: Plumbagin has significantly induced growth inhibition against osteosarcoma MG-63 cells, primarily by S-phase cell cycle arrest which is confirmed by the down regulation of cyclin A and CDK2 protein levels determined by western blot analysis. It was also found that plumbagin has triggered the DNA damage in MG-63 cells, subsequently initiating the arrest in S-phase, which is evident by the up-regulation of phosphorylated p53 and histone. Furthermore, plumbagin resulted in the down-regulation of c-myc protein expression in the MG-63 cells. Conclusion: Plumbagin has triggered DNA damage and had induced S-phase arrest in MG-63 cells, suggesting it to be a potential compound in treatment against malignant human osteosarcoma. PMID:26550431

  6. Kinetics of naphthalene metabolism in target and non-target tissues of rodents and in nasal and airway microsomes from the Rhesus monkey

    SciTech Connect

    Buckpitt, Alan; Morin, Dexter; Murphy, Shannon; Edwards, Patricia; Van Winkle, Laura

    2013-07-15

    Naphthalene produces species and cell selective injury to respiratory tract epithelial cells of rodents. In these studies we determined the apparent K{sub m}, V{sub max}, and catalytic efficiency (V{sub max}/K{sub m}) for naphthalene metabolism in microsomal preparations from subcompartments of the respiratory tract of rodents and non-human primates. In tissues with high substrate turnover, major metabolites were derived directly from naphthalene oxide with smaller amounts from conjugates of diol epoxide, diepoxide, and 1,2- and 1,4-naphthoquinones. In some tissues, different enzymes with dissimilar K{sub m} and V{sub max} appeared to metabolize naphthalene. The rank order of V{sub max} (rat olfactory epithelium > mouse olfactory epithelium > murine airways ? rat airways) correlated well with tissue susceptibility to naphthalene. The V{sub max} in monkey alveolar subcompartment was 2% that in rat nasal olfactory epithelium. Rates of metabolism in nasal compartments of the monkey were low. The catalytic efficiencies of microsomes from known susceptible tissues/subcompartments are 10 and 250 fold higher than in rat airway and monkey alveolar subcompartments, respectively. Although the strong correlations between catalytic efficiencies and tissue susceptibility suggest that non-human primate tissues are unlikely to generate metabolites at a rate sufficient to produce cellular injury, other studies showing high levels of formation of protein adducts support the need for additional studies. - Highlights: • Naphthalene is metabolized with high catalytic efficiency in susceptible tissue. • Naphthalene is metabolized at low catalytic efficiency in non-susceptible tissue. • Respiratory tissues of the non human primate metabolize naphthalene slowly.

  7. Induction of intrinsic apoptosis pathway in colon cancer HCT-116 cells by novel 2-substituted-5,6,7,8-tetrahydronaphthalene derivatives.

    PubMed

    Gamal-Eldeen, Amira M; Hamdy, Nehal A; Abdel-Aziz, Hatem A; El-Hussieny, Enas A; Fakhr, Issa M I

    2014-04-22

    2-Acetyl tetralin (1) reacted with N,N-dimethylformamide dimethylacetal (DMF-DMA) to afford the enaminone 3. The reaction of 3 with piperidine and morpholine afforded the trans enaminone 5a,b, respectively. Compound 3 was treated with primary aromatic amines to give secondary enaminones 6a-e. The enaminone 3 reacted with acetylglycine and hippuric acid to yield pyranones 10a, b, respectively. The reaction of enaminone 3 with 1,4-benzoquinone and 1,4-naphthoquinone gave benzofuranyl tetralin derivatives 14a,b, respectively. Also, when 3 reacted with 5-amino-3-phenyl-1H-pyrazole 15a and 5-amino-1,2,3-triazole 15b, it afforded the new pyrazolo[1,5-a]pyrimidine 17a and 1,2,3-triazolo[1,5-a]pyrimidine 17b, respectively. While the reaction of 3 with pyrimidines 18a, b resulted in the formation of pyrido[2,3-d]pyrimidine derivatives 20a, b, respectively. Investigations of the cytotoxic effect of those compounds against different human cell lines indicated that some compounds showed high selective cytotoxicity against colon cancer HCT-116 cells. Some of these compounds led to DNA damaging and fragmentation that was associated with the induction of apoptosis via mitochondrial pathway. This pathway is initiated by the impairment of mitochondrial transmembrane potential (??m) and in response to that the mitochondria released cytochrome c increased, that in turn activated caspase-9 and caspase-3 and induced apoptosis. Compounds 17b and 20b were promising anti-cancer agents that induced intrinsic apoptosis pathway in colon cancer cells. PMID:24657569

  8. Promotion or suppression of experimental metastasis of B16 melanoma cells after oral administration of lapachol

    SciTech Connect

    Maeda, Masayo; Murakami, Manabu; Takegami, Tsutomu; Ota, Takahide

    2008-06-01

    Lapachol [2-hydroxy-3-(3-methyl-2-butenyl)-1,4-naphthoquinone] is a vitamin K antagonist with antitumor activity. The effect of lapachol on the experimental metastasis of murine B16BL6 melanoma cells was examined. A single oral administration of a high toxic dose of lapachol (80-100 mg/kg) 6 h before iv injection of tumor cells drastically promoted metastasis. This promotion of metastasis was also observed in T-cell-deficient mice and NK-suppressed mice. In vitro treatment of B16BL6 cells with lapachol promoted metastasis only slightly, indicating that lapachol promotes metastasis primarily by affecting host factors other than T cells and NK cells. A single oral administration of warfarin, the most commonly used vitamin K antagonist, 6 h before iv injection of tumor cells also drastically promoted the metastasis of B16BL6 cells. The promotion of metastasis by lapachol and warfarin was almost completely suppressed by preadministration of vitamin K3, indicating that the promotion of metastasis by lapachol was derived from vitamin K antagonism. Six hours after oral administration of lapachol or warfarin, the protein C level was reduced maximally, without elongation of prothrombin time. These observations suggest that a high toxic dose of lapachol promotes metastasis by inducing a hypercoagulable state as a result of vitamin K-dependent pathway inhibition. On the other hand, serial oral administration of low non-toxic doses of lapachol (5-20 mg/kg) weakly but significantly suppressed metastasis by an unknown mechanism, suggesting the possible use of lapachol as an anti-metastatic agent.

  9. Antileishmanial, antitrypanosomal, and cytotoxic screening of ethnopharmacologically selected Peruvian plants.

    PubMed

    González-Coloma, Azucena; Reina, Matías; Sáenz, Claudia; Lacret, Rodney; Ruiz-Mesia, Lastenia; Arán, Vicente J; Sanz, Jesús; Martínez-Díaz, Rafael A

    2012-04-01

    Extracts (34) from eight plant species of the Peruvian Amazonia currently used in traditional Peruvian medicine, mostly as antileishmanial remedies and also as painkiller, antiseptic, antipyretic, anti-inflamatory, antiflu, astringent, diuretic, antipoison, anticancerous, antiparasitic, insecticidal, or healing agents, have been tested for their antileishmanial, antitrypanosomal, and cytotoxic activity. Plant species were selected based on interviews conducted with residents of rural areas. The different plant parts were dried, powdered, and extracted by maceration with different solvents (hexane, chloroform, and 70% ethanol-water). These extracts were tested on promastigote forms of Leishmania infantum strain PB75, epimastigote forms of Trypanosoma cruzi strain Y, and the mammalian CHO cell line. Parasite viability and nonspecific cytotoxicity were analyzed by a modified MTT colorimetric assay method. The isolation and identification of pure compounds from selected extracts were performed by column chromatography, gas chromatography mass spectrometry (GC-MS; mixtures), spectroscopic techniques [MS, infrared (IR), ultraviolet (UV)], and mono and two-dimensional (1)H and (13)C nuclear magnetic resonance (NMR; COSY, HSQC, NOESY) experiments. Chondodendron tomentosum bark and Cedrela odorata were the most active extracts against Leishmania, while C. odorata and Aristoloquia pilosa were the most active against Trypanosoma, followed by Tabebuia serratifolia, Tradescantia zebrina, and Zamia ulei. Six compounds and two mixtures were isolated from Z. ulei [cycasin (1)], T. serratifolia {mixtures 1-2, and naphthoquinones 2-acetyl-4H,9H-naphtho[2,3-b]furan-4,9-dione (2) and 2-(1-hydroxyethyl)-4H,9H-naphtho[2,3-b]furan-4,9-dione (3)}, and C. tomentosum [chondrocurine (4); (S,S')-12-O-methyl(+)-curine (5); and cycleanine (6)]. Four compounds and the two mixtures exhibited significant activity. PMID:21922239

  10. Induction of apoptosis by plumbagin through reactive oxygen species-mediated inhibition of topoisomerase II

    SciTech Connect

    Kawiak, Anna; Piosik, Jacek; Stasilojc, Grzegorz; Gwizdek-Wisniewska, Anna; Marczak, Lukasz; Stobiecki, Maciej; Lojkowska, Ewa

    2007-09-15

    Reactive oxygen species (ROS) have been recognized as key molecules, which can selectively modify proteins and therefore regulate cellular signalling including apoptosis. Plumbagin, a naphthoquinone exhibiting antitumor activity, is known to generate ROS and has been found to inhibit the activity of topoisomerase II (Topo II) through the stabilization of the Topo II-DNA cleavable complex. The objective of this research was to clarify the role of ROS and Topo II inhibition in the induction of apoptosis mediated by plumbagin. As determined by the comet assay, plumbagin induced DNA cleavage in HL-60 cells, whereas in a cell line with reduced Topo II activity-HL-60/MX2, the level of DNA damage was significantly decreased. The onset of DNA strand break formation in HL-60 cells was delayed in comparison with the generation of intracellular ROS. In HL-60/MX2 cells, ROS were generated at a similar rate, whereas a significant reduction in the level of DNA damage was detected. The pretreatment of cells with N-acetylcysteine (NAC) attenuated plumbagin-induced DNA damage, pointing out to the involvement of ROS generation in cleavable complex formation. These results suggest that plumbagin-induced ROS does not directly damage DNA but requires the involvement of Topo II. Furthermore, experiments carried out using light spectroscopy indicated no direct interactions between plumbagin and DNA. The induction of apoptosis was significantly delayed in HL-60/MX2 cells indicating the involvement of Topo II inhibition in plumbagin-mediated apoptosis. Thus, these findings strongly suggest ROS-mediated inhibition of Topo II as an important mechanism contributing to the apoptosis-inducing properties of plumbagin.

  11. Isolation and characterization of photosynthetic reaction centers from Rhodopseudomonas capsulata and Rhodopseudomonas sphaeroides

    SciTech Connect

    Worland, S.T.

    1984-09-01

    Reaction centers were isolated by affinity chromatography on equine cytochrome C. Peripheral proteins were removed with 0.05% LDAO. Absorption and EPR spectra and bleaching assays indicate that the reaction centers retained their electron donors and acceptors in the native environment. Three reaction center polypeptides were isolated and submitted for amino-terminal sequence determination. By comparing these sequences to those deduced from DNA, it was established that the M and L subunits are post-translationally modified to remove the aminoterminal Met, whereas the H subunit is not. Inhibition of O/sub 2/ evolution in photosystem II particles from spinach by naphthoquinone derivatives show O/sub 2/ inhibition by bromomethyl and acetoxymethyl derivatives but not with hydroxymethyl derivatives. Inhibition by acetoxymethyl derivatives in irreversible and dependent on illumination suggesting that reduction of the quinone is necessary. Therefore acetoxymethyl derivatives may be useful as suicide reagents for labelling quinone binding sites. Procedures were developed to extract one or both of the quinones present in reaction centers and preserve the integrity of the co-factor binding sites. The H and M subunits were cleaned using furmic acid. Both fragments were isolated from the H subunit, while the larger fragment was isolated from the M subunit. Electrophoretic mobilities of the isolated fragments agrees well with the expected molecular weights. The L subunit was digested with Staphylococcus areus vs protease. The pattern obtained was consistant with the potential sites of cleavage, but it was not possible to assign cleavage sites unambiguously. 112 references, 37 figures, 2 tables.

  12. YY1 positively regulates human UBIAD1 expression.

    PubMed

    Funahashi, Nobuaki; Hirota, Yoshihisa; Nakagawa, Kimie; Sawada, Natumi; Watanabe, Masato; Suhara, Yoshitomo; Okano, Toshio

    2015-05-01

    Vitamin K is involved in bone formation and blood coagulation. Natural vitamin K compounds are composed of the plant form phylloquinone (vitamin K1) and a series of bacterial menaquionones (MK-n; vitamin K2). Menadione (vitamin K3) is an artificial vitamin K compound. MK-4 contains 4-isoprenyl as a side group in the 2-methyl-1,4-naphthoquinone common structure and has various bioactivities. UbiA prenyltransferase domain containing 1 (UBIAD1 or TERE1) is the menaquinone-4 biosynthetic enzyme. UBIAD1 transcript expression significantly decreases in patients with prostate carcinoma and overexpressing UBIAD1 inhibits proliferation of a tumour cell line. UBIAD1 mRNA expression is ubiquitous in mouse tissues, and higher UBIAD1 mRNA expression levels are detected in the brain, heart, kidneys and pancreas. Several functions of UBIAD1 have been reported; however, regulation of the human UBIAD1 gene has not been elucidated. Here we report cloning and characterisation of the human UBIAD1 promoter. A 5' rapid amplification of cDNA ends analysis revealed that the main transcriptional start site was 306 nucleotides upstream of the translation initiation codon. Deletion and mutation analyses revealed the functional importance of the YY1 consensus motif. Electrophoretic gel mobility shift and chromatin immunoprecipitation assays demonstrated that YY1 binds the UBIAD1 promoter in vitro and in vivo. In addition, YY1 small interfering RNA decreased endogenous UBIAD1 mRNA expression and UBIAD1 conversion activity. These results suggest that YY1 up-regulates UBIAD1 expression and UBIAD1 conversion activity through the UBIAD1 promoter. PMID:25772619

  13. Dinuclear cobalt(II) and cobalt(III) complexes of bis-bidentate napthoquinone ligands.

    PubMed

    Mulyana, Yanyan; Alley, Kerwyn G; Davies, Kristian M; Abrahams, Brendan F; Moubaraki, Boujemaa; Murray, Keith S; Boskovic, Colette

    2014-02-14

    The combination of bridging bis-bidentate redox-active ligands derived from 3,3-bis-2-hydroxy-1,4-naphthoquinone (bhnqH2), ancillary ligands based on tris(2-pyridylmethyl)amine (tpa) and cobalt salts has afforded a new family of dinuclear cobalt complexes. Compounds of the complexes [Co2(bhnq)(tpa)2](2+) (1), [Co2(bhnq)(Metpa)2](2+) (2), [Co2(bhnq)(Me2tpa)2](2+) (3) [Co2(bhnq)(Me3tpa)2](2+) (4), [Co2(bhnq)(tpa)2](4+) (5), [Co2(bhMenaph)(tpa)2](2+) (6) and [Co2(bhPronaph)(tpa)2](2+) (7) (Mentpa involves n = 0, 1, 2 and 3 methyl groups at the 6-position of the tpa pyridine rings; bhMenaphH4 = bis-3,4-dihydroxy-4-methoxynaphthalene-1-one; bhPronaphH4 = bis-3,4-dihydroxy-4-(2-oxopropyl)naphthalen-1(4H)-one) have been characterised by single crystal X-ray diffraction. While complexes 1-4 possess divalent cobalt centres, trivalent cobalt is evident in complexes 5-7. The bis-bidentate redox-active bridging ligand remains in the diamagnetic quinone bhnq(2-) redox state in complexes 1-5. Metal-catalysed reaction with methoxide or acetone enolate ions gives rise to the derivatised bridging ligands present in 6 and 7. The electronic properties of compounds of 1-7 have been explored in the solid state by infrared spectroscopy and variable temperature magnetic measurements and in solution by electronic absorption spectroscopy and cyclic voltammetry. PMID:24306162

  14. Synthesis and evaluation of the cytotoxic activity of 1,2-furanonaphthoquinones tethered to 1,2,3-1H-triazoles in myeloid and lymphoid leukemia cell lines.

    PubMed

    Cardoso, Mariana F C; Rodrigues, Patrícia C; Oliveira, Maria Eduarda I M; Gama, Ivson L; da Silva, Illana M C B; Santos, Isabela O; Rocha, David R; Pinho, Rosa T; Ferreira, Vitor F; de Souza, Maria Cecília B V; da Silva, Fernando de C; Silva-Jr, Floriano Paes

    2014-09-12

    Leukemia is the most common blood cancer, and its development starts at diverse points, leading to distinct subtypes that respond differently to therapy. This heterogeneity is rarely taken into account in therapies, so it is still essential to look for new specific drugs for leukemia subtypes or even for therapy-resistant cases. Naphthoquinones (NQ) are considered privileged structures in medicinal chemistry due to their plethora of biological activities, including antimicrobial and anticancer effects. Nitrogen-containing heterocycles such as 1,2,3-1H-triazoles have been identified as general scaffolds for generating glycosidase inhibitors. In the present study, the NQ and 1,2,3-1H-triazole cores have been combined to chemically synthesize 18 new 1,2-furanonaphthoquinones tethered to 1,2,3-1H-triazoles (1,2-FNQT). Their cytotoxicities were evaluated against four different leukemia cell lines, including MOLT-4 and CEM (lymphoid cell lines) and K562 and KG1 (myeloid cell lines), as well as normal human peripheral blood mononucleated cells (PBMCs). The new 1,2-FNQT series showed high cytotoxic potential against all leukemia cell lines tested, and some compounds (12o and 12p) showed even better results than the classical therapeutic compounds such as doxorubicin or cisplatin. Others compounds, such as 12b, are promising because of their high selectivity against lymphoblastic leukemia and their low activity against normal hematopoietic cells. The cells of lymphoid origin (MOLT and CEM) were generally more sensitive than the myeloid cell lines to this series of compounds, and most of the compounds that showed the highest cytotoxicity were similarly active against both cell lines. PMID:25064348

  15. Formation of environmentally persistent free radicals from the heterogeneous reaction of ozone and polycyclic aromatic compounds.

    PubMed

    Borrowman, Cuyler K; Zhou, Shouming; Burrow, Timothy E; Abbatt, Jonathan P D

    2016-01-01

    In the 1980s long-lived radical species were identified in cigarette tar. Since then, environmentally persistent free radicals (EPFRs) have been observed in ambient particulate matter, and have been generated in particulate matter generated from internal combustion engines. For the first time, we measure in situ the formation and decay of EPFRs through the heterogeneous reaction of ozone and several polycyclic aromatic compounds (PAC). Solid anthracene (ANT), pyrene (PY), benzo[a]pyrene (BAP), benzo[ghi]perylene (BGHIP), 1,4-naphthoquinone (1,4NQ), and 9,10-anthraquinone (AQ) were reacted with gas-phase ozone in a flow system placed in the active cavity of an electron paramagnetic resonance (EPR) spectrometer, and the formation of radicals was measured on the timescale of tens of minutes at ambient levels of ozone down to 30 ppb. For most substrates the net radical production is initially rapid, slows at intermediate times, and is followed by a slow decay. For oxidized solid BAP, radical signal persists for many days in the absence of ozone. To evaluate the effect of substrate phase, the solid PAHs were also dissolved in squalane, an organic oil inert to ozone, which yielded a much higher maximum radical concentration and faster radical decay when exposed to ozone. With higher mobility, reactants were apparently able to more easily diffuse and react with each other, yielding the higher radical concentrations. The EPR spectra exhibit three radicals types, two of which have been assigned to semiquinone species and one to a PAH-derived, carbon-centered radical. Although our system uses levels of PAC not typically found in the environment it is worth noting that the amounts of radical formed, on the order of 10(18) radicals per g, are comparable to those observed in ambient particulate matter. PMID:26603953

  16. Promotion or suppression of experimental metastasis of B16 melanoma cells after oral administration of lapachol.

    PubMed

    Maeda, Masayo; Murakami, Manabu; Takegami, Tsutomu; Ota, Takahide

    2008-06-01

    Lapachol [2-hydroxy-3-(3-methyl-2-butenyl)-1,4-naphthoquinone] is a vitamin K antagonist with antitumor activity. The effect of lapachol on the experimental metastasis of murine B16BL6 melanoma cells was examined. A single oral administration of a high toxic dose of lapachol (80-100 mg/kg) 6 h before iv injection of tumor cells drastically promoted metastasis. This promotion of metastasis was also observed in T-cell-deficient mice and NK-suppressed mice. In vitro treatment of B16BL6 cells with lapachol promoted metastasis only slightly, indicating that lapachol promotes metastasis primarily by affecting host factors other than T cells and NK cells. A single oral administration of warfarin, the most commonly used vitamin K antagonist, 6 h before iv injection of tumor cells also drastically promoted the metastasis of B16BL6 cells. The promotion of metastasis by lapachol and warfarin was almost completely suppressed by preadministration of vitamin K3, indicating that the promotion of metastasis by lapachol was derived from vitamin K antagonism. Six hours after oral administration of lapachol or warfarin, the protein C level was reduced maximally, without elongation of prothrombin time. These observations suggest that a high toxic dose of lapachol promotes metastasis by inducing a hypercoagulable state as a result of vitamin K-dependent pathway inhibition. On the other hand, serial oral administration of low non-toxic doses of lapachol (5-20 mg/kg) weakly but significantly suppressed metastasis by an unknown mechanism, suggesting the possible use of lapachol as an anti-metastatic agent. PMID:18294668

  17. Antiparasitic activities of novel ruthenium/lapachol complexes.

    PubMed

    Barbosa, Marília I F; Corrêa, Rodrigo S; de Oliveira, Katia Mara; Rodrigues, Claudia; Ellena, Javier; Nascimento, Otaciro R; Rocha, Vinícius P C; Nonato, Fabiana R; Macedo, Taís S; Barbosa-Filho, José Maria; Soares, Milena B P; Batista, Alzir A

    2014-07-01

    The present study describes the synthesis, characterization, antileishmanial and antiplasmodial activities of novel diimine/(2,2'-bipyridine (bipy), 1,10-phenanthroline (phen), 4,4'-methylbipyridine (Me-bipy) and 4,4'-methoxybipyridine (MeO-bipy)/phosphine/ruthenium(II) complexes containing lapachol (Lap, 2-hydroxy-3-(3-33 methyl-2-buthenyl)-1,4-naphthoquinone) as bidentate ligand. The [Ru(Lap)(PPh3)2(bipy)]PF6 (1), [Ru(Lap)(PPh3)2(Me-bipy)]PF6 (2), [Ru(Lap)(PPh3)2(MeO-bipy)]PF6(3) and[Ru(Lap)(PPh3)2(phen)]PF6 (4) complexes, PPh3=triphenylphospine, were synthesized from the reactions of cis-[RuCl2(PPh3)2(X-bipy)] or cis-[RuCl2(PPh3)2(phen)], with lapachol. The [RuCl2(Lap)(dppb)] (5) [dppb=1,4-bis(diphenylphosphine)butane] was synthesized from the mer-[RuCl3(dppb)(H2O)] complex. The complexes were characterized by elemental analysis, molar conductivity, infrared and UV-vis spectroscopy, (31)P{(1)H} and (1)H NMR, and cyclic voltammetry. The Ru(III) complex, [RuCl2(Lap)(dppb)], was also characterized by the EPR technique. The structure of the complexes [Ru(Lap)(PPh3)2(bipy)]PF6 and [RuCl2(Lap)(dppb)] was elucidated by X-ray diffraction. The evaluation of the antiparasitic activities of the complexes against Leishmania amazonensis and Plasmodium falciparum demonstrated that lapachol-ruthenium complexes are more potent than the free lapachol. The [RuCl2(Lap)(dppb)] complex is the most potent and selective antiparasitic compound among the five new ruthenium complexes studied in this work, exhibiting an activity comparable to the reference drugs. PMID:24727183

  18. Antimicrobial activity of the methanolic extract and of the chemical constituents isolated from Newbouldia laevis.

    PubMed

    Kuete, V; Eyong, K O; Folefoc, G N; Beng, V P; Hussain, H; Krohn, K; Nkengfack, A E

    2007-07-01

    The methanolic extract (NLB) and ten compounds isolated from the root bark of Newbouldia laevis Seem, namely chrysoeriol (1), newbouldiaquinone (2), 2-acetylfuro-1,4-naphthoquinone (3), 2-hydroxy-3-methoxy-9,10-dioxo-9,10-dihydroanthracene-1-carbaldehyde (4), lapachol (5), beta-sitosterol-3-O-beta-D-glucopyranoside (6), oleanolic acid (7), canthic acid (8) newbouldiamide (9) and 2-(4-hydroxyphenyl)-ethyltrioctanoate (10), were tested for in vitro antimicrobial activity. Twenty one microorganisms belonging to six Gram-positive and twelve Gram-negative bacterial species as well as three yeasts from Candida species were tested for their susceptibility to NLB and the pure isolated compounds based on the Agar Hole Diffusion test and the Liquid Dilution method. The Hole Diffusion assay indicated that NLB and compound 7 were active against all tested pathogens while other compounds showed selective activity with the antimicrobial spectra varying from 76% (compound 10) to 95 % (compound 6). Minimal inhibitory concentrations (MIC) also illustrated the important antimicrobial activity of NLB and of the isolated compounds. MIC values obtained varied from 9.76 to 312.50 microg/ml for NLB, and 0.038 to 9.76 microg/ml for pure compounds against most of the tested microorganisms. The antimicrobial activities of compounds 2, 4 and 9 are described here extensively for the first time. The results indicate a promising basis for the use of Newbouldia laevis and some of its active principles in the treatment of infectious diseases. PMID:17718200

  19. From body art to anticancer activities: perspectives on medicinal properties of henna.

    PubMed

    Pradhan, Rohan; Dandawate, Prasad; Vyas, Alok; Padhye, Subhash; Biersack, Bernhard; Schobert, Rainer; Ahmad, Aamir; Sarkar, Fazlul H

    2012-12-01

    Nature has been a rich source of therapeutic agents for thousands of years and an impressive number of modern drugs have been isolated from natural sources based on the uses of these plants in traditional medicine. Henna is one such plant commonly known as Persian Henna or Lawsonia inermis, a bushy, flowering tree, commonly found in Australia, Asia and along the Mediterranean coasts of Africa. Paste made from the leaves of Henna plant has been used since the Bronze Age to dye skin, hairs and fingernails especially at the times of festivals. In recent times henna paste has been used for body art paintings and designs in western countries. Despite such widespread use in dyeing and body art painting, Henna extracts and constituents possess numerous biological activities including antioxidant, anti-inflammatory, antibacterial and anticancer activities. The active coloring and biologically active principle of Henna is found to be Lawsone (2- hydroxy-1, 4-naphthoquinone) which can serve as a starting building block for synthesizing large number of therapeutically useful compounds including Atovaquone, Lapachol and Dichloroallyl lawsone which have been shown to possess potent anticancer activities. Some other analogs of Lawsone have been found to exhibit other beneficial biological properties such as antioxidant, anti-inflammatory, antitubercular and antimalarial. The ability of Lawsone to undergo the redox cycling and chelation of trace metal ions has been thought to be partially responsible for some of its biological activities. Despite such diverse biological properties and potent anticancer activities the compound has remained largely unexplored and hence in the present review we have summarized the chemistry and biological activities of Lawsone along with its analogs and metal complexes. PMID:23140289

  20. A proteomic insight into the effects of the immunomodulatory hydroxynaphthoquinone lapachol on activated macrophages.

    PubMed

    Oliveira, Renato A S; Correia-Oliveira, Janaina; Tang, Li-Jun; Garcia, Rodolfo C

    2012-09-01

    We report the effect of an immunomodulatory and anti-mycobacterial naphthoquinone, lapachol, on the bi-dimensional patterns of protein expression of toll-like receptor 2 (TLR2)-agonised and IFN-?-treated THP-1 macrophages. This non-hypothesis driven proteomic analysis intends to shed light on the cellular functions lapachol may be affecting. Proteins of both cytosol and membrane fractions were analysed. After quantification of the protein spots, the protein levels corresponding to macrophages activated in the absence or presence of lapachol were compared. A number of proteins were identified, the levels of which were appreciably and significantly increased or decreased as a result of the action of lapachol on the activated macrophages: cofilin-1, fascin, plastin-2, glucose-6-P-dehydrogenase, adenylyl cyclase-associated protein 1, pyruvate kinase, sentrin-specific protease 6, cathepsin B, cathepsin D, cytosolic aminopeptidase, proteasome ? type-4 protease, tryptophan-tRNA ligase, DnaJ homolog and protein disulphide isomerase. Altogether, the comparative analysis performed indicates that lapachol could be hypothetically causing an impairment of cell migration and/or phagocytic capacity, an increase in NADPH availability, a decrease in pyruvate concentration, protection from proteosomal protein degradation, a decrease in lysosomal protein degradation, an impairment of cytosolic peptide generation, and an interference with NOS2 activation and grp78 function. The present proteomic results suggest issues that should be experimentally addressed ex- and in-vivo, to establish more accurately the potential of lapachol as an anti-infective drug. This study also constitutes a model for the pre-in-vivo evaluation of drug actions. PMID:22705049

  1. Bioactive furonaphtoquinones from Tabebuia barbata (Bignoniaceae).

    PubMed

    Colman de Saizarbitoria, T; Anderson, J E; Alfonso, D; McLaughlin, J L

    1997-01-01

    Tabebuia barbata (E. Mey) Sandw. (Bignoniaceae), locally known as "palo de arco", is indigenous to the upper Orinoco and Amazonas rivers. Brine shrimp lethality-directed fractionation and extensive column chromatography, normal-phase preparative TLC and normal-phase HPLC separation of the ethanol extract of the bark of this previously uninvestigated species has led to the isolation of five active compounds 1-5. The combined spectral evidence (UV, IR, 1H and 13C NMR and mass) identified these compounds as naphthoquinones. These compounds, characterized as lapachol (1), 2-acetylnaphtho-[2,3-b]-furan-4,9-dione (2), 2-acetyl-5-hydroxy-naphtho-[2,3-b]-furan-4,9-dione (3), 2-acetyl-8-hydroxy-naphtho-[2,3-b]-furan-4,9-dione (4), and (+)-8-hydroxy-2(1-hydroxy-ethyl) naphtho-[2,3-b]-furan-4,9-dione (5), were reported previously from other species of the genus Tabebuia but not from T. barbata. Compounds 2-5, reference adriamycin, were significantly cytotoxic against A-549 human lung adeno-carcinoma, MCF-7 human breast carcinoma, and HT-29 human colon carcinoma cells. The compounds isolated (1-5) were also shown to be inhibitors of electron transport in rat liver mitochondria, reference to rotenone, with IC50 values in the range of 15 microM to 82.5 microM. In addition, this study demonstrated that screening and activity-directed fractionation, using brine shrimp lethality as a simple and inexpensive bioassay, can effectively lead to potential antitumor compounds. PMID:9567326

  2. Molecular structures and antiproliferative activity of side-chain saturated and homologated analogs of 2-chloro-3-(n-alkylamino)-1,4-napthoquinone

    NASA Astrophysics Data System (ADS)

    Pal, Sanjima; Jadhav, Mahesh; Weyhermüller, Thomas; Patil, Yogesh; Nethaji, M.; Kasabe, Umesh; Kathawate, Laxmi; Konkimalla, V. Badireenath; Salunke-Gawali, Sunita

    2013-10-01

    Side chain homologated derivatives of 2-chloro-3-(n-alkylamino)-1,4-naphthoquinone {n-alkyl: pentyl; L-5, hexyl; L-6, heptyl; L-7 and octyl; L-8} have been synthesized and characterized by elemental analysis, FT-IR, 1H NMR, UV-visible spectroscopy and LC-MS. Compounds, L-4, {n-alkyl: butyl; L-4}, L-6 and L-8 have been characterized by single crystal X-ray diffraction studies. The single crystal X-ray structures reveal that L-4 and L-8 crystallizes in P21 space group, while L-6 in P21/c space group. Molecules of L-4 and L-8 from polymeric chains through Csbnd H⋯O and Nsbnd H⋯O close contacts. L-6 is a dimer formed by Nsbnd H⋯O interaction. Slipped ?-? stacking interactions are observed between quinonoid and benzenoid rings of L-4 and L-8. Orientations of alkyl group in L-4 and L-8 is on same side of the chain and polymeric chains run opposite to one another to form zip like structure to the alkyl groups. Antiproliferative activities of L-1 to L-8{n-alkyl: methyl; L-1, ethyl; L-2, propyl; L-3 and butyl; L-4} were studied in cancer cells of colon (COLO205), brain (U87MG) and pancreas (MIAPaCa2) where L-1, L-2 and L-3 were active in MIAPaCa2 (L-1 = L-2 > L-3) and COLO205 (L-2 = L-3 > L-1) and inactive in U87MG. From antiproliferative studies with compounds L-1 to L-8 it can be concluded that homologation of 2-chloro-3-(n-alkylamino)-1,4-napthoquinone with saturated methyl groups yielded tissue specific compounds such as L-2 (for MIAPaCa2) and L-3 (for COLO205) with optimal activity.

  3. Modeling Bimolecular Reactions and Transport in Porous Media Via Particle Tracking

    SciTech Connect

    Dong Ding; David Benson; Amir Paster; Diogo Bolster

    2012-01-01

    We use a particle-tracking method to simulate several one-dimensional bimolecular reactive transport experiments. In this numerical method, the reactants are represented by particles: advection and dispersion dominate the flow, and molecular diffusion dictates, in large part, the reactions. The particle/particle reactions are determined by a combination of two probabilities dictated by the physics of transport and energetics of reaction. The first is that reactant particles occupy the same volume over a short time interval. The second is the conditional probability that two collocated particles favorably transform into a reaction. The first probability is a direct physical representation of the degree of mixing in an advancing displacement front, and as such lacks empirical parameters except for the user-defined number of particles. This number can be determined analytically from concentration autocovariance, if this type of data is available. The simulations compare favorably to two physical experiments. In one, the concentration of product, 1,2-naphthoquinoe-4-aminobenzene (NQAB) from reaction between 1,2-naphthoquinone-4-sulfonic acid (NQS) and aniline (AN), was measured at the outflow of a column filled with glass beads at different times. In the other, the concentration distribution of reactants (CuSO_4 and EDTA^{4-}) and products (CuEDTA^{4-}) were quantified by snapshots of transmitted light through a column packed with cryloite sand. The thermodynamic rate coefficient in the latter experiment was 10^7 times greater than the former experiment, making it essentially instantaneous. When compared to the solution of the advection-dispersion-reaction equation (ADRE) with the well-mixed reaction coefficient, the experiments and the particle-tracking simulations showed on the order of 20% to 40% less overall product, which is attributed to poor mixing. The poor mixing also leads to higher product concentrations on the edges of the mixing zones, which the particle model simulates more accurately than the ADRE.

  4. Electron and hydrogen atom transfer mechanisms for the photoreduction of o-quinones. Visible light induced photoreactions of. beta. -lapachone with amines, alcohols, and amino alcohols

    SciTech Connect

    Xiaohong Ci; Whitten, D.G. ); Silveira da Silva, R.; Nicodem, D. )

    1989-02-15

    {beta}-Lapachone (1), a substituted o-naphthoquinone absorbing into the visible ({lambda}{sub max} = 424 nm in benzene), is cleanly and efficiently reduced to the corresponding semiquinone radical upon photolysis in degassed solutions with alcohols, amines, and {beta}-amino alcohols. The course and products of these photoreactions have been followed by NMR, ESR, fluorescence, and absorption spectroscopy. For all three types of reductant the overall reaction involves 2e{sup {minus}} oxidation of the donor, and the quantum efficiencies show a dependence upon quinone concentration indicative of the role of a second dark reduction of 1 by products of the primary photolysis. For amines and amino alcohols the reaction is initiated by single electron transfer quenching of triplet 1. For triethylamine the mechanism is indicated to be a sequence of two electron transfer-proton transfer steps culminating in two semiquinone radicals and the enamine Et{sub 2}NCH{double bond}CH{sub 2}. For amino alcohols a C-C cleavage concurrent with deprotonation of the alcohol (oxidative photofragmentation) occurs, in competition with reverse electron transfer, following the quenching step. For both amines and amino alcohols, limiting efficiencies of reaction approach 2 (for QH{sup {sm bullet}} formation). In contrast, both 2-propanol and benzyl alcohol are oxidized by excited states of 1 with much lower efficiency. The probable mechanism for photooxidation of the alcohols involves a H atom abstraction quenching of the excited state followed by an electron transfer-proton transfer sequence in which a ground-state 1 is reduced. Lower limiting efficiencies for photoreduction of 1 by the alcohols are attributed to inefficiencies of net H-atom transfer in the quenching step. 54 refs., 3 figs., 9 tabs.

  5. A discrete interaction model/quantum mechanical method to describe the interaction of metal nanoparticles and molecular absorption.

    PubMed

    Morton, Seth Michael; Jensen, Lasse

    2011-10-01

    A frequency-dependent quantum mechanics/molecular mechanics method for the calculation of response properties of molecules adsorbed on metal nanoparticles is presented. This discrete interaction model/quantum mechanics (DIM/QM) method represents the nanoparticle atomistically, thus accounting for the local environment of the nanoparticle surface on the optical properties of the adsorbed molecule. Using the DIM/QM method, we investigate the coupling between the absorption of a silver nanoparticle and of a substituted naphthoquinone. This system is chosen since it shows strong coupling due to a molecular absorption peak that overlaps with the plasmon excitation in the metal nanoparticle. We show that there is a strong dependence not only on the distance of the molecule from the metal nanoparticle but also on its orientation relative to the nanoparticle. We find that when the transition dipole moment of an excitation is oriented towards the nanoparticle there is a significant increase in the molecular absorption as a result of coupling to the metal nanoparticle. In contrast, we find that the molecular absorption is decreased when the transition dipole moment is oriented parallel to the metal nanoparticle. The coupling between the molecule and the metal nanoparticle is found to be surprisingly long range and important on a length scale comparable to the size of the metal nanoparticle. A simple analytical model that describes the molecule and the metal nanoparticle as two interacting point objects is found to be in excellent agreement with the full DIM/QM calculations over the entire range studied. The results presented here are important for understanding plasmon-exciton hybridization, plasmon enhanced photochemistry, and single-molecule surface-enhanced Raman scattering. PMID:21992278

  6. A discrete interaction model/quantum mechanical method to describe the interaction of metal nanoparticles and molecular absorption

    NASA Astrophysics Data System (ADS)

    Morton, Seth Michael; Jensen, Lasse

    2011-10-01

    A frequency-dependent quantum mechanics/molecular mechanics method for the calculation of response properties of molecules adsorbed on metal nanoparticles is presented. This discrete interaction model/quantum mechanics (DIM/QM) method represents the nanoparticle atomistically, thus accounting for the local environment of the nanoparticle surface on the optical properties of the adsorbed molecule. Using the DIM/QM method, we investigate the coupling between the absorption of a silver nanoparticle and of a substituted naphthoquinone. This system is chosen since it shows strong coupling due to a molecular absorption peak that overlaps with the plasmon excitation in the metal nanoparticle. We show that there is a strong dependence not only on the distance of the molecule from the metal nanoparticle but also on its orientation relative to the nanoparticle. We find that when the transition dipole moment of an excitation is oriented towards the nanoparticle there is a significant increase in the molecular absorption as a result of coupling to the metal nanoparticle. In contrast, we find that the molecular absorption is decreased when the transition dipole moment is oriented parallel to the metal nanoparticle. The coupling between the molecule and the metal nanoparticle is found to be surprisingly long range and important on a length scale comparable to the size of the metal nanoparticle. A simple analytical model that describes the molecule and the metal nanoparticle as two interacting point objects is found to be in excellent agreement with the full DIM/QM calculations over the entire range studied. The results presented here are important for understanding plasmon-exciton hybridization, plasmon enhanced photochemistry, and single-molecule surface-enhanced Raman scattering.

  7. Posttranslational Regulation of Human DNA Polymerase ?*

    PubMed Central

    McIntyre, Justyna; McLenigan, Mary P.; Frank, Ekaterina G.; Dai, Xiaoxia; Yang, Wei; Wang, Yinsheng; Woodgate, Roger

    2015-01-01

    Human DNA polymerases (pols) ? and ? are Y-family DNA polymerase paralogs that facilitate translesion synthesis past damaged DNA. Both pol? and pol? can be monoubiquitinated in vivo. Pol? has been shown to be ubiquitinated at one primary site. When this site is unavailable, three nearby lysines may become ubiquitinated. In contrast, mass spectrometry analysis of monoubiquitinated pol? revealed that it is ubiquitinated at over 27 unique sites. Many of these sites are localized in different functional domains of the protein, including the catalytic polymerase domain, the proliferating cell nuclear antigen-interacting region, the Rev1-interacting region, and its ubiquitin binding motifs UBM1 and UBM2. Pol? monoubiquitination remains unchanged after cells are exposed to DNA-damaging agents such as UV light (generating UV photoproducts), ethyl methanesulfonate (generating alkylation damage), mitomycin C (generating interstrand cross-links), or potassium bromate (generating direct oxidative DNA damage). However, when exposed to naphthoquinones, such as menadione and plumbagin, which cause indirect oxidative damage through mitochondrial dysfunction, pol? becomes transiently polyubiquitinated via Lys11- and Lys48-linked chains of ubiquitin and subsequently targeted for degradation. Polyubiquitination does not occur as a direct result of the perturbation of the redox cycle as no polyubiquitination was observed after treatment with rotenone or antimycin A, which both inhibit mitochondrial electron transport. Interestingly, polyubiquitination was observed after the inhibition of the lysine acetyltransferase KATB3/p300. We hypothesize that the formation of polyubiquitination chains attached to pol? occurs via the interplay between lysine acetylation and ubiquitination of ubiquitin itself at Lys11 and Lys48 rather than oxidative damage per se. PMID:26370087

  8. Ultrasonic nebulization extraction/low pressure photoionization mass spectrometry for direct analysis of chemicals in matrices.

    PubMed

    Liu, Chengyuan; Zhu, Yanan; Zhou, Zhongyue; Yang, Jiuzhong; Qi, Fei; Pan, Yang

    2015-09-01

    A novel ultrasonic nebulization extraction/low-pressure photoionization (UNE-LPPI) system has been designed and employed for the rapid mass spectrometric analysis of chemicals in matrices. An ultrasonic nebulizer was used to extract the chemicals in solid sample and nebulize the solvent in the nebulization cell. Aerosols formed by ultrasonic were evaporated by passing through a transferring tube, and desolvated chemicals were ionized by the emitted light (10.6 eV) from a Krypton discharge lamp at low pressure (?68 Pa). First, a series of semi/non-volatile compounds with different polarities, such as polycyclic aromatic hydrocarbons (PAHs), amino acids, dipeptides, drugs, nucleic acids, alkaloids, and steroids were used to test the system. Then, the quantification capability of UNE-LPPI was checked with: 1) pure chemicals, such as 9,10-phenanthrenequinone and 1,4-naphthoquinone dissolved in solvent; 2) soil powder spiked with different amounts of phenanthrene and pyrene. For pure chemicals, the correlation coefficient (R(2)) for the standard curve of 9,10-phenanthrenequinone in the range of 3 ng-20 ?g mL(-1) was 0.9922, and the measured limits of detection (LOD) was 1 ng ml(-1). In the case of soil powder, linear relationships for phenanthrene and pyrene from 10 to 400 ng mg(-1) were obtained with correlation coefficients of 0.9889 and 0.9893, respectively. At last, the feasibility of UNE-LPPI for the detection of chemicals in real matrices such as tablets and biological tissues (tea, Citrus aurantium peel and sage (Salvia officinalis) leaf) were successfully demonstrated. PMID:26388379

  9. Discovery of Potent Small-Molecule Inhibitors of Multidrug-Resistant Plasmodium falciparum Using a Novel Miniaturized High-Throughput Luciferase-Based Assay ? †

    PubMed Central

    Lucumi, Edinson; Darling, Claire; Jo, Hyunil; Napper, Andrew D.; Chandramohanadas, Rajesh; Fisher, Nicholas; Shone, Alison E.; Jing, Huiyan; Ward, Stephen A.; Biagini, Giancarlo A.; DeGrado, William F.; Diamond, Scott L.; Greenbaum, Doron C.

    2010-01-01

    Malaria is a global health problem that causes significant mortality and morbidity, with more than 1 million deaths per year caused by Plasmodium falciparum. Most antimalarial drugs face decreased efficacy due to the emergence of resistant parasites, which necessitates the discovery of new drugs. To identify new antimalarials, we developed an automated 384-well plate screening assay using P. falciparum parasites that stably express cytoplasmic firefly luciferase. After initial optimization, we tested two different types of compound libraries: known bioactive collections (Library of Pharmacologically Active Compounds [LOPAC] and the library from the National Institute of Neurological Disorders and Stroke [NINDS]) and a library of uncharacterized compounds (ChemBridge). A total of 12,320 compounds were screened at 5.5 ?M. Selecting only compounds that reduced parasite growth by 85% resulted in 33 hits from the combined bioactive collection and 130 hits from the ChemBridge library. Fifteen novel drug-like compounds from the bioactive collection were found to be active against P. falciparum. Twelve new chemical scaffolds were found from the ChemBridge hits, the most potent of which was a series based on the 1,4-naphthoquinone scaffold, which is structurally similar to the FDA-approved antimalarial atovaquone. However, in contrast to atovaquone, which acts to inhibit the bc1 complex and block the electron transport chain in parasite mitochondria, we have determined that our new 1,4-napthoquinones act in a novel, non-bc1-dependent mechanism and remain potent against atovaquone- and chloroquine-resistant parasites. Ultimately, this study may provide new probes to understand the molecular details of the malaria life cycle and to identify new antimalarials. PMID:20547797

  10. Inhibition of c-MYC with involvement of ERK/JNK/MAPK and AKT pathways as a novel mechanism for shikonin and its derivatives in killing leukemia cells.

    PubMed

    Zhao, Qiaoli; Assimopoulou, Andreana N; Klauck, Sabine M; Damianakos, Harilaos; Chinou, Ioanna; Kretschmer, Nadine; Rios, José-Luis; Papageorgiou, Vassilios P; Bauer, Rudolf; Efferth, Thomas

    2015-11-17

    Leukemia remains life-threatening despite remarkable advances in chemotherapy. The poor prognosis and drug resistance are challenging treatment. Novel drugs are urgently needed. Shikonin, a natural naphthoquinone, has been previously shown by us to be particularly effective towards various leukemia cell lines compared to solid tumors. However, the underlying mechanisms are still poorly understood. Here, we investigated shikonin and 14 derivatives on U937 leukemia cells. Four derivatives (isobutyrylshikonin, 2-methylbutyrylshikonin, isovalerylshikonin and ?,?-dimethylacrylshikonin) were more active than shikonin. AnnexinV-PI analysis revealed that shikonins induced apoptosis. Cell cycle G1/S check point regulation and the transcription factor c-MYC, which plays a vital role in cell cycle regulation and proliferation, were identified as the most commonly down-regulated mechanisms upon treatment with shikonins in mRNA microarray hybridizations. Western blotting and DNA-binding assays confirmed the inhibition of c-MYC expression and transcriptional activity by shikonins. Reduction of c-MYC expression was closely associated with deregulated ERK, JNK MAPK and AKT activity, indicating their involvement in shikonin-triggered c-MYC inactivation. Molecular docking studies revealed that shikonin and its derivatives bind to the same DNA-binding domain of c-MYC as the known c-MYC inhibitors 10058-F4 and 10074-G5. This finding indicates that shikonins bind to c-MYC. The effect of shikonin on U937 cells was confirmed in other leukemia cell lines (Jurkat, Molt4, CCRF-CEM, and multidrug-resistant CEM/ADR5000), where shikonin also inhibited c-MYC expression and influenced phosphorylation of AKT, ERK1/2, and SAPK/JNK. In summary, inhibition of c-MYC and related pathways represents a novel mechanism of shikonin and its derivatives to explain their anti-leukemic activity. PMID:26472107

  11. The Lipids of Pneumocystis carinii

    PubMed Central

    Kaneshiro, Edna S.

    1998-01-01

    Information about a number of Pneumocystis carinii lipids obtained by the analyses of organisms isolated and purified from infected lungs of corticosteroid-immunosuppressed rats has been reported in recent years. Of the common opportunistic protists associated with AIDS (Cryptosporidium, Toxoplasma, and the microsporidia), more is currently known about the lipids of P. carinii than the others. Lipids that are synthesized by the organism but not by humans are attractive targets for drug development. Thus, the elucidation of ?7C-24-alykylated sterol and cis-9,10-epoxystearic acid biosyntheses in P. carinii is currently being examined in detail, since these have been identified as P. carinii-specific lipids. The development of low-toxicity drugs that prevent sterol C-24 alkylation and the specific inhibition of the lipoxygenase that forms cis-9,10-epoxystearic acid might prove fruitful. Although humans can synthesize coenzyme Q10, the anti-P. carinii activity and low toxicity of ubiquinone analogs such as atovaquone suggest that the electron transport chain in the pathogen may differ importantly from that in the host. Although resistance to atovaquone has been observed, development of other naphthoquinone drugs would provide a broader armamentarium of drugs to treat patients with P. carinii pneumonia. Studies of bronchoalveolar lavage fluid and of infected lungs have demonstrated that the infection causes a number of chemical abnormalities. Bronchoalveolar lavage fluid obtained after the removal of lung cellular material and the organisms has been shown to contain larger amounts of surfactant proteins and smaller amounts of phospholipids than do comparable samples from P. carinii-free lungs. Increased phospholipase activity, inhibition of surfactant secretion by type II cells, and uptake and catabolism of lipids by the pathogen may explain this phenomenon related to P. carinii pneumonia. Although not yet thoroughly examined, initial studies on the uptake and metabolism of lipids by P. carinii suggest that the organism relies heavily on exogenous lipid nutrients. PMID:9457427

  12. Development of enantioselective synthetic routes to (-)-kinamycin F and (-)-lomaiviticin aglycon.

    PubMed

    Woo, Christina M; Gholap, Shivajirao L; Lu, Liang; Kaneko, Miho; Li, Zhenwu; Ravikumar, P C; Herzon, Seth B

    2012-10-17

    The development of enantioselective synthetic routes to (-)-kinamycin F (9) and (-)-lomaiviticin aglycon (6) are described. The diazotetrahydrobenzo[b]fluorene (diazofluorene) functional group of the targets was prepared by fluoride-mediated coupling of a ?-trimethylsilylmethyl-?,?-unsaturated ketone (38) with an oxidized naphthoquinone (19), palladium-catalyzed cyclization (39?37), and diazo transfer (37?53). The D-ring precursors 60 and 68 were prepared from m-cresol and 3-ethylphenol, respectively. Coupling of the ?-trimethylsilylmethyl-?,?-unsaturated ketone 60 with the juglone derivative 61, cyclization, and diazo transfer provided the advanced diazofluorene 63, which was elaborated to (-)-kinamycin F (9) in three steps. The diazofluorene 87 was converted to the C(2)-symmetric lomaiviticin aglycon precursor 91 by enoxysilane formation and oxidative dimerization with manganese tris(hexafluoroacetylacetonate) (94, 26%). The stereochemical outcome in the coupling is attributed to the steric bias engendered by the mesityl acetal of 87 and contact ion pairing of the intermediates. The coupling product 91 was deprotected (tert-butylhydrogen peroxide, trifluoroacetic acid-dichloromethane) to form mixtures of the chain isomer of lomaiviticin aglycon 98 and the ring isomer 6. These mixtures converged on purification or standing to the ring isomer 6 (39-41% overall). The scope of the fluoride-mediated coupling process is delineated (nine products, average yield = 72%); a related enoxysilane quinonylation reaction is also described (10 products, average yield = 77%). We establish that dimeric diazofluorenes undergo hydrodediazotization 2-fold faster than related monomeric diazofluorenes. This enhanced reactivity may underlie the cytotoxic effects of (-)-lomaiviticin A (1). The simple diazofluorene 103 is a potent inhibitor of ovarian cancer stem cells (IC(50) = 500 nM). PMID:23030272

  13. Mode-of-Action Uncertainty for Dual-Mode Carcinogens:Lower Bounds for Naphthalene-Induced Nasal Tumors in Rats Implied byPBPK and 2-Stage Stochastic Cancer Risk Models

    SciTech Connect

    Bogen, K T

    2007-01-30

    As reflected in the 2005 USEPA Guidelines for Cancer Risk Assessment, some chemical carcinogens may have a site-specific mode of action (MOA) that is dual, involving mutation in addition to cell-killing induced hyperplasia. Although genotoxicity may contribute to increased risk at all doses, the Guidelines imply that for dual MOA (DMOA) carcinogens, judgment be used to compare and assess results obtained using separate ''linear'' (genotoxic) vs. ''nonlinear'' (nongenotoxic) approaches to low-level risk extrapolation. However, the Guidelines allow the latter approach to be used only when evidence is sufficient to parameterize a biologically based model that reliably extrapolates risk to low levels of concern. The Guidelines thus effectively prevent MOA uncertainty from being characterized and addressed when data are insufficient to parameterize such a model, but otherwise clearly support a DMOA. A bounding factor approach--similar to that used in reference dose procedures for classic toxicity endpoints--can address MOA uncertainty in a way that avoids explicit modeling of low-dose risk as a function of administered or internal dose. Even when a ''nonlinear'' toxicokinetic model cannot be fully validated, implications of DMOA uncertainty on low-dose risk may be bounded with reasonable confidence when target tumor types happen to be extremely rare. This concept was illustrated for the rodent carcinogen naphthalene. Bioassay data, supplemental toxicokinetic data, and related physiologically based pharmacokinetic and 2-stage stochastic carcinogenesis modeling results all clearly indicate that naphthalene is a DMOA carcinogen. Plausibility bounds on rat-tumor-type specific DMOA-related uncertainty were obtained using a 2-stage model adapted to reflect the empirical link between genotoxic and cytotoxic effects of the most potent identified genotoxic naphthalene metabolites, 1,2- and 1,4-naphthoquinone. Resulting bounds each provided the basis for a corresponding ''uncertainty'' factor <1 appropriate to apply to estimates of naphthalene risk obtained by linear extrapolation under a default genotoxic MOA assumption. This procedure is proposed as scientifically credible method to address MOA uncertainty for DMOA carcinogens.

  14. Mode-of-Action Uncertainty for Dual-Mode Carcinogens: A Bounding Approach for Naphthalene-Induced Nasal Tumors in Rats Based on PBPK and 2-Stage Stochastic Cancer Risk Models

    SciTech Connect

    Bogen, K T

    2007-05-11

    A relatively simple, quantitative approach is proposed to address a specific, important gap in the appr approach recommended by the USEPA Guidelines for Cancer Risk Assessment to oach address uncertainty in carcinogenic mode of action of certain chemicals when risk is extrapolated from bioassay data. These Guidelines recognize that some chemical carcinogens may have a site-specific mode of action (MOA) that is dual, involving mutation in addition to cell-killing induced hyperplasia. Although genotoxicity may contribute to increased risk at all doses, the Guidelines imply that for dual MOA (DMOA) carcinogens, judgment be used to compare and assess results obtained using separate 'linear' (genotoxic) vs. 'nonlinear' (nongenotoxic) approaches to low low-level risk extrapolation. However, the Guidelines allow the latter approach to be used only when evidence is sufficient t to parameterize a biologically based model that reliably o extrapolates risk to low levels of concern. The Guidelines thus effectively prevent MOA uncertainty from being characterized and addressed when data are insufficient to parameterize such a model, but otherwise clearly support a DMOA. A bounding factor approach - similar to that used in reference dose procedures for classic toxicity endpoints - can address MOA uncertainty in a way that avoids explicit modeling of low low-dose risk as a function of administere administered or internal dose. Even when a 'nonlinear' toxicokinetic model cannot be fully validated, implications of DMOA uncertainty on low low-dose risk may be bounded with reasonable confidence when target tumor types happen to be extremely rare. This concept was i illustrated llustrated for a likely DMOA rodent carcinogen naphthalene, specifically to the issue of risk extrapolation from bioassay data on naphthalene naphthalene-induced nasal tumors in rats. Bioassay data, supplemental toxicokinetic data, and related physiologically based p pharmacokinetic and 2 harmacokinetic 2-stage stochastic carcinogenesis modeling results all clearly indicate that naphthalene is a DMOA carcinogen. Plausibility bounds on rat rat-tumor tumor-type specific DMOA DMOA-related uncertainty were obtained using a 2-stage model adapted to reflec reflect the empirical link between genotoxic and cytotoxic effects of t the most potent identified genotoxic naphthalene metabolites, 1,2 1,2- and 1,4 1,4-naphthoquinone. Bound Bound-specific 'adjustment' factors were then used to reduce naphthalene risk estimated by linear ex extrapolation (under the default genotoxic MOA assumption), to account for the DMOA trapolation exhibited by this compound.

  15. Understanding amyloid fibril nucleation and a? oligomer/drug interactions from computer simulations.

    PubMed

    Nguyen, Phuong; Derreumaux, Philippe

    2014-02-18

    Evolution has fine-tuned proteins to accomplish a variety of tasks. Yet, with aging, some proteins assemble into harmful amyloid aggregates associated with neurodegenerative diseases, such as Alzheimer's disease (AD), which presents a complex and costly challenge to our society. Thus, far, drug after drug has failed to slow the progression of AD, characterized by the self-assembly of the 39-43 amino acid ?-amyloid (A?) protein into extracellular senile plaques that form a cross-? structure. While there is experimental evidence that the A? small oligomers are the primary toxic species, standard tools of biology have failed to provide structures of these transient, inhomogeneous assemblies. Despite extensive experimental studies, researchers have not successfully characterized the nucleus ensemble, the starting point for rapid fibril formation. Similarly scientists do not have atomic data to show how the compounds that reduce both fibril formation and toxicity in cells bind to A?42 oligomers. In this context, computer simulations are important tools for gaining insights into the self-assembly of amyloid peptides and the molecular mechanism of inhibitors. This Account reviews what analytical models and simulations at different time and length scales tell us about the dynamics, kinetics, and thermodynamics of amyloid fibril formation and, notably, the nucleation process. Though coarse-grained and mesoscopic protein models approximate atomistic details by averaging out unimportant degrees of freedom, they provide generic features of amyloid formation and insights into mechanistic details of the self-assembly process. The thermodynamics and kinetics vary from linear peptides adopting straight ?-strands in fibrils to longer peptides adopting in parallel U shaped conformations in fibrils. In addition, these properties change with the balance between electrostatic and hydrophobic interactions and the intrinsic disorder of the system. However, simulations suggest that the critical nucleus size might be on the order of 20 chains under physiological conditions. The transition state might be characterized by a simultaneous change from mixed antiparallel/parallel ?-strands with random side-chain packing to the final antiparallel or parallel states with the steric zipper packing of the side chains. Second, we review our current computer-based knowledge of the 3D structures of inhibitors with A?42 monomer and oligomers, a prerequisite for developing new drugs against AD. Recent extensive all-atom simulations of A?42 dimers with known inhibitors such as the green tea compound epigallocatechin-3-gallate and 1,4-naphthoquinon-2-yl-l-tryptophan provide a spectrum of initial A?42/inhibitor structures useful for screening and drug design. We conclude by discussing future directions that may offer opportunities to fully understand nucleation and further AD drug development. PMID:24368046

  16. Investigations of solvent properties and solvent effects on chemical equilibria and reaction rates

    NASA Astrophysics Data System (ADS)

    Defeo, Laura Lynn Thomas

    Thermodynamic and structural properties computed via simulations of pure liquids and dilute solutions are routinely used as a metric of accuracy for condensed-phase force fields and in the development and testing of new methodology. Additionally, reliable modeling of solvent systems is critical to investigations of physical phenomena, such as the elucidation of solvent effects on chemical equilibria and reaction rates. This dissertation highlights a series of studies that span these topics. The Lennard-Jones 12-6 functional form, often invoked to model van der Waals interactions, has been argued to be too repulsive at short internuclear separations. Monte Carlo simulations of organic liquids at various temperatures and pressures show that this function, in conjunction with OPLS parameters, is capable of reproducing experimental densities. In order to address potential cumulative deviations of computed properties and conformational differences between the gas phase and pure liquids, Monte Carlo simulations have been carried out for the homologous n-alkane series C4H10-C12H26 using the OPLS-AA force field. Favorable structural motifs of longer alkanes were also investigated to study self solvation in the gas phase. Next, an overview of the computation of free energy changes in solution using perturbation theory, overlap sampling, and related approximate methods is presented. Results are provided for free energies of hydration of OPLS-AA substituted benzenes in TIP4P water. For comparable amounts of computer time, the double-wide and overlap sampling methods yield very similar results. QM/MM simulations of the Diels-Alder reactions of cyclopentadiene with 1,4-naphthoquinone, methyl vinyl ketone, and acrylonitrile have been carried out at the water-vacuum interface and in the gas phase. The relative free energies of activation and transition structure geometries at the interface were intermediate between those calculated in the gas phase and in bulk water, consistent with estimated experimental rate constants. Energy pair distributions reveal a loss of slightly favorable solute-solvent pair contacts but retention of stronger interactions upon transition from bulk to surface hydration. These strong interactions cause the methyl vinyl ketone transition structure to preferentially orient its carbonyl toward the surface, while the other transition structures prefer orientations parallel to the surface.

  17. Identification of natural inhibitors of Entamoeba histolytica cysteine synthase from microbial secondary metabolites

    PubMed Central

    Mori, Mihoko; Jeelani, Ghulam; Masuda, Yui; Sakai, Kazunari; Tsukui, Kumiko; Waluyo, Danang; Tarwadi; Watanabe, Yoshio; Nonaka, Kenichi; Matsumoto, Atsuko; ?mura, Satoshi; Nozaki, Tomoyoshi; Shiomi, Kazuro

    2015-01-01

    Amebiasis is a common worldwide diarrheal disease, caused by the protozoan parasite, Entamoeba histolytica. Metronidazole has been a drug of choice against amebiasis for decades despite its known side effects and low efficacy against asymptomatic cyst carriers. E. histolytica is also capable of surviving sub-therapeutic levels of metronidazole in vitro. Novel drugs with different mode of action are therefore urgently needed. The sulfur assimilatory de novo L-cysteine biosynthetic pathway is essential for various cellular activities, including the proliferation and anti-oxidative defense of E. histolytica. Since the pathway, consisting of two reactions catalyzed by serine acetyltransferase (SAT) and cysteine synthase (CS, O-acetylserine sulfhydrylase), does not exist in humans, it is a rational drug target against amebiasis. To discover inhibitors against the CS of E. histolytica (EhCS), the compounds of Kitasato Natural Products Library were screened against two recombinant CS isozymes: EhCS1 and EhCS3. Nine compounds inhibited EhCS1 and EhCS3 with IC50 values of 0.31–490 ?M. Of those, seven compounds share a naphthoquinone moiety, indicating the structural importance of the moiety for binding to the active site of EhCS1 and EhCS3. We further screened >9,000 microbial broths for CS inhibition and purified two compounds, xanthofulvin and exophillic acid from fungal broths. Xanthofulvin inhibited EhCS1 and EhCS3. Exophillic acid showed high selectivity against EhCS1, but exhibited no inhibition against EhCS3. In vitro anti-amebic activity of the 11 EhCS inhibitors was also examined. Deacetylkinamycin C and nanaomycin A showed more potent amebicidal activity with IC50 values of 18 and 0.8 ?M, respectively, in the cysteine deprived conditions. The differential sensitivity of trophozoites against deacetylkinamycin C in the presence or absence of L-cysteine in the medium and the IC50 values against EhCS suggest the amebicidal effect of deacetylkinamycin C is due to CS inhibition. PMID:26441896

  18. Plumbagin induces cell cycle arrest and autophagy and suppresses epithelial to mesenchymal transition involving PI3K/Akt/mTOR-mediated pathway in human pancreatic cancer cells

    PubMed Central

    Wang, Feng; Wang, Qi; Zhou, Zhi-Wei; Yu, Song-Ning; Pan, Shu-Ting; He, Zhi-Xu; Zhang, Xueji; Wang, Dong; Yang, Yin-Xue; Yang, Tianxing; Sun, Tao; Li, Min; Qiu, Jia-Xuan; Zhou, Shu-Feng

    2015-01-01

    Plumbagin (PLB), an active naphthoquinone compound, has shown potent anticancer effects in preclinical studies; however, the effect and underlying mechanism of PLB for the treatment of pancreatic cancer is unclear. This study aimed to examine the pancreatic cancer cell killing effect of PLB and investigate the underlying mechanism in human pancreatic cancer PANC-1 and BxPC-3 cells. The results showed that PLB exhibited potent inducing effects on cell cycle arrest in PANC-1 and BxPC-3 cells via the modulation of cell cycle regulators including CDK1/CDC2, cyclin B1, cyclin D1, p21 Waf1/Cip1, p27 Kip1, and p53. PLB treatment concentration- and time-dependently increased the percentage of autophagic cells and significantly increased the expression level of phosphatase and tensin homolog, beclin 1, and the ratio of LC3-II over LC3-I in both PANC-1 and BxPC-3 cells. PLB induced inhibition of phosphatidylinositol 3-kinase (PI3K)/protein kinase B/mammalian target of rapamycin and p38 mitogen-activated protein kinase (p38 MAPK) pathways and activation of 5?-AMP-dependent kinase as indicated by their altered phosphorylation, contributing to the proautophagic activities of PLB in both cell lines. Furthermore, SB202190, a selective inhibitor of p38 MAPK, and wortmannin, a potent, irreversible, and selective PI3K inhibitor, remarkably enhanced PLB-induced autophagy in PANC-1 and BxPC-3 cells, indicating the roles of PI3K and p38 MAPK mediated signaling pathways in PLB-induced autophagic cell death in both cell lines. In addition, PLB significantly inhibited epithelial to mesenchymal transition phenotype in both cell lines with an increase in the expression level of E-cadherin and a decrease in N-cadherin. Moreover, PLB treatment significantly suppressed the expression of Sirt1 in both cell lines. These findings show that PLB promotes cell cycle arrest and autophagy but inhibits epithelial to mesenchymal transition phenotype in pancreatic cancer cells with the involvement of PI3K/protein kinase B/mammalian target of rapamycin and p38 MAPK mediated pathways. PMID:25632222

  19. Plumbagin attenuates cancer cell growth and osteoclast formation in the bone microenvironment of mice

    PubMed Central

    Yan, Wei; Wang, Ting-yu; Fan, Qi-ming; Du, Lin; Xu, Jia-ke; Zhai, Zan-jing; Li, Hao-wei; Tang, Ting-ting

    2014-01-01

    Aim: To investigate the effects of plumbagin, a naphthoquinone derived from the medicinal plant Plumbago zeylanica, on human breast cancer cell growth and the cancer cell-induced osteolysis in the bone microenvironment of mice. Methods: Human breast cancer cell subline MDA-MB-231SA with the ability to spread and grow in the bone was tested. The cell proliferation was determined using the CCK-8 assay. Apoptosis was detected with Annexin V/PI double-labeled flow cytometry. Red fluorescent protein-labeled MDA-MB-231SArfp cells were injected into the right tibia of female BALB/c-nu/nu mice. Three days after the inoculation, the mice were injected with plumbagin (2, 4, or 6 mg/kg, ip) 5 times per week for 7 weeks. The growth of the tumor cells was monitored using an in vivo imaging system. After the mice were sacrificed, the hind limbs were removed for radiographic and histological analyses. Results: Plumbagin (2.5–20 ?mol/L) concentration-dependently inhibited the cell viability and induced apoptosis of MDA-MB-231SA cells in vitro (the IC50 value of inhibition of cell viability was 14.7 ?mol/L). Administration of plumbagin to breast cancer bearing mice delayed the tumor growth by 2–3 weeks and reduced the tumor volume by 44%–74%. The in vivo imaging study showed that plumbagin dose-dependently inhibited MDA-MB-231SArfp cell growth in bone microenvironment. Furthermore, X-ray images and micro-CT study demonstrated that plumbagin reduced bone erosion area and prevented a decrease in bone tissue volume. Histological studies showed that plumbagin dose-dependently inhibited the breast cancer cell growth, enhanced the cell apoptosis and reduced the number of TRAcP-positive osteoclasts. Conclusion: Plumbagin inhibits the cell growth and induces apoptosis in human breast cancer cells in mice bone microenvironment, leading to significant reduction in osteolytic lesions caused by the tumor cells. PMID:24384612

  20. Shikonin, a constituent of Lithospermum erythrorhizon exhibits anti-allergic effects by suppressing orphan nuclear receptor Nr4a family gene expression as a new prototype of calcineurin inhibitors in mast cells.

    PubMed

    Wang, Xiaoyu; Hayashi, Shusaku; Umezaki, Masahito; Yamamoto, Takeshi; Kageyama-Yahara, Natsuko; Kondo, Takashi; Kadowaki, Makoto

    2014-10-29

    Over the last few decades, food allergy (FA) has become a common disease in infants in advanced countries. However, anti-allergic medicines available in the market have no effect on FA, and consequently effective drug therapies for FA are not yet available. We have already demonstrated that mucosal mast cells play an essential role in the development of FA in a murine model. Thus, we screened many constituents from medicinal herbs for the ability to inhibit rat basophilic leukemia-2H3 mast-like cell degranulation, and found that shikonin, a naphthoquinone dye from Lithospermum erythrorhizon, exhibited the most potent inhibitory effect among them. Furthermore, shikonin extremely inhibited the IgE/antigen-induced and calcium ionophore-induced upregulation of tumor necrosis factor (TNF)-? mRNA expression in mucosal-type bone marrow-derived mast cells (mBMMCs). Global gene expression analysis confirmed by real-time PCR revealed that shikonin drastically inhibited the IgE/antigen-induced and calcium ionophore-induced upregulation of mRNA expression of the nuclear orphan receptor 4a family (Nr4a1, Nr4a2 and Nr4a3) in mBMMCs, and knockdown of Nr4a1 or Nr4a2 suppressed the IgE/antigen-induced upregulation of TNF-? mRNA expression. Computational docking simulation of a small molecule for a target protein is a useful technique to elucidate the molecular mechanisms underlying the effects of drugs. Therefore, the simulation revealed that the predicted binding sites of shikonin to immunophilins (cyclophilin A and FK506 binding protein (FKBP) 12) were almost the same as the binding sites of immunosuppressants (cyclosporin A and FK506) to immunophilins. Indeed, shikonin inhibited the calcineurin activity to a similar extent as cyclosporin A that markedly suppressed the IgE/antigen-enhanced mRNA expression of TNF-? and the Nr4a family in mBMMCs. These findings suggest that shikonin suppresses mucosal mast cell activation by reducing Nr4a family gene expression through the inhibition of calcineurin activity. Therefore, shikonin has therapeutic potential for the treatment of allergic diseases as a new calcineurin inhibitor. PMID:25451590

  1. Seasonal nutrient dynamics in the Anacostia River (D.C., USA): geochemistry and hydrocarbon biomarkers

    NASA Astrophysics Data System (ADS)

    Sarraino, S.; Frantz, D. E.; Macavoy, S. E.

    2010-12-01

    The seasonal biogeochemistry of the urban Anacostia River (Washington D.C. USA) was investigated. Chemical parameters examined include: inorganics (Ca, Mg, Na, S, K, P, NO3, NH4, PO4, B, Ba, Ni, Co); fatty acids and other hydrocarbons; C, N and S stable isotopes; and other water chemistry indicators (hardness, salinity, alkalinity, soluble salts, SAR, TDS). Between April and July 2010, water and sediment were sampled from three tidal freshwater sites along the Anacostia River (UP, MID, and DWN). Two of the selected sites, UP and DWN, are located next to a combined sewage outflow. Water column nutrient analysis shows increasing availability of ammonium (NH4) and nitrate (NO3) at all sites between April and July. At MID, the site showing the highest rates of nutrient growth over the sampling period, NH4 concentrations increase from 0.13 to 1.49 µg/L and NO3 concentrations increase from 0.71 to 2.88 mg/L. A marked NO3 pulse is observed at the DWN site in early May; NO3 concentrations jump from 0.68 to 3.36 mg/L between April 5 and May 6, decreasing to 1.22 mg/L by May 20. Unlike UP and MID, which show NH4 and NO3 increasing concurrently, this NO3 pulse at DWN is accompanied with a decline in NH4 levels, suggestive of an allochthonous NO3 source. Forthcoming stable isotope data are expected to characterize the source of such nitrogen inputs, as well as organic material, throughout the year. Preliminary GC-MS analysis of isolated fatty acids does not explicitly suggest bacterial or higher plant dominance in the spring; however, some notable compounds were identified, such as the PAH fluoranthene, naphthoquinone, and testosterone, as well as a number of cholesterols and other steroids. Higher proportions of bacterial fatty acid biomarkers are expected during the summer. Principle Component Analysis (PCA) of the chemistry data suggests geochemical variables, rather than nutrients, are the driving forces of observed trends. PCA, along with fatty acid characterization and nutrient analysis, is expected to demonstrate an increasing role of bacterial production and nutrient variables later in the season, while stable isotope values will facilitate organic material source identification.

  2. Arnebin-1 promotes angiogenesis by inducing eNOS, VEGF and HIF-1? expression through the PI3K-dependent pathway

    PubMed Central

    ZENG, ZHI; HUANG, WEN-DONG; GAO, QI; SU, MEI-LING; YANG, YONG-FEI; LIU, ZHAO-CHUN; ZHU, BANG-HAO

    2015-01-01

    Arnebin-1, a naphthoquinone derivative, plays a crucial role in the wound healing properties of Zicao (a traditional wound healing herbal medicine). It has been noted that Arnebin-1, in conjunction with vascular endothelial growth factor (VEGF), exerts a synergistic pro-angiogenic effect on human umbilical vein endothelial cells (HUVECs) and accelerates the healing process of diabetic wounds. However, the mechanisms responsible for the pro-angiogenic effect of arnebin-1 on HUVECs and its healing effect on diabetic wounds have not yet been fully elucidated. In this study, in an aim to elucidate these mechanisms of action of arnebin-1, we investigated the effects of arnebin-1 on the VEGF receptor 2 (VEGFR2) and the phosphoinositide 3-kinase (PI3K)-dependent signaling pathways in HUVECs treated with VEGF by western blot analysis. The pro-angiogenic effects of arnebin-1 on HUVECs, including its effects on proliferation and migration, were evaluated by MTT assay, Transwell assay and tube formation assay in vitro. The expression levels of hypoxia-inducible factor (HIF)-1?, endothelial nitric oxide synthase (eNOS) and VEGF were determined by western blot analysis in the HUVECs and wound tissues obtained from non-diabetic and diabetic rats. CD31 expression in the rat wounds was evaluated by immunofluorescence staining. We found that the activation of the VEGFR2 signaling pathway induced by VEGF was enhanced by arnebin-1. Arnebin-1 promoted endothelial cell proliferation, migration and tube formation through the PI3K-dependent pathway. Moreover, Arnebin-1 significantly increased the eNOS, VEGF and HIF-1? expression levels in the HUVECs and accelerated the healing of diabetic wounds through the PI3K-dependent signaling pathway. CD31 expression was markedly enhanced in the wounds of diabetic rats treated with arnebin-1 compared to the wounds of untreated diabetic rats. Therefore, the findings of the present study indicate that arnebin-1 promotes the wound healing process in diabetic rats by eliciting a pro-angiogenic response. PMID:26202335

  3. New strategies and building blocks for functionalised 9,10-bis(1,3-dithiol-2-ylidene)-9,10-dihydroanthracene derivatives, including pyrrolo-annelated derivatives and pi-extended systems with intramolecular charge-transfer.

    PubMed

    Christensen, Christian A; Bryce, Martin R; Batsanov, Andrei S; Becher, Jan

    2003-02-01

    A range of new functionalised 9,10-bis(1,3-dithiol-2-ylidene)-9,10-dihydroanthracene (TTFAQ) derivatives have been synthesised from the key di(halomethyl) building blocks, 10-[4,5-bis(bromomethyl)-1,3-dithiol-2-ylidene]-anthracene-9(10H)-one 10, 10-[4,5-bis(chloromethyl)-1,3-dithiol-2-ylidene]anthracene-9(10H)-one 11 and 9-[4,5-bis(chloromethyl)-1,3-dithiol-2-ylidene]-10-[4,5-bis(hexylsulfanyl)- 1,3-dithiol-2-ylidene]-9,10-dihydroanthracene 18. A Diels-Alder strategy comprising trapping of the transient exocyclic diene 19, which is derived from 18, with 1,4-naphthoquinone leads to the aromatised TTFAQ anthraquinone system 21. Horner-Wadsworth-Emmons olefination of 21 with the anion generated from reagent 22 gave the fused bis(TTFAQ) structure 23. Pyrrolo-annelated derivatives 30-34 have been obtained in a sequence of reactions from compound 10. Mono-formylation of the pyrrole ring of 32 and 33 under Vilsmeier conditions gave 35 and 36 which upon reaction with 2,4,5,7-tetranitrofluorene gave the donor-pi-acceptor diads 38 and 39. Cyclic voltammetry (CV) in solution for all the TTFAQ derivatives shows the typical quasi-reversible two-electron oxidation wave of the TTFAQ core at potentials which vary slightly depending on the substituents. For example, the value of Eox is raised by the electron withdrawing anthraquinone and tetranitrofluorene units of 21 and 38, respectively. The CV of the conjugated TTFAQ dimer 23 showed two, two-electron oxidation waves corresponding to the sequential formation of 23(2+) and 23(4+) (delta Eox = 130 mV) providing evidence for a significant intramolecular electronic interaction, i.e. the dication 23(2+) acts as a conjugated donor-pi-acceptor diad, thereby raising the oxidation potential of its partner TTFAQ unit. Spectroelectrochemical studies on 23 support this explanation. A strong intramolecular charge transfer band at lambda max 538 nm is seen in the UV-Vis spectra of the TTFAQ-pi-tetranitrofluorene diads 38 and 39. The X-ray crystal structures are reported for compounds 30, 33 and 34. The pyrrolo-TTFAQ moiety adopts a saddle-shape with the central ring of the dihydroanthracene moiety folded along the C(9) ... C(10) vector in each case. Significant intermolecular interactions are observed in the structures. PMID:12926254

  4. Kinetic phases in the electron transfer from P{sup +}Q{sub A}{sup -}Q{sub B} to P{sup +}Q{sub A}Q{sub B}{sup -} and the associated processes in Rhodobacter sphaeroides R-26 reaction centers.

    SciTech Connect

    Li, J.-L.; Gilroy, D.; Tiede, D. M.; Gunner, M. R.; Chemistry; City Coll. of New York

    1998-03-03

    Electron transfer from P{sup +}Q{sub A}{sup -}Q{sub B} to form P{sup +}Q{sub A}Q{sub B}{sup -} was measured in Rhodobacter sphaeroides R-26 reaction centers (RCs) where the native primary quinone, ubiquinone-10 (UQ{sub A}), was replaced by 2-methyl-3-phytyl-1,4-naphthoquinone (MQA). The native secondary quinone, UQ-10, was retained as UQ{sub B}. The difference spectrum of the semiquinone MQ{sub A}- minus UQ{sub B}- absorption is very similar to that of MQ- minus UQ- in solution (398-480 nm). Thus, the absorption change provides a direct monitor of the electron transfer from MQ{sub A}- to UQ{sub B}. In contrast, when both Q{sub A} and Q{sub B} are UQ-10 the spectral difference between UQ{sub A}- and UQ{sub B}- arises from electrochromic responses of RC chromophores. Three kinetic processes are seen in the near UV (390-480 nm) and near-IR (740-820 nm). Analysis of the time-correlated spectra support the conclusion that the changes at {tau}{sub 1} {approx} 3 {micro}s are mostly due to electron transfer, electron transfer and charge compensation are mixed in {tau}{sub 2} {approx} 80 {micro}s, while little or no electron transfer occurs at 200-600 {micro}s ({tau}{sub 3}) in MQAUQB RCs. The 80-{micro}s rate has been previously observed, while the fast component has not. The fast phase represents 60% of the electron-transfer reaction (398 nm). The activation energy for electron transfer is {Delta}G {approx} 3.5 kcal/mol for both {tau}{sub 1} and {tau}{sub 2} between 0 and 30 C. In isolated RCs with UQ{sub A}, if there is any fast component, it appears to be faster and less important than in the MQ{sub A} reconstituted RCs.

  5. Vitamin K3 disrupts the microtubule networks by binding to tubulin: a novel mechanism of its antiproliferative activity.

    PubMed

    Acharya, Bipul R; Choudhury, Diptiman; Das, Amlan; Chakrabarti, Gopal

    2009-07-28

    Vitamin K3 (2-methyl-1,4-naphthoquinone), also known as menadione, is the synthetic precursor of all the naturally occurring vitamin K in the body. Vitamin K is necessary for the production of prothrombin and five other blood-clotting factors in humans. We have examined the effects of menadione on cellular microtubules ex vivo as well as its binding with purified tubulin and microtubules in vitro. Cell viability experiments using human cervical epithelial cancer cells (HeLa) and human oral epithelial cancer cells (KB) indicated that the IC(50) values for menadione are 25.6 +/- 0.6 and 64.3 +/- 0.36 microM, respectively, in those cells. Mendione arrests HeLa cells in mitosis. Immunofluorescence studies using an anti-alpha-tubulin antibody showed a significant irreversible depolymeriztion of the interphase microtubule network and spindle microtubule in a dose-dependent manner. In vitro polymerization of purified tubulin into microtubules is inhibited by menadione with an IC(50) value of 47 +/- 0.65 microM. The binding of menadione with tubulin was studied using menadione fluorescence and intrinsic tryptophan fluorescence of tubulin. Binding of menadione to tubulin is slow, taking 35 min for equilibration at 25 degrees C. The association reaction kinetics is biphasic in nature, and the association rate constants for fast and slow phases are 189.12 +/- 17 and 32.44 +/- 21 M(-1) s(-1) at 25 degrees C, respectively. The stoichiometry of menadione binding to tubulin is 1:1 (molar ratio) with a dissociation constant from 2.44 +/- 0.34 to 3.65 +/- 0.25 microM at 25 degrees C. Menadione competes for the colchicine binding site with a K(i) of 2.5 muM as determined from a modified Dixon plot. The obtained data suggested that menadione binds at the colchicine binding site to tubulin. Thus, we can conclude one novel mechanism of inhibition of cancer cell proliferation by menadione is through tubulin binding. PMID:19527023

  6. Naphthalene distributions and human exposure in Southern California

    NASA Astrophysics Data System (ADS)

    Lu, Rong; Wu, Jun; Turco, Richard P.; Winer, Arthur M.; Atkinson, Roger; Arey, Janet; Paulson, Suzanne E.; Lurmann, Fred W.; Miguel, Antonio H.; Eiguren-Fernandez, Arantzazu

    The regional distribution of, and human exposure to, naphthalene are investigated for Southern California. A comprehensive approach is taken in which advanced models are linked for the first time to quantify population exposure to the emissions of naphthalene throughout Southern California. Naphthalene is the simplest and most abundant of the polycyclic aromatic hydrocarbons found in polluted urban environments, and has been detected in both outdoor and indoor air samples. Exposure to high concentrations of naphthalene may have adverse health effects, possibly causing cancer in humans. Among the significant emission sources are volatilization from naphthalene-containing products, petroleum refining, and combustion of fossil fuels and wood. Gasoline and diesel engine exhaust, with related vaporization from fuels, are found to contribute roughly half of the daily total naphthalene burden in Southern California. As part of this study, the emission inventory for naphthalene has been verified against new field measurements of the naphthalene-to-benzene ratio in a busy traffic tunnel in Los Angeles, supporting the modeling work carried out here. The Surface Meteorology and Ozone Generation (SMOG) airshed model is used to compute the spatial and temporal distributions of naphthalene and its photooxidation products in Southern California. The present simulations reveal a high degree of spatial variability in the concentrations of naphthalene-related species, with large diurnal and seasonal variations as well. Peak naphthalene concentrations are estimated to occur in the early morning hours in the winter season. The naphthalene concentration estimates obtained from the SMOG model are employed in the Regional Human Exposure (REHEX) model to calculate population exposure statistics. Results show average hourly naphthalene exposures in Southern California under summer and winter conditions of 270 and 430 ng m -3, respectively. Exposure to significantly higher concentrations may occur for individuals close to local sources, or in naphthalene "hotspots" revealed by simulations and observations. Such levels of naphthalene exposure may be used to gauge the potential health impacts of long-term naphthalene exposure. Results are also given for the distributions of 1,4-naphthoquinone, a naphthalene reaction product that may have significant health effects.

  7. Oxidative reactions of tetrametal Pd(0)...Mo(II)-Mo(II)...Pd(0) clusters: electrochemical communication of two Pd(0) centers through the Mo(2) moiety and oxidative formation of a Pd(I)-Mo(II)-Mo(II)-Pd(I) array.

    PubMed

    Mashima, Kazushi; Shima, Asuka; Nakao, Keisuke; Fukumoto, Atsushi; Kaneda, Yutaka; Kusumi, Yoshitaka

    2009-03-01

    Reaction of Mo(2)(pyphos)(4) (1) (pyphos = 6-diphenylphosphino-2-pyridonate) with Pd(dba)(2) (dba = dibenzylideneacetone) afforded the Pd(0) complex Mo(2)Pd(2)(pyphos)(4) (2) which has two Pd(0) centers at both axial positions of the Mo(2) core. The unsaturated Pd(0) centers of 2 were coordinated with donor molecules such as olefins, acetylenes, isonitriles, carbon monoxide, and triphenylphosphine to give the corresponding adducts, Mo(2)Pd(2)(pyphos)(4)(L)(2) (3a: L = acrylonitrile, 3b: L = fumaronitrile, 3c: L = tetracyanoethylene, 3d: L = diisopropyl fumarate, 3e: L = diethyl fumarate, 3f: L = dimethyl fumarate, 3g: L = dimethyl maleate, 3h: L = 2,6-xylylisocyanide, 3i: L = tert-butylisocyanide, 3j: L = dimethyl acetylenedicarboxylate, 3k: L = 1,4-benzoquinone, 3l: L = 1,4-naphthoquinone, 3m: L = carbon monooxide, and 3n: L = triphenylphosphine). Oxidative 1,4-addition of ArSSAr and benzoyl peroxide to the Pd(0) centers of 2 afforded the corresponding Pd(I) complexes Mo(2)Pd(2)(SAr)(2)(pyphos)(4) (7a: Ar = C(6)H(5), 7b: Ar = 4-Me(3)CC(6)H(4), 7c: Ar = 4-MeC(6)H(4), 7d: 4-NO(2)C(6)H(4)) and Mo(2)Pd(2)(OCOPh)(2)(pyphos)(4) (9). Chemical oxidation of 2 with [Cp(2)Fe][BF(4)] in CH(3)CN afforded a dicationic Pd(I) complex [Mo(2)Pd(2)(pyphos)(4)(CH(3)CN)(2)][BF(4)](2) (10a). Similarly, the reaction of 2 with [Cp(2)Fe][BF(4)] in the presence of excess amounts of various donor molecules in THF gave rise to corresponding dicationic Pd(I) complexes [Mo(2)Pd(2)(pyphos)(4)(L')(2)][BF(4)](2) (10b; L' = dimethylsulfoxide, 10c: L' = THF, 10d: L' = benzonitrile, 10e: L' = p-methoxyphenylnitrile, 10f: L' = p-trifluoromethylphenylnitrile, 10g: L' = pyridine, and 10h: L' = p-dimethylaminopyridine), whereas complexes [Mo(2)Pd(2)(pyphos)(4)(CNXyl)(2)][BF(4)](2) (10i) and [Mo(2)Pd(2)(pyphos)(4)(CN(t)Bu)(2)][BF(4)](2) (10j) were prepared by oxidation of the corresponding isonitrile-Pd(0) complexes 3h and 3i. Cyclic voltammetry of 10aj displayed two different oxidation profiles of Pd(0) depending on the donor molecules: complexes 10af showed two waves ascribed to electron communication through monocationic species as intermediates, whereas complexes 10gj showed one wave due to two-electron process. Furthermore, the oxidative addition of alkyl and aryl halides to 2 gave rise to two different reaction patterns: excess amounts of benzyl halides BnX (X = Cl, Br, I), PhCl, and PhBr, and 2 equiv of PhI reacted with 2 to give Pd(I) complexes Mo(2)Pd(2)(X)(2)(pyphos)(4) (4a: X = Cl, 4b: X = Br, 4c: X = I), and the reactions of 2 with excess amounts of PhI and MeI afforded Pd(II) complexes Mo(2)Pd(2)(Ph)(2)I(2)(pyphos)(4) (11) and Mo(2)Pd(2)(CH(3))(2)I(2)(pyphos)(4) (13) bearing two "Pd(Ph)I" and "Pd(CH(3))I" moieties. PMID:19235951