Lead Optimization of Anti-Malarial Propafenone Analogs

PubMed Central

Lowes, David; Pradhan, Anupam; Iyer, Lalitha V.; Parman, Toufan; Gow, Jason; Zhu, Fangyi; Furimsky, Anna; Lemoff, Andrew; Guiguemde, W. Armand; Sigal, Martina; Clark, Julie A.; Wilson, Emily; Tang, Liang; Connelly, Michele C.; DeRisi, Joseph L.; Kyle, Dennis E.; Mirsalis, Jon; Guy, R. Kiplin

2015-01-01

Previously reported studies identified analogs of propafenone that had potent antimalarial activity, reduced cardiac ion channel activity, and properties that suggested the potential for clinical development for malaria. Careful examination of the bioavailability, pharmacokinetics, toxicology, and efficacy of this series of compounds using rodent models revealed orally bioavailable compounds that are non-toxic and suppress parasitemia in vivo. Although these compounds possess potential for further preclinical development, they also carry some significant challenges. PMID:22708838

Asymmetric synthesis and in vitro and in vivo activity of tetrahydroquinolines featuring a diverse set of polar substitutions at the 6 position as mixed-efficacy μ opioid receptor/δ opioid receptor ligands.

PubMed

Bender, Aaron M; Griggs, Nicholas W; Anand, Jessica P; Traynor, John R; Jutkiewicz, Emily M; Mosberg, Henry I

2015-08-19

We previously reported a small series of mixed-efficacy μ opioid receptor (MOR) agonist/δ opioid receptor (DOR) antagonist peptidomimetics featuring a tetrahydroquinoline scaffold and showed the promise of this series as effective analgesics after intraperitoneal administration in mice. We report here an expanded structure-activity relationship study of the pendant region of these compounds and focus in particular on the incorporation of heteroatoms into this side chain. These analogues provide new insight into the binding requirements for this scaffold at MOR, DOR, and the κ opioid receptor (KOR), and several of them (10j, 10k, 10m, and 10n) significantly improve upon the overall MOR agonist/DOR antagonist profile of our previous compounds. In vivo data for 10j, 10k, 10m, and 10n are also reported and show the antinociceptive potency and duration of action of compounds 10j and 10m to be comparable to those of morphine.

Synthesis and evaluation of novel N-H and N-substituted indole-2- and 3-carboxamide derivatives as antioxidants agents.

PubMed

Olgen, Süreyya; Kiliç, Zuhal; Ada, Ahmet O; Coban, Tulay

2007-08-01

We have previously reported on the synthesis of novel indole derivatives where some compounds showed significant antioxidant activity. Here, we report the synthesis of novel N-H and N-substituted indole-2- and 3-carboxamide derivatives and investigated their antioxidant role in order to identify structural characteristics responsible for activity. Although all compounds showed a strong inhibitory (95-100%) effect on superoxide anion (SOD) only compounds 4, 5 and 6 showed simliar potency for the inhibition of lipid peroxidation (81-94%) which revealed that compounds 4, 5 and 6 possessed highly potent antioxidant properties. Substitution in the 1-position of the indole ring caused the significant differences between the activity results regarding lipid peroxidation inhibition.

Trace element, semivolatile organic, and chlorinated organic compound concentrations in bed sediments of selected streams at Fort Gordon, Georgia, February-April 2010

USGS Publications Warehouse

Thomas, Lashun K.; Journey, Celeste A.; Stringfield, Whitney J.; Clark, Jimmy M.; Bradley, Paul M.; Wellborn, John B.; Ratliff, Hagan; Abrahamsen, Thomas A.

2011-01-01

A spatial survey of streams was conducted from February to April 2010 to assess the concentrations of major ions, selected trace elements, semivolatile organic compounds, organochlorine pesticides, and polychlorinated biphenyls associated with the bed sediments of surface waters at Fort Gordon military installation near Augusta, Georgia. This investigation expanded a previous study conducted in May 1998 by the U.S. Geological Survey, in cooperation with the U.S. Department of the Army Environmental and Natural Resources Management Office of the U.S. Army Signal Center and Fort Gordon, that evaluated the streambed sediment quality of selected surface waters at Fort Gordon. The data presented in this report are intended to help evaluate bed sediment quality in relation to guidelines for the protection of aquatic life, and identify temporal trends in trace elements and semivolatile organic compound concentrations at streambed sites previously sampled. Concentrations of 34 major ions and trace elements and 102 semivolatile organic, organochlorine pesticide, and polychlorinated biphenyl compounds were determined in the fine-grained fraction of bed sediment samples collected from 13 of the original 29 sites in the previous study, and 22 additional sites at Fort Gordon. Three of the sites were considered reference sites as they were presumed to be located away from potential sources of contaminants and were selected to represent surface waters flowing onto the fort, and the remaining 32 nonreference sites were presumed to be located within the contamination area at the fort. Temporal trends in trace elements and semivolatile organic compound concentrations also were evaluated at 13 of the 32 nonreference sites to provide an assessment of the variability in the number of detections and concentrations of constituents in bed sediment associated with potential sources, accumulation, and attenuation processes. Major ion and trace element concentrations in fine-grained bed sediment samples from most nonreference sites exceeded concentrations in samples from reference sites at Fort Gordon. Bed sediments from one of the nonreference sites sampled contained the highest concentrations of copper and lead with elevated levels of zinc and chromium relative to reference sites. The percentage change of major ions, trace elements, and total organic carbon that had been detected at sites previously sampled in May 1998 and current bed sediment sites ranged from -4 to 8 percent with an average percentage change of less than 1 percent. Concentrations of major ions and trace elements in bed sediments exceeded probable effect levels for aquatic life (based on the amphipod Hyalella azteca) established by the U.S. Environmental Protection Agency at 46 and 69 percent of the current and previously sampled locations, respectively. The greatest frequency of exceedances for major ions and trace elements in bed sediments was observed for lead. Concentrations of semivolatile organic compounds, organochlorine pesticides, and polychlorinated biphenyls were detected in bed sediment samples at 94 percent of the sites currently sampled. Detections of these organic compounds were reported with greater frequency in bed sediments at upstream sampling locations, when compared to downstream locations. The greatest number of detections of these compounds was reported for bed sediment samples collected from two creeks above a lake. The percentage change of semivolatile organic compounds detected at previously sampled and current bed sediment sites ranged from -68 to 100 percent with the greatest percentage increase reported for one of the creeks above the lake. Concentrations of semivolatile organic compounds and polychlorinated biphenyls in bed sediments exceeded aquatic life criteria established by the U.S. Environmental Protection Agency at three sites. Contaminant compounds exceeding aquatic life criteria included fluoranthene, phenanthrene, anthracene, benzo(a)anthracene

Gene expression response of Salmonella enterica serotype Enteritidis phage type 8 to the subinhibitory concentrations of the plant-derived compounds,trans-cinnamaldehyde,and eugenol

USDA-ARS?s Scientific Manuscript database

Background: Salmonella Enteritidis phage type 8 (PT8) is a major poultry-associated Salmonella strain implicated in foodborne outbreaks in the United States. We previously reported that two GRAS-status, plant-derived compounds, trans-cinnamaldehyde (TC) and eugenol (EG) significantly reduced S. Ent...

Design, synthesis, crystallization and biological evaluation of new symmetrical biscationic compounds as selective inhibitors of human Choline Kinase α1 (ChoKα1)

NASA Astrophysics Data System (ADS)

Schiaffino-Ortega, Santiago; Baglioni, Eleonora; Mariotto, Elena; Bortolozzi, Roberta; Serrán-Aguilera, Lucía; Ríos-Marco, Pablo; Carrasco-Jimenez, M. Paz; Gallo, Miguel A.; Hurtado-Guerrero, Ramon; Marco, Carmen; Basso, Giuseppe; Viola, Giampietro; Entrena, Antonio; López-Cara, Luisa Carlota

2016-03-01

A novel family of compounds derivative of 1,1‧-(((ethane-1,2-diylbis(oxy))bis(4,1-phenylene))bis(methylene))-bispyridinium or -bisquinolinium bromide (10a-l) containing a pair of oxygen atoms in the spacer of the linker between the biscationic moieties, were synthesized and evaluated as inhibitors of choline kinase against a panel of cancer-cell lines. The most promising compounds in this series were 1,1‧-(((ethane-1,2-diylbis(oxy))bis(4,1-phenylene))bis(methylene))bis(4-(dimethylamino)pyridinium) bromide (10a) and 1,1‧-(((ethane-1,2-diylbis(oxy))bis(4,1-phenylene))bis(methylene))-bis(7-chloro-4-(pyrrolidin-1-yl)quinolinium) bromide (10l), which inhibit human choline kinase (ChoKα1) with IC50 of 1.0 and 0.92 μM, respectively, in a range similar to that of the previously reported biscationic compounds MN58b and RSM932A. Our compounds show greater antiproliferative activities than do the reference compounds, with unprecedented values of GI50 in the nanomolar range for several of the cancer-cell lines assayed, and more importantly they present low toxicity in non-tumoral cell lines, suggesting a cancer-cell-selective antiproliferative activity. Docking studies predict that the compounds interact with the choline-binding site in agreement with the binding mode of most previously reported biscationic compounds. Moreover, the crystal structure of ChoKα1 with compound 10a reveals that this compound binds to the choline-binding site and mimics HC-3 binding mode as never before.

Isolated lower brachial plexus (Klumpke) palsy with compound arm presentation: case report.

PubMed

Buchanan, Edward P; Richardson, Randal; Tse, Raymond

2013-08-01

Klumpke palsy has yet to be clearly documented in the newborn, because previous reports lack any description of the obstetrical history, clinical progression, or outcome. Based on a high incidence of breach presentation in the few clinical series that report Klumpke palsy, hyperabduction with arm overhead during delivery has been the presumed mechanism. We report a child with isolated lower brachial plexus palsy and Horner syndrome who presented at birth with a vertex compound arm presentation. Recognition of this condition and details of the clinical progression and outcome are important, because guidelines for management are currently not available. Copyright © 2013. Published by Elsevier Inc.

A study revealing the key aroma compounds of steamed bread made by Chinese traditional sourdough*

PubMed Central

Zhang, Guo-hua; Wu, Tao; Sadiq, Faizan A.; Yang, Huan-yi; Liu, Tong-jie; Ruan, Hui; He, Guo-qing

2016-01-01

Aroma of Chinese steamed bread (CSB) is one of the important parameters that determines the overall quality attributes and consumer acceptance. However, the aroma profile of CSB still remains poorly understood, mainly because of relying on only a single method for aroma extraction in previous studies. Therefore, the objective of this study was to determine the volatile aroma compounds of five different samples of CSB using three different aroma extraction methods, namely solid-phase microextraction (SPME), simultaneous distillation–extraction (SDE), and purge and trap (P&T). All samples showed a unique aroma profile, which could be attributed to their unique microbial consortia. (E)-2-Nonenal and (E,E)-2,4-decadienal were the most prevalent aromatic compounds revealed by SDE, which have not been reported previously, while ethanol and acetic acid proved to be the most dominant compounds by both SPME and P&T. Our approach of combining three different aroma extraction methods provided better insights into the aroma profile of CSB, which had remained largely unknown in previous studies. PMID:27704748

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mehboob, Shahila; Hevener, Kirk E.; Truong, Kent

Because of structural and mechanistic differences between eukaryotic and prokaryotic fatty acid synthesis enzymes, the bacterial pathway, FAS-II, is an attractive target for the design of antimicrobial agents. We have previously reported the identification of a novel series of benzimidazole compounds with particularly good antibacterial effect against Francisella tularensis, a Category A biowarfare pathogen. Herein we report the crystal structure of the F. tularensis FabI enzyme in complex with our most active benzimidazole compound bound with NADH. The structure reveals that the benzimidazole compounds bind to the substrate site in a unique conformation that is distinct from the binding motifmore » of other known FabI inhibitors. Detailed inhibition kinetics have confirmed that the compounds possess a novel inhibitory mechanism that is unique among known FabI inhibitors. These studies could have a strong impact on future antimicrobial design efforts and may reveal new avenues for the design of FAS-II active antibacterial compounds.« less

An endophytic fungus isolated from finger millet (Eleusine coracana) produces anti-fungal natural products

PubMed Central

Mousa, Walaa K.; Schwan, Adrian; Davidson, Jeffrey; Strange, Philip; Liu, Huaizhi; Zhou, Ting; Auzanneau, France-Isabelle; Raizada, Manish N.

2015-01-01

Finger millet is an ancient African cereal crop, domesticated 7000 years ago in Ethiopia, reaching India at 3000 BC. Finger millet is reported to be resistant to various fungal pathogens including Fusarium sp. We hypothesized that finger millet may host beneficial endophytes (plant-colonizing microbes) that contribute to the antifungal activity. Here we report the first isolation of endophyte(s) from finger millet. Five distinct fungal species were isolated from roots and predicted taxonomically based on 18S rDNA sequencing. Extracts from three putative endophytes inhibited growth of F. graminearum and three other pathogenic Fusarium species. The most potent anti-Fusarium strain (WF4, predicted to be a Phoma sp.) was confirmed to behave as an endophyte using pathogenicity and confocal microscopy experiments. Bioassay-guided fractionation of the WF4 extract identified four anti-fungal compounds, viridicatol, tenuazonic acid, alternariol, and alternariol monomethyl ether. All the purified compounds caused dramatic breakage of F. graminearum hyphae in vitro. These compounds have not previously been reported to have anti-Fusarium activity. None of the compounds, except for tenuazonic acid, have previously been reported to be produced by Phoma. We conclude that the ancient, disease-tolerant crop, finger millet, is a novel source of endophytic anti-fungal natural products. This paper suggests the value of the crops grown by subsistence farmers as sources of endophytes and their natural products. Application of these natural chemicals to solve real world problems will require further validation. PMID:26539183

An endophytic fungus isolated from finger millet (Eleusine coracana) produces anti-fungal natural products.

PubMed

Mousa, Walaa K; Schwan, Adrian; Davidson, Jeffrey; Strange, Philip; Liu, Huaizhi; Zhou, Ting; Auzanneau, France-Isabelle; Raizada, Manish N

2015-01-01

Finger millet is an ancient African cereal crop, domesticated 7000 years ago in Ethiopia, reaching India at 3000 BC. Finger millet is reported to be resistant to various fungal pathogens including Fusarium sp. We hypothesized that finger millet may host beneficial endophytes (plant-colonizing microbes) that contribute to the antifungal activity. Here we report the first isolation of endophyte(s) from finger millet. Five distinct fungal species were isolated from roots and predicted taxonomically based on 18S rDNA sequencing. Extracts from three putative endophytes inhibited growth of F. graminearum and three other pathogenic Fusarium species. The most potent anti-Fusarium strain (WF4, predicted to be a Phoma sp.) was confirmed to behave as an endophyte using pathogenicity and confocal microscopy experiments. Bioassay-guided fractionation of the WF4 extract identified four anti-fungal compounds, viridicatol, tenuazonic acid, alternariol, and alternariol monomethyl ether. All the purified compounds caused dramatic breakage of F. graminearum hyphae in vitro. These compounds have not previously been reported to have anti-Fusarium activity. None of the compounds, except for tenuazonic acid, have previously been reported to be produced by Phoma. We conclude that the ancient, disease-tolerant crop, finger millet, is a novel source of endophytic anti-fungal natural products. This paper suggests the value of the crops grown by subsistence farmers as sources of endophytes and their natural products. Application of these natural chemicals to solve real world problems will require further validation.

ALD5, PAD1, ATF1 and ATF2 facilitate the catabolism of coniferyl aldehyde, ferulic acid and p-coumaric acid in Saccharomyces cerevisiae

PubMed Central

Adeboye, Peter Temitope; Bettiga, Maurizio; Olsson, Lisbeth

2017-01-01

The ability of Saccharomyces cerevisiae to catabolize phenolic compounds remains to be fully elucidated. Conversion of coniferyl aldehyde, ferulic acid and p-coumaric acid by S. cerevisiae under aerobic conditions was previously reported. A conversion pathway was also proposed. In the present study, possible enzymes involved in the reported conversion were investigated. Aldehyde dehydrogenase Ald5, phenylacrylic acid decarboxylase Pad1, and alcohol acetyltransferases Atf1 and Atf2, were hypothesised to be involved. Corresponding genes for the four enzymes were overexpressed in a S. cerevisiae strain named APT_1. The ability of APT_1 to tolerate and convert the three phenolic compounds was tested. APT_1 was also compared to strains B_CALD heterologously expressing coniferyl aldehyde dehydrogenase from Pseudomonas, and an ald5Δ strain, all previously reported. APT_1 exhibited the fastest conversion of coniferyl aldehyde, ferulic acid and p-coumaric acid. Using the intermediates and conversion products of each compound, the catabolic route of coniferyl aldehyde, ferulic acid and p-coumaric acid in S. cerevisiae was studied in greater detail. PMID:28205618

Imidazo[2,1-b]thiazoles and their use as pharmaceuticals: Sanofi-Aventis EP 1 923 062 A1 (equivalent to WO2008058641).

PubMed

Karimian, K

2009-03-01

Imidazothiazoles are well-known compounds and many derivatives of this fused ring system have been evaluated for potential biological activity. The present application is focused on imidazo[2,1-b]thiazoles with pharmacological ability to stimulate the expression (transcription) of the enzyme endothelial nitric oxide (NO) synthase. This invention contains two types of claims. First, several imidazo[2,1-b]thiazoles (and compositions thereof) that were not previously reported in chemical literature are claimed (claims 6 - 15). Second, the use of the claimed compounds in the treatment of several different diseases is claimed (claims 1 - 5 and 16). The claimed imidazo[2,1-b]thiazoles are synthesized by the condensation of 2-aminothiazole with an alpha-halo ketone. Evaluation of pharmacological activity of the claimed compounds is based on previously reported methodologies. Results are at their best reported in descriptive terms. The descriptive presentation of results in this application does not allow a critical evaluation of the claims. However, this does not diminish the potential commercial importance of this application. Because of the importance of nitric oxide regulation in physiological systems, more research in this area of medicinal chemistry can be anticipated.

Design, synthesis, and taste evaluation of a high-intensity umami-imparting oxazole-based compound.

PubMed

Amino, Yusuke; Tahara, Yu-Ki; Yamada, Kei; Nakazawa, Masakazu; Tagami, Uno; Tajima, Takaho; Kuroda, Motonaka

2017-09-01

Umami taste is imparted predominantly by monosodium glutamate (MSG) and 5'-ribonucleotides. Recently, several different classes of hydrophobic umami-imparting compounds, the structures of which are quite different from MSG, have been reported. To obtain a novel umami-imparting compound, N-cinnamoyl phenethylamine was chosen as the lead compound, and a rational structure-optimization study was conducted on the basis of the pharmacophore model of previously reported compounds. The extremely potent umami-imparting compound 2-[[[2-[(1E)-2-(1,3-benzodioxol-5-yl)ethenyl]-4-oxazolyle]methoxy]methyl]pyridine, which exhibits 27,000 times the umami taste of MSG, was found. Its terminal pyridine residue and linear structure are suggested to be responsible for its strong activity. The time taken to reach maximum taste intensity exhibited by it, as determined by the time-intensity method, is 22.0 s, whereas the maximum taste intensity of MSG occurs immediately. This distinct difference in the time-course taste profile may be due to the hydrophobicity and strong receptor affinity of the new compound.

Allelochemical effects of volatile compounds and organic extracts from Muscodor yucatanensis, a tropical endophytic fungus from Bursera simaruba.

PubMed

Macías-Rubalcava, Martha L; Hernández-Bautista, Blanca E; Oropeza, Fabiola; Duarte, Georgina; González, María C; Glenn, Anthony E; Hanlin, Richard T; Anaya, Ana Luisa

2010-10-01

Muscodor yucatanensis, an endophytic fungus, was isolated from the leaves of Bursera simaruba (Burseraceae) in a dry, semideciduous tropical forest in the Ecological Reserve El Eden, Quintana Roo, Mexico. We tested the mixture of volatile organic compounds (VOCs) produced by M. yucatanensis for allelochemical effects against other endophytic fungi, phytopathogenic fungi and fungoids, and plants. VOCs were lethal to Guignardia mangifera, Colletotrichum sp., Phomopsis sp., Alternaria solani, Rhizoctonia sp., Phytophthora capsici, and P. parasitica, but had no effect on Fusarium oxysporum, Xylaria sp., the endophytic isolate 120, or M. yucatanensis. VOCs inhibited root elongation in amaranth, tomato, and barnyard grass, particularly those produced during the first 15 days of fungal growth. VOCs were identified by gas chromatography/mass spectrometry and included compounds not previously reported from other Muscodor species and the previously reported compounds octane, 2-methyl butyl acetate, 2-pentyl furan, caryophyllene, and aromadendrene. We also evaluated organic extracts from the culture medium and mycelium of M. yucatanensis on the same endophytes, phytopathogens, and plants. In general, extracts inhibited plants more than endophytic or phytopathogens fungi. G. mangifera was the only organism that was significantly stimulated by both extracts regardless of concentration. Compounds in both organic extracts were identified by gas chromatography/mass spectrometry. We discuss the possible allelopathic role that metabolites of M. yucatanensis play in its ecological interactions with its host plant and other organisms.

Characterization of Cladosporols from the Marine Algal-Derived Endophytic Fungus Cladosporium cladosporioides EN-399 and Configurational Revision of the Previously Reported Cladosporol Derivatives.

PubMed

Li, Hong-Lei; Li, Xiao-Ming; Mándi, Attila; Antus, Sándor; Li, Xin; Zhang, Peng; Liu, Yang; Kurtán, Tibor; Wang, Bin-Gui

2017-10-06

Four new cladosporol derivatives, cladosporols F-I (1-4), the known cladosporol C (5), and its new epimer, cladosporol J (6), were isolated and identified from the marine algal-derived endophytic fungus Cladosporium cladosporioides EN-399. Their structures were determined by detailed interpretation of NMR and MS data, and the absolute configurations were established on the basis of TDDFT-ECD and OR calculations. The configurational assignment of cladosporols F (1) and G (2) showed that the previously reported absolute configuration of cladosporol A and all the related cladosporols need to be revised from (4'R) to (4'S). Compounds 1-6 showed antibacterial activity against Escherichia coli, Micrococcus luteus, and Vibrio harveyi with MIC values ranging from 4 to 128 μg/mL. Compound 3 showed significant cytotoxicity against A549, Huh7, and LM3 cell lines with IC 50 values of 5.0, 1.0, and 4.1 μM, respectively, and compound 5 showed activity against H446 cell line with IC 50 value of 4.0 μM.

Fullerene-like CS x: A first-principles study of synthetic growth

NASA Astrophysics Data System (ADS)

Goyenola, C.; Gueorguiev, G. K.; Stafström, S.; Hultman, L.

2011-04-01

Fullerene-Like (FL) Sulpho-Carbide (CSx) compounds have been addressed by first principles calculations. Geometry optimization and cohesive energy results are presented for the relative stability of precursor species such as C2S, CS2, and C2S2 in isolated form. The energy cost for structural defects, arising from the substitution of C by S is also reported. Similar to previously synthesized FL-CNx and FL-CPx compounds, the pentagon, the double pentagon defects as well as the Stone-Wales defects are confirmed as energetically feasible in CSx compounds.

Estrogenic Activities of Fatty Acids and a Sterol Isolated from Royal Jelly

PubMed Central

Isohama, Yoichiro; Maruyama, Hiroe; Yamada, Yayoi; Narita, Yukio; Ohta, Shozo; Araki, Yoko; Miyata, Takeshi; Mishima, Satoshi

2008-01-01

We have previously reported that royal jelly (RJ) from honeybees (Apis mellifera) has weak estrogenic activity mediated by interaction with estrogen receptors that leads to changes in gene expression and cell proliferation. In this study, we isolated four compounds from RJ that exhibit estrogenic activity as evaluated by a ligand-binding assay for the estrogen receptor (ER) β. These compounds were identified as 10-hydroxy-trans-2-decenoic acid, 10-hydroxydecanoic acid, trans-2-decenoic acid and 24-methylenecholesterol. All these compounds inhibited binding of 17β-estradiol to ERβ, although more weakly than diethylstilbestrol or phytoestrogens. However, these compounds had little or no effect on the binding of 17β-estradiol to ERα. Expression assays suggested that these compounds activated ER, as evidenced by enhanced transcription of a reporter gene containing an estrogen-responsive element. Treatment of MCF-7 cells with these compounds enhanced their proliferation, but concomitant treatment with tamoxifen blocked this effect. Exposure of immature rats to these compounds by subcutaneous injection induced mild hypertrophy of the luminal epithelium of the uterus, but was not associated with an increase in uterine weight. These findings provide evidence that these compounds contribute to the estrogenic effect of RJ. PMID:18830443

Identification and quantification of glucosinolate and flavonol compounds in rocket salad (Eruca sativa, Eruca vesicaria and Diplotaxis tenuifolia) by LC–MS: Highlighting the potential for improving nutritional value of rocket crops

PubMed Central

Bell, Luke; Oruna-Concha, Maria Jose; Wagstaff, Carol

2015-01-01

Liquid chromatography mass spectrometry (LC–MS) was used to obtain glucosinolate and flavonol content for 35 rocket accessions and commercial varieties. 13 glucosinolates and 11 flavonol compounds were identified. Semi-quantitative methods were used to estimate concentrations of both groups of compounds. Minor glucosinolate composition was found to be different between accessions; concentrations varied significantly. Flavonols showed differentiation between genera, with Diplotaxis accumulating quercetin glucosides and Eruca accumulating kaempferol glucosides. Several compounds were detected in each genus that have only previously been reported in the other. We highlight how knowledge of phytochemical content and concentration can be used to breed new, nutritionally superior varieties. We also demonstrate the effects of controlled environment conditions on the accumulations of glucosinolates and flavonols and explore the reasons for differences with previous studies. We stress the importance of consistent experimental design between research groups to effectively compare and contrast results. PMID:25442630

MDN-0170, a New Napyradiomycin from Streptomyces sp. Strain CA-271078

PubMed Central

Lacret, Rodney; Pérez-Victoria, Ignacio; Oves-Costales, Daniel; de la Cruz, Mercedes; Domingo, Elizabeth; Martín, Jesús; Díaz, Caridad; Vicente, Francisca; Genilloud, Olga; Reyes, Fernando

2016-01-01

A new napyradiomycin, MDN-0170 (1), was isolated from the culture broth of the marine-derived actinomycete strain CA-271078, together with three known related compounds identified as 4-dehydro-4a-dechloronapyradiomycin A1 (2), napyradiomycin A1 (3) and 3-chloro-6,8-dihydroxy-8-α-lapachone (4). The structure of the new compound was determined using a combination of spectroscopic techniques, including 1D and 2D NMR and electrospray-time of flight mass spectrometry (ESI-TOF MS). The relative configuration of compound 1, which contains two independent stereoclusters, has been established by molecular modelling in combination with nOe and coupling constant analyses. Biosynthetic arguments also allowed us to propose its absolute stereochemistry. The antimicrobial properties of the compounds isolated were evaluated against methicillin-resistant Staphylococcus aureus (MRSA), Escherichia coli, Aspergillus fumigatus, and Candida albicans. The potent bioactivity previously reported for compounds 2 and 3 against methicillin-sensitive S. aureus has been extended to methicillin-resistant strains in this report. PMID:27763545

Surfactants, Aromatic and Isoprenoid Compounds, and Fatty Acid Biosynthesis Inhibitors Suppress Staphylococcus aureus Production of Toxic Shock Syndrome Toxin 1▿

PubMed Central

McNamara, Peter J.; Syverson, Rae Ellen; Milligan-Myhre, Kathy; Frolova, Olga; Schroeder, Sarah; Kidder, Joshua; Hoang, Thanh; Proctor, Richard A.

2009-01-01

Menstrual toxic shock syndrome is a rare but potentially life-threatening illness manifest through the actions of Staphylococcus aureus toxic shock syndrome toxin 1 (TSST-1). Previous studies have shown that tampon additives can influence staphylococcal TSST-1 production. We report here on the TSST-1-suppressing activity of 34 compounds that are commonly used additives in the pharmaceutical, food, and perfume industries. Many of the tested chemicals had a minimal impact on the growth of S. aureus and yet were potent inhibitors of TSST-1 production. The TSST-1-reducing compounds included surfactants with an ether, amide, or amine linkage to their fatty acid moiety (e.g., myreth-3-myristate, Laureth-3, disodium lauroamphodiacetate, disodium lauramido monoethanolamido, sodium lauriminodipropionic acid, and triethanolamine laureth sulfate); aromatic compounds (e.g. phenylethyl and benzyl alcohols); and several isoprenoids and related compounds (e.g., terpineol and menthol). The membrane-targeting and -altering effects of the TSST-1-suppressing compounds led us to assess the activity of molecules that are known to inhibit fatty acid biosynthesis (e.g., cerulenin, triclosan, and hexachlorophene). These compounds also reduced S. aureus TSST-1 production. This study suggests that more additives than previously recognized inhibit the production of TSST-1. PMID:19223628

4-Alkylated homoibotenic acid (HIBO) analogues: versatile pharmacological agents with diverse selectivity profiles towards metabotropic and ionotropic glutamate receptor subtypes.

PubMed

Madsen, Ulf; Pickering, Darryl S; Nielsen, Birgitte; Bräuner-Osborne, Hans

2005-01-01

4-Alkylated analogues of homoibotenic acid (HIBO) have previously shown high potency and selectivity at ionotropic and metabotropic glutamic acid receptor (iGluR and mGluR) subtypes. Compounds with different selectivity profiles are valuable pharmacological tools for neuropharmacological studies, and the series of 4-alkyl-HIBO analogues have been extended in this paper in the search for versatile agents. Pharmacological characterization of five new analogues, branched and unbranched 4-alkyl-HIBO analogues, have been carried out. The present compounds are all weak antagonists at Group I mGluRs (mGluR1 and 5) presenting only small differences in potencies (Ki values ranging from 89 to 670 microM). Affinities were studied at native and cloned iGluRs, and the compounds described show preference for the AMPA receptor subtypes GluR1 and 2 over GluR3 and 4. However, compared to previous 4-alkyl-HIBO analogues, these compounds show a remarkably high affinity for the Kain preferring subtype GluR5. The observed GluR5 affinities were either similar or higher compared to their GluR1 and 2 affinity. Isopropyl-HIBO showed the highest affinity for GluR5 (Ki=0.16 microM), and represents a unique compound with high affinity towards the three subtypes GluR1, 2 and 5. In general, these compounds represent new selectivity profiles compared to previously reported Glu receptor analogues.

LAMM syndrome with middle ear dysplasia associated with compound heterozygosity for FGF3 mutations.

PubMed

Sensi, Alberto; Ceruti, Stefano; Trevisi, Patrizia; Gualandi, Francesca; Busi, Micol; Donati, Ilaria; Neri, Marcella; Ferlini, Alessandra; Martini, Alessandro

2011-05-01

We report on the first cases of FGF3 compound heterozygotes in two European families from non-consanguineous marriages, affected with labyrinthine aplasia, microtia, and microdontia (LAMM) Syndrome. Three not previously described mutations (p.W153VfsX51, p.Y106C, and p.Y49C) and a recurrent one (p.R104X) were found. Analysis of 50 unrelated control subjects (100 chromosomes) of the same European background did not show any of the two newly reported missense variations. We confirm the absence of otodental syndrome in heterozygous carriers, but report unilateral microtia in one of them. We also report on the involvement of the middle ear structures in LAMM Syndrome. Copyright © 2011 Wiley-Liss, Inc.

Determination of Henry`s law constants by equilibrium partitioning in a closed system using a new in situ optical absorbance method

DOE Office of Scientific and Technical Information (OSTI.GOV)

Allen, J.M.; Balcavage, W.X.; Ramachandran, B.R.

Currently, a great deal of interest exists in developing quantitative descriptions of the transport behavior for organic chemical compounds in the environment. Transport between water and air is of particular significance in this regard. A new method for measurement of thermodynamic Henry`s law constants (H) is reported. In this method, the optical absorbance of a dilute aqueous solution containing an organic compound is followed with time as the compound partitions into the air above the solution in a sealed vessel. The change in optical absorbance and the vapor to liquid volume ratio of the vessel are then used to calculatemore » the value for H. The concentration of the organic compound in the aqueous and vapor phases need not be known. This method allows the approach to equilibrium to be observed in real time so that attainment of equilibrium is readily apparent. This method works particularly well for water-soluble compounds having low vapor pressures. The applicability of this method is limited to compounds that exhibit significant optical absorbance in the ultraviolet and visible regions of the electromagnetic spectrum. Values for H and their temperature dependencies measured using this new method are reported for methacrolein, methyl vinyl ketone, benzaldehyde, and acetophenone. Values for H are also reported for benzene, toluene, and ethylbenzene at 298 K. All reported H data are compared with previously reported values.« less

Identification of genotoxic compounds using isogenic DNA repair deficient DT40 cell lines on a quantitative high throughput screening platform

PubMed Central

Nishihara, Kana; Huang, Ruili; Zhao, Jinghua; Shahane, Sampada A.; Witt, Kristine L.; Smith-Roe, Stephanie L.; Tice, Raymond R.; Takeda, Shunichi; Xia, Menghang

2016-01-01

DNA repair pathways play a critical role in maintaining cellular homeostasis by repairing DNA damage induced by endogenous processes and xenobiotics, including environmental chemicals. Induction of DNA damage may lead to genomic instability, disruption of cellular homeostasis and potentially tumours. Isogenic chicken DT40 B-lymphocyte cell lines deficient in DNA repair pathways can be used to identify genotoxic compounds and aid in characterising the nature of the induced DNA damage. As part of the US Tox21 program, we previously optimised several different DT40 isogenic clones on a high-throughput screening platform and confirmed the utility of this approach for detecting genotoxicants by measuring differential cytotoxicity in wild-type and DNA repair-deficient clones following chemical exposure. In the study reported here, we screened the Tox21 10K compound library against two isogenic DNA repair-deficient DT40 cell lines (KU70 −/−/RAD54 −/− and REV3 −/−) and the wild-type cell line using a cell viability assay that measures intracellular adenosine triphosphate levels. KU70 and RAD54 are genes associated with DNA double-strand break repair processes, and REV3 is associated with translesion DNA synthesis pathways. Active compounds identified in the primary screening included many well-known genotoxicants (e.g. adriamycin, melphalan) and several compounds previously untested for genotoxicity. A subset of compounds was further evaluated by assessing their ability to induce micronuclei and phosphorylated H2AX. Using this comprehensive approach, three compounds with previously undefined genotoxicity—2-oxiranemethanamine, AD-67 and tetraphenylolethane glycidyl ether—were identified as genotoxic. These results demonstrate the utility of this approach for identifying and prioritising compounds that may damage DNA. PMID:26243743

Identification of a powerful aroma compound in munster and camembert cheeses: ethyl 3-mercaptopropionate.

PubMed

Sourabié, Alain M; Spinnler, Henry-Eric; Bonnarme, Pascal; Saint-Eve, Anne; Landaud, Sophie

2008-06-25

With the view to investigate the presence of thiols in cheese, the use of different methods of preparation and extraction with an organomercuric compound ( p-hydroxymercuribenzoate) enabled the isolation of a new compound. The analysis of cheese extracts by gas chromatography coupled with pulse flame photometry, mass spectrometry, and olfactometry detections led to the identification of ethyl 3-mercaptopropionate in Munster and Camembert cheeses. This compound, described at low concentrations as having pleasant, fruity, grapy, rhubarb, and empyreumatic characters, has previously been reported in wine and Concord grape but was never mentioned before in cheese. A possible route for the formation of this compound in relation with the catabolism of sulfur amino acids is proposed.

The Dynamics of Autism Spectrum Disorders: How Neurotoxic Compounds and Neurotransmitters Interact

PubMed Central

Quaak, Ilona; Brouns, Madeleine R.; de Bor, Margot Van

2013-01-01

In recent years concern has risen about the increasing prevalence of Autism Spectrum Disorders (ASD). Accumulating evidence shows that exposure to neurotoxic compounds is related to ASD. Neurotransmitters might play a key role, as research has indicated a connection between neurotoxic compounds, neurotransmitters and ASD. In the current review a literature overview with respect to neurotoxic exposure and the effects on neurotransmitter systems is presented. The aim was to identify mechanisms and related factors which together might result in ASD. The literature reported in the current review supports the hypothesis that exposure to neurotoxic compounds can lead to alterations in the GABAergic, glutamatergic, serotonergic and dopaminergic system which have been related to ASD in previous work. However, in several studies findings were reported that are not supportive of this hypothesis. Other factors also might be related, possibly altering the mechanisms at work, such as time and length of exposure as well as dose of the compound. Future research should focus on identifying the pathway through which these factors interact with exposure to neurotoxic compounds making use of human studies. PMID:23924882

The south Karelia air pollution study: Effects of low-level expsoure to malodorous sulfur compounds on symptoms

DOE Office of Scientific and Technical Information (OSTI.GOV)

Partti-Pellinen, K.; Marttila, O.; Vilkka, V.

1996-07-01

Exposure to very low levels of ambient-air malodorous sulfur compounds and their effect on eye irritation, respiratory-tract symptoms, and central nervous system symptoms in adults were assessed. A cross-sectional self-administered questionnaire (response rate = 77%) was distributed during March and April 1992 to adults (n = 336) who lived in a neighborhood that contained a pulp mill and in a nonpolluted reference community (n = 380). In the exposed community, the measured annual mean concentrations of total reduced sulfur compounds and sulfur dioxide measured in two stations were 2 to 3 {mu}g/m{sup 3} and 1 {mu}g/m{sup 3}, respectively. In themore » reference community, the annual mean concentration of sulfur dioxide was 1 {mu}g/m{sup 3}. The residents of the community near the pulp mill reported an excess of cough, respiratory infections, and headache during the previous 4 wk, as well as during the preceding 12 mo. The relative risk for headache was increased significantly in the exposed community, compared with the reference area: the adjusted odds ratio (aOR) was 1.83 (95% confidence interval [95% Cl] = 1.06-3.15) during the previous 4 wk and 1.70 (95% Cl = 1.05-2.73) during the preceding 12 mo. The relative risk for cough was also increased during the preceding 12 mo (aOR = 1.64, 95% Cl = 1.01-2.64). These results indicated that adverse health effects of malodorous sulfur compounds occur at lower concentrations than reported previously. 25 refs., 3 tabs.« less

Responses of polar organic compounds to different ionic environments in aqueous media are interrelated.

PubMed

Ferreira, L A; Chervenak, A; Placko, S; Kestranek, A; Madeira, P P; Zaslavsky, B Y

2014-11-14

Solubilities of 17 polar organic compounds in aqueous solutions of Na2SO4, NaCl, NaClO4, and NaSCN at the salt concentrations of up to 1.0-2.0 M were determined and the Setschenow constant, ksalt, values were estimated. It was found that NaClO4 may display both salting-in and salting-out effects depending on the particular compound structure. The Setschenow constant values for all the polar compounds examined in different salt solutions are found to be interrelated. Similar relationships were observed for partition coefficients of nonionic organic compounds in aqueous polyethylene glycol-sodium sulfate two-phase systems in the presence of different salt additives reported previously [Ferreira et al., J. Chromatogr. A, 2011, 1218, 5031], and for the effects of different salts on optical rotation of amino acids reported by Rossi et al. [J. Phys. Chem. B, 2007, 111, 10510]. In order to explain the observed relationships it is suggested that all the effects observed originate as responses of the compounds to the presence of a given ionic environment and its interaction with the compounds by forming direct or solvent-separated ionic pairs. The response is compound-specific and its strength is determined by the compound structure and the type (and concentration) of ions inducing the response.

Investigation of anodic and chemical oxides grown on p-type InP with applications to surface passivation for n(+)-p solar cell fabrication

NASA Technical Reports Server (NTRS)

Faur, Maria; Faur, Mircea; Goradia, Manju; Goradia, Chandra; Jenkins, Phillip; Jayne, Douglas; Weinberg, Irving

1991-01-01

Most of the previously reported InP anodic oxides were grown on a n-type InP with applications to fabrication of MISFET structures and were described as a mixture of In2O3 and P2O5 stoichiometric compounds or nonstoichiometric phases which have properties similar to crystalline compounds In(OH)3, InPO4, and In(PO3)3. Details of the compositional change of the anodic oxides grown under different anodization conditions were previously reported. The use of P-rich oxides grown either by anodic or chemical oxidation are investigated for surface passivation of p-type InP and as a protective cap during junction formation by closed-ampoule sulfur diffusion. The investigation is based on but not limited to correlations between PL intensity and X-ray photoelectron spectroscopy (XPS) chemical composition data.

Indole Alkaloids Inhibiting Neural Stem Cell from Uncaria rhynchophylla.

PubMed

Wei, Xin; Jiang, Li-Ping; Guo, Ying; Khan, Afsar; Liu, Ya-Ping; Yu, Hao-Fei; Wang, Bei; Ding, Cai-Feng; Zhu, Pei-Feng; Chen, Ying-Ying; Zhao, Yun-Li; Chen, Yong-Bing; Wang, Yi-Fen; Luo, Xiao-Dong

2017-10-01

Uncaria rhynchophylla is commonly recognized as a traditional treatment for dizziness, cerebrovascular diseases, and nervous disorders in China. Previously, the neuro-protective activities of the alkaloids from U. rhynchophylla were intensively reported. In current work, three new indole alkaloids (1-3), identified as geissoschizic acid (1), geissoschizic acid N 4 -oxide (2), and 3β-sitsirikine N 4 -oxide (3), as well as 26 known analogues were isolated from U. rhynchophylla. However, in the neural stem cells (NSCs) proliferation assay for all isolated compounds, geissoschizic acid (1), geissoschizic acid N 4 -oxide (2), isocorynoxeine (6), isorhynchophylline (7), (4S)-akuammigine N-oxide (8), and (4S)-rhynchophylline N-oxide (10) showed unexpected inhibitory activities at 10 μM. Unlike previous neuro-protective reports, as a warning or caution, our finding showcased a clue for possible NSCs toxicity and the neural lesions risk of U. rhynchophylla, while the structure-activity relationships of the isolated compounds were discussed also.

In depth chemical investigation of Glycyrrhiza triphylla Fisch roots guided by a preliminary HPLC-ESIMSn profiling.

PubMed

Shakeri, Abolfazl; Masullo, Milena; D'Urso, Gilda; Iranshahi, Mehrdad; Montoro, Paola; Pizza, Cosimo; Piacente, Sonia

2018-05-15

Chemical investigations on Glycyrrhiza spp. have mostly been focused on G. glabra (typically cultivated in Europe, henceforth called European licorice), G. uralensis and G. inflata (known as Chinese licorice) with little information on the constituents of other Glycyrrhiza species. According to the growing interest in further Glycyrrhiza spp. to be used as sweeteners, the roots of G. triphylla have been investigated. The LC-ESI/LTQOrbitrap/MS profile of the methanolic extract of G. triphylla roots guided the isolation of 21 compounds, of which the structures were elucidated by 1D- and 2D-NMR experiments. Based on this approach, 6 previously unreported compounds including two isoflavones 7,5'-dihydroxy-6,3'-dimethoxy-isoflavone-7-O-β-d-glucopyranoside (4) and 7,5'-dihydroxy-6,3'-dimethoxy-isoflavone-7-O-(7,8-dihydro-p-hydroxycinnamoyl)-β-d-glucopyranoside (7) and four saponins, named licoricesaponins M3 (13), N2 (14), O2 (16) and P2 (18), have been characterized. It is to be noted that the accurate masses of some compounds here reported for the first time corresponded to those of compounds previously described in Glycyrrhiza spp. Thus an approach based only on MS analysis could be misleading; only isolation followed by NMR analysis allowed us to unambiguously assign the structures of these previously unreported compounds. Copyright © 2017 Elsevier Ltd. All rights reserved.

Discovery of a Highly Potent, Cell-Permeable Macrocyclic Peptidomimetic (MM-589) Targeting the WD Repeat Domain 5 Protein (WDR5)–Mixed Lineage Leukemia (MLL) Protein–Protein Interaction

DOE Office of Scientific and Technical Information (OSTI.GOV)

Karatas, Hacer; Li, Yangbing; Liu, Liu

We report herein the design, synthesis, and evaluation of macrocyclic peptidomimetics that bind to WD repeat domain 5 (WDR5) and block the WDR5–mixed lineage leukemia (MLL) protein–protein interaction. Compound 18 (MM-589) binds to WDR5 with an IC50 value of 0.90 nM (Ki value <1 nM) and inhibits the MLL H3K4 methyltransferase (HMT) activity with an IC50 value of 12.7 nM. Compound 18 potently and selectively inhibits cell growth in human leukemia cell lines harboring MLL translocations and is >40 times better than the previously reported compound MM-401. Cocrystal structures of 16 and 18 complexed with WDR5 provide structural basis formore » their high affinity binding to WDR5. Additionally, we have developed and optimized a new AlphaLISA-based MLL HMT functional assay to facilitate the functional evaluation of these designed compounds. Compound 18 represents the most potent inhibitor of the WDR5–MLL interaction reported to date, and further optimization of 18 may yield a new therapy for acute leukemia.« less

A new sesquiterpene and other constituents from Saussurea lappa root.

PubMed

Duan, Jin-Ao; Hou, Pengfei; Tang, Yuping; Liu, Pei; Su, Shulan; Liu, Hanqing

2010-10-01

Five sesquiterpenes, dehydrocostus lactone (1), santamarine (5), beta-cyclocostunolide (6), 4alpha-hydroxy-4beta-methyldihydrocostol (7) and 10alpha-hydroxyl-artemisinic acid (9), along with four other compounds, beta-sitosterol (2), daucosterol (3), 5-hydroxymethyl-furaldehyde (4), and trans-syingin (8), were isolated and identified from the roots of Saussurea lappa (Compositae). Based on previous reports and our study, sesquiterpene derivatives are common and characteristic constituents of the genus Saussurea. Among the nine compounds obtained, 9 is a new sesquiterpene. It is an artemisinic acid derivative, whose structural skeleton has not been reported for Saussurea species before, but artemisinic acid is a common compound in another Compositae species, Artemisia annua. Dehydrocostus lactone (1) is present in high-content and is a possible bioprecursor of 10alpha-hydroxyartemisinic acid (9).

N-cinnamoylated chloroquine analogues as dual-stage antimalarial leads.

PubMed

Pérez, Bianca C; Teixeira, Cátia; Albuquerque, Inês S; Gut, Jiri; Rosenthal, Philip J; Gomes, José R B; Prudêncio, Miguel; Gomes, Paula

2013-01-24

The control of malaria is challenged by drug resistance, and new antimalarial drugs are needed. New drug discovery efforts include consideration of hybrid compounds as potential multitarget antimalarials. Previous work from our group has demonstrated that hybrid structures resulting from cinnamic acid conjugation with heterocyclic moieties from well-known antimalarials present improved antimalarial activity. Now, we report the synthesis and SAR analysis of an expanded series of cinnamic acid derivatives displaying remarkably high activities against both blood- and liver-stage malaria parasites. Two compounds judged most promising, based on their in vitro activity and druglikeness according to the Lipinski rules and Veber filter, were active in vivo against blood-stage rodent malaria parasites. Therefore, the compounds reported represent a new entry as promising dual-stage antimalarial leads.

New Cerebroside and Nucleoside Derivatives from a Red Sea Strain of the Marine Cyanobacterium Moorea producens.

PubMed

Youssef, Diaa T A; Ibrahim, Sabrin R M; Shaala, Lamiaa A; Mohamed, Gamal A; Banjar, Zainy M

2016-03-09

In the course of our ongoing efforts to identify marine-derived bioactive compounds, the marine cyanobacterium Moorea producens was investigated. The organic extract of the Red Sea cyanobacterium afforded one new cerebroside, mooreaside A (1), two new nucleoside derivatives, 3-acetyl-2'-deoxyuridine (2) and 3-phenylethyl-2'-deoxyuridine (3), along with the previously reported compounds thymidine (4) and 2,3-dihydroxypropyl heptacosanoate (5). The structures of the compounds were determined by different spectroscopic studies (UV, IR, 1D, 2D NMR, and HRESIMS), as well as comparison with the literature data. Compounds 1-5 showed variable cytotoxic activity against three cancer cell lines.

Ionic liquids and solids with paramagnetic anions.

PubMed

Krieger, Brenna M; Lee, Heather Y; Emge, Thomas J; Wishart, James F; Castner, Edward W

2010-08-21

Four paramagnetic ionic compounds have been prepared and their magnetic, structural and thermal properties have been investigated. The four compounds are methylbutylpyrrolidinium tetrachloroferrate(III) ([Pyrr(14)](+)/[FeCl(4)](-)), methyltributylammonium tetrachloroferrate(III) ([N(1444)](+)/[FeCl(4)](-)), butylmethylimidazolium tetrachloroferrate(III) ([bmim](+)/[FeCl(4)](-)) and tetrabutylammonium bromotrichloroferrate(III) ([N(4444)](+)/[FeBrCl(3)](-)). Temperature-dependent studies of their magnetic behaviors show that all four compounds are paramagnetic at ambient temperatures. Glass transitions are observed for only two of the four compounds, [Pyrr(14)](+)/[FeCl(4)](-) and [bmim](+)/[FeCl(4)](-). Crystal structures for [Pyrr(14)](+)/[FeCl(4)](-) and [N(1444)](+)/[FeCl(4)](-) are compared with the previously reported [N(4444)](+)/[FeBrCl(3)](-).

Structure and bioactivity of steroidal saponins isolated from the roots of Chamaelirium luteum (false unicorn).

PubMed

Challinor, Victoria L; Stuthe, Julia M U; Parsons, Peter G; Lambert, Lynette K; Lehmann, Reginald P; Kitching, William; De Voss, James J

2012-08-24

Phytochemical investigation of Chamaelirium luteum ("false unicorn") resulted in the isolation of 15 steroidal glycosides. Twelve of these (1, 2, 4-9, 11-13, and 15) are apparently unique to this species, and eight of these (6-9, 11-13, and 15) are previously unreported compounds; one (15) possesses a new steroidal aglycone. In addition, the absolute configuration of (23R,24S)-chiograsterol A (10) was defined, and its full spectroscopic characterization is reported for the first time. The structures and configurations of the saponins were determined using a combination of multistage mass spectrometry (MS(n)), 1D and 2D NMR experiments, and chemical degradation. The antiproliferative activity of nine compounds obtained in the present work, and eight related compounds generated in previous work, was compared in six human tumor cell lines, with aglycones 3 and 10 and related derivatives 16, 17, 19, and 20 all displaying significant antiproliferative activity.

Triterpenes and saponins from Rudgea viburnioides.

PubMed

Young, M C; Araújo, A R; da Silva, C A; Lopes, M N; Trevisan, L M; Bolzani, V S

1998-07-01

A novel triterpene, viburgenin (1), has been isolated from an extract of the ripe fruit rinds of Rudgea viburnioides, together with the known saponins, arjunglucoside I and trachelosperosides B-1 and E-1, and the triterpenes trachelosperogenin B (2) and arjungenin. Compound 2 was previously obtained as a product from enzymatic hydrolysis, and it is reported for the first time as a natural product. The structure of compound 1 was determined as 2alpha,3beta, 19alpha,23,24-pentahydroxyurs-12-ene by extensive use of 1D and 2D NMR spectroscopic methods. Compound 1 exhibited moderate antifungal activity against Cladosporium cladosporioides.

Quantitative Assay of Pyrazofurin a New Antiviral, Antitumor Antibiotic1

PubMed Central

Westhead, J. E.; Price, H. D.

1974-01-01

Pyrazofurin, a carbon-linked nucleoside, has been previously reported to possess antiviral and antitumor activity. The antagonistic effect of pyrazofurin against Neurospora crassa has been utilized to develop a quantitative assay for the compound. PMID:4275616

The acyl desaturase CER17 is involved in producing wax unsaturated primary alcohols and cutin monomers

USDA-ARS?s Scientific Manuscript database

We report here n-6 mono-unsaturated primary alcohols (the C26:1, C28:1, and C30:1 homologues) in the cuticular waxes of Arabidopsis inflorescence stem, a class of wax compound not previously reported in Arabidopsis. Further, we used mutation and transgenic complementation analyses to demonstrate tha...

Characterization of a Novel Class of Polyphenolic Inhibitors of Plasminogen Activator Inhibitor-1*

PubMed Central

Cale, Jacqueline M.; Li, Shih-Hon; Warnock, Mark; Su, Enming J.; North, Paul R.; Sanders, Karen L.; Puscau, Maria M.; Emal, Cory D.; Lawrence, Daniel A.

2010-01-01

Plasminogen activator inhibitor type 1, (PAI-1) the primary inhibitor of the tissue-type (tPA) and urokinase-type (uPA) plasminogen activators, has been implicated in a wide range of pathological processes, making it an attractive target for pharmacologic inhibition. Currently available small-molecule inhibitors of PAI-1 bind with relatively low affinity and do not inactivate PAI-1 in the presence of its cofactor, vitronectin. To search for novel PAI-1 inhibitors with improved potencies and new mechanisms of action, we screened a library selected to provide a range of biological activities and structural diversity. Five potential PAI-1 inhibitors were identified, and all were polyphenolic compounds including two related, naturally occurring plant polyphenols that were structurally similar to compounds previously shown to provide cardiovascular benefit in vivo. Unique second generation compounds were synthesized and characterized, and several showed IC50 values for PAI-1 between 10 and 200 nm. This represents an enhanced potency of 10–1000-fold over previously reported PAI-1 inactivators. Inhibition of PAI-1 by these compounds was reversible, and their primary mechanism of action was to block the initial association of PAI-1 with a protease. Consistent with this mechanism and in contrast to previously described PAI-1 inactivators, these compounds inactivate PAI-1 in the presence of vitronectin. Two of the compounds showed efficacy in ex vivo plasma and one blocked PAI-1 activity in vivo in mice. These data describe a novel family of high affinity PAI-1-inactivating compounds with improved characteristics and in vivo efficacy, and suggest that the known cardiovascular benefits of dietary polyphenols may derive in part from their inactivation of PAI-1. PMID:20061381

Mechanistic insight of bivalent compound 21MO as potential neuroprotectant for Alzheimer’s disease

PubMed Central

Saathoff, John M.; Liu, Kai; Chojnacki, Jeremy E.; He, Liu; Chen, Qun; Lesnefsky, Edward J.; Zhang, Shijun

2016-01-01

We have recently developed a bivalent strategy to provide novel compounds that potentially target multiple risk factors involved in the development of Alzheimer’s disease (AD). Our previous studies employing a bivalent compound with a shorter spacer (17MN) implicated that this compound can localize into mitochondria and endoplasmic reticulum (ER), thus interfering with the change of mitochondria membrane potential (ΔΨm) and Ca2+ levels in MC65 cells upon removal of tetracycline (TC). In this report, we examined the effects by a bivalent compound with a longer spacer (21MO) in MC65 cells. Our results demonstrated that 21MO suppressed the change of ΔΨm, possibly via interaction with the mitochondrial complex I in MC65 cells. Interestingly, 21MO did not show any effects on the Ca2+ level upon TC removal in MC65 cells. Our previous studies suggested that the mobilization of Ca2+ in MC65 cells, upon withdraw of TC, is originated from ER, so the results implicated that 21MO may preferentially interact with mitochondria in MC65 cells under the current experimental conditions. Collectively, the results suggest that bivalent compounds with varied spacer length and cell membrane anchor moiety may exhibit neuroprotective activities via different mechanisms of action. PMID:27023508

m- And p-halobenzoyl derivatives of p-halo-DL-phenylalanine as inhibitors in a microbial antitumor prescreen.

PubMed

Otani, T T; Briley, M R

1983-05-01

Meta- and p-halobenzoyl-p-halo-phenylalanine compounds were prepared and tested for growth-inhibitory activity in a Lactobacillus casei system. The activity of 13 of the most active of these compounds, reported here, was greater than that of any other acyl derivatives of amino acid analogs previously studied in this system and was from 2 to 8 times greater than that of 6-mercaptopurine, a known antitumor agent.

HPLC-Based Activity Profiling for GABAA Receptor Modulators in Searsia pyroides Using a Larval Zebrafish Locomotor Assay.

PubMed

Moradi-Afrapoli, Fahimeh; van der Merwe, Hannes; De Mieri, Maria; Wilhelm, Anke; Stadler, Marco; Zietsman, Pieter C; Hering, Steffen; Swart, Kenneth; Hamburger, Matthias

2017-10-01

A dichloromethane extract from leaves of Searsia pyroides potentiated gamma aminobutyric acid-induced chloride currents by 171.8 ± 54% when tested at 100 µg/mL in Xenopus oocytes transiently expressing gamma aminobutyric acid type A receptors composed of α 1 β 2 γ 2 s subunits. In zebrafish larvae, the extract significantly lowered pentylenetetrazol-provoked locomotion when tested at 4 µg/mL. Active compounds of the extract were tracked with the aid of HPLC-based activity profiling utilizing a previously validated zebrafish larval locomotor activity assay. From two active HPLC fractions, compounds 1  -  3 were isolated. Structurally related compounds 4  -  6 were purified from a later eluting inactive HPLC fraction. With the aid of 1 H and 13 C NMR and high-resolution mass spectrometry, compounds 1  -  6 were identified as analogues of anacardic acid. Compounds 1  -  3 led to a concentration-dependent decrease of pentylenetetrazol-provoked locomotion in the zebrafish larvae model, while 4  -  6 were inactive. Compounds 1  -  3 enhanced gamma aminobutyric acid-induced chloride currents in Xenopus oocytes in a concentration-dependent manner, while 4  -  6 only showed marginal enhancements of gamma aminobutyric acid-induced chloride currents. Compounds 2, 3 , and 5 have not been reported previously. Georg Thieme Verlag KG Stuttgart · New York.

Kissing nevus of the penis. Report of two cases and review of the literature*

PubMed Central

Wang, Songting; Zhou, Mingshu; Qiao, Jianjun

2014-01-01

Kissing nevus is a curious type of nevus that was first described on the eyelids and rarely described on the penis. We report two cases of kissing nevus of the penis and review previously reported cases. The lesions of the kissing nevus of the penis showed characteristic mirror-image symmetry relative to the coronal sulcus. On histopathology, the lesion showed a compound nevus. PMID:24770514

Engineering Escherichia coli coculture systems for the production of biochemical products.

PubMed

Zhang, Haoran; Pereira, Brian; Li, Zhengjun; Stephanopoulos, Gregory

2015-07-07

Engineering microbial consortia to express complex biosynthetic pathways efficiently for the production of valuable compounds is a promising approach for metabolic engineering and synthetic biology. Here, we report the design, optimization, and scale-up of an Escherichia coli-E. coli coculture that successfully overcomes fundamental microbial production limitations, such as high-level intermediate secretion and low-efficiency sugar mixture utilization. For the production of the important chemical cis,cis-muconic acid, we show that the coculture approach achieves a production yield of 0.35 g/g from a glucose/xylose mixture, which is significantly higher than reported in previous reports. By efficiently producing another compound, 4-hydroxybenzoic acid, we also demonstrate that the approach is generally applicable for biosynthesis of other important industrial products.

Antifungal activities of (E)-4-benzylidene-5-oxopyrrolidine- 2-carboxamides and 6-oxo-1,2,3,6-tetrahydropyridin-2- carboxamides synthezed via ugi reaction from baylis-hillman bromides

NASA Astrophysics Data System (ADS)

Zeng, X. H.; Xiang, L. C.; Li, H. L.; Wang, H. M.; Wang, X. B.

2016-08-01

The derivatives of N-containing heterocycles containing the pyrrolidone or pyridinone moiety are of high importance because they have extensive biological properties including antifungal, anti-muscarinic, anti-cancer, anti-viral and anti-HIV activities. In our previous work, we described an one-pot transition-metal-free, base-mediated synthesis of pyrrolidinones ((E)-4-benzylidene-5-oxopyrrolidine-2-carboxamides 6) and an one-pot regioselective synthesis of previously seldom reported pyridinones (6-oxo-1,2,3,6- tetrahydropyridin-2-carboxamides 9) via Ugi reaction from Baylis-Hillman Bromides. Herein, the growth inhibitory effect of one concentration (50mg/L) of compounds 6 and 9 against fungi (Gibberella zeae) in vitro was tested by the method of toxic medium. Ihe results showed that the inhibitory effects of compounds 6 against Gibberella zeae are not obvious, but compounds 9 showed moderate to good inhibitory effects against Gibberella zeae. Compound 9h showed the best inhibition rate against Gibberella zeae with 95%.

Identification and quantification of glucosinolate and flavonol compounds in rocket salad (Eruca sativa, Eruca vesicaria and Diplotaxis tenuifolia) by LC-MS: highlighting the potential for improving nutritional value of rocket crops.

PubMed

Bell, Luke; Oruna-Concha, Maria Jose; Wagstaff, Carol

2015-04-01

Liquid chromatography mass spectrometry (LC-MS) was used to obtain glucosinolate and flavonol content for 35 rocket accessions and commercial varieties. 13 glucosinolates and 11 flavonol compounds were identified. Semi-quantitative methods were used to estimate concentrations of both groups of compounds. Minor glucosinolate composition was found to be different between accessions; concentrations varied significantly. Flavonols showed differentiation between genera, with Diplotaxis accumulating quercetin glucosides and Eruca accumulating kaempferol glucosides. Several compounds were detected in each genus that have only previously been reported in the other. We highlight how knowledge of phytochemical content and concentration can be used to breed new, nutritionally superior varieties. We also demonstrate the effects of controlled environment conditions on the accumulations of glucosinolates and flavonols and explore the reasons for differences with previous studies. We stress the importance of consistent experimental design between research groups to effectively compare and contrast results. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

Survey of sterile admixture practices in canadian hospital pharmacies: part 2. More results and discussion.

PubMed

Warner, Travis; Nishi, Cesilia; Checkowski, Ryan; Hall, Kevin W

2009-05-01

The 1996 Guidelines for Preparation of Sterile Products in Pharmacies of the Canadian Society of Hospital Pharmacists (CSHP) represent the current standard of practice for sterile compounding in Canada. However, these guidelines are practice recommendations, not enforceable standards. Previous surveys of sterile compounding practices have shown that actual practice deviates markedly from voluntary practice recommendations. In 2004, the United States Pharmacopeia (USP) published its "General Chapter <797> Pharmaceutical Compounding-Sterile Preparations", which set a more rigorous and enforceable standard for sterile compounding in the United States. To assess sterile compounding practices in Canadian hospital pharmacies and to compare them with current CSHP recommendations and USP chapter <797> standards. An online survey, based on previous studies of sterile compounding practices, the CSHP guidelines, and the chapter <797> standards, was created and distributed to 193 Canadian hospital pharmacies. A total of 133 pharmacies completed at least part of the survey, for a response rate of 68.9%. All respondents reported the preparation of sterile products. Various degrees of deviation from the practice recommendations were noted for virtually all areas of the CSHP guidelines and the USP standards. Low levels of compliance were most notable in the areas of facilities and equipment, process validation, and product testing. Availability in the central pharmacy of a clean room facility meeting or exceeding the criteria of International Organization for Standardization (ISO) class 8 is a requirement of the chapter <797> standards, but more than 40% of responding pharmacies reported that they did not have such a facility. Higher levels of compliance were noted for policies and procedures, garbing requirements, aseptic technique, and handling of hazardous products. The survey methods for this study and results relating to policies, personnel, raw materials, storage and handling, facilities and equipment, and garments were reported in Part 1. Part 2 reports results relating to preparation of aseptic products, expiry dating, labelling, process validation, product testing and release, documentation, records, and disposal of hazardous pharmaceuticals. It also highlights some of the key areas where there is considerable opportunity for improvement. This survey identified numerous deficiencies in sterile compounding practices in Canadian hospital pharmacies. Awareness of these deficiencies may create an impetus for critical assessment and improvements in practice.

Survey of sterile admixture practices in canadian hospital pharmacies: part 1. Methods and results.

PubMed

Warner, Travis; Nishi, Cesilia; Checkowski, Ryan; Hall, Kevin W

2009-03-01

The 1996 Guidelines for Preparation of Sterile Products in Pharmacies of the Canadian Society of Hospital Pharmacists (CSHP) represent the current standard of practice for sterile compounding in Canada. However, these guidelines are practice recommendations, not enforceable standards. Previous surveys of sterile compounding practices have shown that actual practice deviates markedly from voluntary practice recommendations. In 2004, the United States Pharmacopeia (USP) published its "General Chapter <797> Pharmaceutical Compounding-Sterile Preparations", which set a more rigorous and enforceable standard for sterile compounding in the United States. To assess sterile compounding practices in Canadian hospital pharmacies and to compare them with current CSHP recommendations and USP chapter <797> standards. An online survey, based on previous studies of sterile compounding practices, the CSHP guidelines, and the chapter <797> standards, was created and distributed to 193 Canadian hospital pharmacies. A total of 133 pharmacies completed at least part of the survey, for a response rate of 68.9%. All respondents reported the preparation of sterile products. Various degrees of deviation from the practice recommendations were noted for virtually all areas of the CSHP guidelines and the USP standards. Low levels of compliance were most notable in the areas of facilities and equipment, process validation, and product testing. Availability in the central pharmacy of a clean room facility meeting or exceeding the criteria of International Organization for Standardization (ISO) class 8 is a requirement of the chapter <797> standards, but more than 40% of responding pharmacies reported that they did not have such a facility. Higher levels of compliance were noted for policies and procedures, garbing requirements, aseptic technique, and handling of hazardous products. Part 1 of this series reports the survey methods and results relating to policies, personnel, raw materials, storage and handling, facilities and equipment, and garments. Part 2 will report results relating to preparation of aseptic products, expiry dating, labelling, process validation, product testing and release, documentation, records, and disposal of hazardous pharmaceuticals. It will also highlight some of the key areas where there is considerable opportunity for improvement. This survey identified numerous deficiences in sterile compounding practices in Canadian hospital pharmacies. Awareness of these deficiencies may create an impetus for critical assessment and improvements in practice.

Crystal structures of fac-tri-chlorido-tris-(tri-methyl-phosphane-κP)rhodium(III) monohydrate and fac-tri-chlorido-tris-(tri-methyl-phosphane-κP)rhodium(III) methanol hemisolvate: rhodium structures that are isotypic with their iridium analogs.

PubMed

Merola, Joseph S; Franks, Marion A

2015-02-01

The crystal structures of two solvates of fac-tri-chlorido-tris-(tri-methyl-phosphane-κP)rhodium(III) are reported, i.e. one with water in the crystal lattice, fac-[RhCl3(Me3P)3]·H2O, and one with methanol in the crystal lattice, fac-[RhCl3(Me3P)3]·0.5CH3OH. These rhodium compounds exhibit distorted octahedral coordination spheres at the metal and are isotypic with the analogous iridium compounds previously reported by us [Merola et al. (2013 ▶). Polyhedron, 54, 67-73]. Comparison is made between the rhodium and iridium compounds, highlighting their isostructural relationships.

A Potent and Highly Efficacious Bcl-2/Bcl-xL Inhibitor

PubMed Central

McEachern, Donna; Yang, Chao-Yie; Meagher, Jennifer; Stuckey, Jeanne; Wang, Shaomeng

2013-01-01

Our previously reported Bcl-2/Bcl-xL inhibitor, 4, effectively inhibited tumor growth but failed to achieve complete regression in vivo. We have now performed extensive modifications on its pyrrole core structure, which has culminated in the discovery of 32 (BM-1074). Compound 32 binds to Bcl-2 and Bcl-xL proteins with Ki values of < 1 nM and inhibits cancer cell growth with IC50 values of 1-2 nM in four small-cell lung cancer cell lines sensitive to potent and specific Bcl-2/Bcl-xL inhibitors. Compound 32 is capable of achieving rapid, complete and durable tumor regression in vivo at a well-tolerated dose-schedule. Compound 32 is the most potent and efficacious Bcl-2/Bcl-xL inhibitor reported to date. PMID:23448298

Discovery of novel S1P2 antagonists. Part 2: Improving the profile of a series of 1,3-bis(aryloxy)benzene derivatives.

PubMed

Kusumi, Kensuke; Shinozaki, Koji; Yamaura, Yoshiyuki; Hashimoto, Ai; Kurata, Haruto; Naganawa, Atsushi; Ueda, Hideyuki; Otsuki, Kazuhiro; Matsushita, Takeshi; Sekiguchi, Tetsuya; Kakuuchi, Akito; Seko, Takuya

2015-10-15

Our initial lead compound 2 was modified to improve its metabolic stability. The resulting compound 5 showed excellent metabolic stability in rat and human liver microsomes. We subsequently designed and synthesized a hybrid compound of 5 and the 1,3-bis(aryloxy) benzene derivative 1, which was previously reported by our group to be an S1P2 antagonist. This hybridization reaction gave compound 9, which showed improved S1P2 antagonist activity and good metabolic stability. The subsequent introduction of a carboxylic acid moiety into 9 resulted in 14, which showed potent antagonist activity towards S1P2 with a much smaller species difference between human S1P2 and rat S1P2. Compound 14 also showed good metabolic stability and an improved safety profile compared with compound 9. Copyright © 2015 Elsevier Ltd. All rights reserved.

Amino Acids in the Antarctic Martian Meteorite MIL03346

NASA Technical Reports Server (NTRS)

Glavin, D. P.; Aubrey, A.; Dworkin, J. P.; Botta, O.; Bada, J. L.

2005-01-01

The report by McKay et al. that the Martian meteorite ALH84001 contains evidence for life on Mars remains controversial. Of central importance is whether ALH84001 and other Antarctic Martian meteorites contain endogenous organic compounds. In any investigation of organic compounds possibly derived from Mars it is important to focus on compounds that play an essential role in biochemistry as we know it and that have properties such as chirality which can be used to distinguish between biotic versus abiotic origins. Amino acids are one of the few compounds that fulfill these requirements. Previous analyses of the Antarctic Martian meteorites ALH84001 and EETA79001 have shown that these meteorites contain low levels of terrestrial amino acid contamination derived from Antarctic ice meltwater. Here we report preliminary amino acid investigations of a third Antarctic Martian meteorite MIL03346 which was discovered in Antarctica during the 2003-04 ANSMET season. Additional information is included in the original extended abstract

Effects of natural and synthetic alarm pheromone and individual pheromone components on foraging behavior of the giant Asian honey bee, Apis dorsata.

PubMed

Li, Jianjun; Wang, Zhengwei; Tan, Ken; Qu, Yufeng; Nieh, James C

2014-10-01

Social pollinators such as honey bees face attacks from predators not only at the nest, but also during foraging. Pollinating honey bees can therefore release alarm pheromones that deter conspecifics from visiting dangerous inflorescences. However, the effect of alarm pheromone and its chemical components upon bee avoidance of dangerous food sources remains unclear. We tested the responses of giant honey bee foragers, Apis dorsata, presented with alarm pheromone at a floral array. Foragers investigated the inflorescence with natural alarm pheromone, but 3.3-fold more foragers preferred to land on the 'safe' inflorescence without alarm pheromone. Using gas chromatography-mass spectrometry analysis, we identified eight chemical components in the alarm pheromone, of which three components (1-octanol, decanal and gamma-octanoic lactone) have not previously been reported in this species. We bioassayed six major compounds and found that a synthetic mixture of these compounds elicited behaviors statistically indistinguishable from responses to natural alarm pheromone. By testing each compound separately, we show that gamma-octanoic lactone, isopentyl acetate and (E)-2-decen-1-yl acetate are active compounds that elicit significant alarm responses. Gamma-octanoic lactone elicited the strongest response to a single compound and has not been previously reported in honey bee alarm pheromone. Isopentyl acetate is widely found in the alarm pheromones of sympatric Asian honey bee species, and thus alarmed A. dorsata foragers may produce information useful for conspecifics and heterospecifics, thereby broadening the effects of alarm information on plant pollination. © 2014. Published by The Company of Biologists Ltd.

Implication of transcriptional repression in compound C-induced apoptosis in cancer cells

PubMed Central

Dai, R Y; Zhao, X F; Li, J J; Chen, R; Luo, Z L; Yu, L X; Chen, S K; Zhang, C Y; Duan, C Y; Liu, Y P; Feng, C H; Xia, X M; Li, H; Fu, J; Wang, H Y

2013-01-01

Compound C, a well-known inhibitor of AMP-activated protein kinase (AMPK), has been reported to induce apoptosis in some types of cells. However, the underlying mechanisms remain largely unclear. Using a DNA microarray analysis, we found that the expression of many genes was downregulated upon treatment with compound C. Importantly, compound C caused transcriptional repression with the induction of p53, a well-known marker of transcriptional stress response, in several cancer cell lines. Compound C did not induce the phosphorylation of p53 but dramatically increased the protein level of p53 similar to some other transcriptional inhibitors, including 5,6-dichloro-1-β-D-ribobenzimidazole (DRB). Consistent with previous reports, we found that compound C initiated apoptotic death of cancer cells in an AMPK-independent manner. Similar to DRB and actinomycin D (ActD), two classic transcription inhibitors, compound C not only resulted in the loss of Bcl-2 and Bcl-xl protein but also induced the phosphorylation of eukaryotic initiation factor-alpha (eIF2α) on Ser51. Hence, the phosphorylation of eIF2α might be a novel marker of transcriptional inhibition. It is noteworthy that compound C-mediated apoptosis of cancer cells is correlated with decreased expression of Bcl-2 and Bcl-xl and the phosphorylation of eIF2α on Ser51. Remarkably, compound C exhibits potent anticancer activities in vivo. Taken together, our data suggest that compound C may be an attractive candidate for anticancer drug development. PMID:24157877

ALTERED MAMMARY GLAND DEVELOPMENT IN MALE RATS EXPOSED TO GENISTEIN AND METHOXYCHLOR

EPA Science Inventory

Genistein is a prevalent phytoestrogen whose presence in human and animal foods may affect biological actions of synthetic endocrine active compounds. We have previously reported that in utero and lactational exposure to genistein and the endocrine active pesticide methoxychlor c...

Materials Screening for the Discovery of New Half-Heuslers: Machine Learning versus ab Initio Methods.

PubMed

Legrain, Fleur; Carrete, Jesús; van Roekeghem, Ambroise; Madsen, Georg K H; Mingo, Natalio

2018-01-18

Machine learning (ML) is increasingly becoming a helpful tool in the search for novel functional compounds. Here we use classification via random forests to predict the stability of half-Heusler (HH) compounds, using only experimentally reported compounds as a training set. Cross-validation yields an excellent agreement between the fraction of compounds classified as stable and the actual fraction of truly stable compounds in the ICSD. The ML model is then employed to screen 71 178 different 1:1:1 compositions, yielding 481 likely stable candidates. The predicted stability of HH compounds from three previous high-throughput ab initio studies is critically analyzed from the perspective of the alternative ML approach. The incomplete consistency among the three separate ab initio studies and between them and the ML predictions suggests that additional factors beyond those considered by ab initio phase stability calculations might be determinant to the stability of the compounds. Such factors can include configurational entropies and quasiharmonic contributions.

Modeling the gas-phase thermochemistry of organosulfur compounds.

PubMed

Vandeputte, Aäron G; Sabbe, Maarten K; Reyniers, Marie-Françoise; Marin, Guy B

2011-06-27

Key to understanding the involvement of organosulfur compounds in a variety of radical chemistries, such as atmospheric chemistry, polymerization, pyrolysis, and so forth, is knowledge of their thermochemical properties. For organosulfur compounds and radicals, thermochemical data are, however, much less well documented than for hydrocarbons. The traditional recourse to the Benson group additivity method offers no solace since only a very limited number of group additivity values (GAVs) is available. In this work, CBS-QB3 calculations augmented with 1D hindered rotor corrections for 122 organosulfur compounds and 45 organosulfur radicals were used to derive 93 Benson group additivity values, 18 ring-strain corrections, 2 non-nearest-neighbor interactions, and 3 resonance corrections for standard enthalpies of formation, standard molar entropies, and heat capacities for organosulfur compounds and organosulfur radicals. The reported GAVs are consistent with previously reported GAVs for hydrocarbons and hydrocarbon radicals and include 77 contributions, among which 26 radical contributions, which, to the best of our knowledge, have not been reported before. The GAVs allow one to estimate the standard enthalpies of formation at 298 K, the standard entropies at 298 K, and standard heat capacities in the temperature range 300-1500 K for a large set of organosulfur compounds, that is, thiols, thioketons, polysulfides, alkylsulfides, thials, dithioates, and cyclic sulfur compounds. For a validation set of 26 organosulfur compounds, the mean absolute deviation between experimental and group additively modeled enthalpies of formation amounts to 1.9  kJ  mol(-1). For an additional set of 14 organosulfur compounds, it was shown that the mean absolute deviations between calculated and group additively modeled standard entropies and heat capacities are restricted to 4 and 2 J  mol(-1)  K(-1), respectively. As an alternative to Benson GAVs, 26 new hydrogen-bond increments are reported, which can also be useful for the prediction of radical thermochemistry. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Engineering Escherichia coli coculture systems for the production of biochemical products

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhang, Haoran; Pereira, Brian; Li, Zhengjun

Engineering microbial consortia to express complex biosynthetic pathways efficiently for the production of valuable compounds is a promising approach for metabolic engineering and synthetic biology. Here, we report the design, optimization, and scale-up of an Escherichia coli-E. coli coculture that successfully overcomes fundamental microbial production limitations, such as high-level intermediate secretion and low-efficiency sugar mixture utilization. For the production of the important chemical cis,cis-muconic acid, we show that the coculture approach achieves a production yield of 0.35 g/g from a glucose/xylose mixture, which is significantly higher than reported in previous reports. Furthermore, by efficiently producing another compound, 4-hydroxybenzoic acid, wemore » also demonstrate that the approach is generally applicable for biosynthesis of other important industrial products.« less

Engineering Escherichia coli coculture systems for the production of biochemical products

DOE PAGES

Zhang, Haoran; Pereira, Brian; Li, Zhengjun; ...

2015-06-25

Engineering microbial consortia to express complex biosynthetic pathways efficiently for the production of valuable compounds is a promising approach for metabolic engineering and synthetic biology. Here, we report the design, optimization, and scale-up of an Escherichia coli-E. coli coculture that successfully overcomes fundamental microbial production limitations, such as high-level intermediate secretion and low-efficiency sugar mixture utilization. For the production of the important chemical cis,cis-muconic acid, we show that the coculture approach achieves a production yield of 0.35 g/g from a glucose/xylose mixture, which is significantly higher than reported in previous reports. Furthermore, by efficiently producing another compound, 4-hydroxybenzoic acid, wemore » also demonstrate that the approach is generally applicable for biosynthesis of other important industrial products.« less

Pharmacophore reassignment for induction of the immunosurveillance cytokine TRAIL.

PubMed

Jacob, Nicholas T; Lockner, Jonathan W; Kravchenko, Vladimir V; Janda, Kim D

2014-06-23

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is an immunosurveillance cytokine that kills cancer cells but demonstrates little toxicity against normal cells. While investigating the TRAIL-inducing imidazolinopyrimidinone TIC10, a misassignment of its active structure was uncovered. Syntheses of the two isomers, corresponding to the published and reassigned structures, are reported. The ability of each to induce TRAIL expression in macrophages was investigated and it was found that only the compound corresponding to the reassigned structure shows the originally reported activity; the compound corresponding to the published structure is inactive. Importantly, this structural reassignment has furnished a previously unknown antitumor pharmacophore. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

A New Aggreceride analogue and a peltogynoid isolated from the stem bark of Entada abyssinica (Fabaceae).

PubMed

Melong, Raduis; Kapche, Deccaux G F W; Feussia, Michel T; Laatsch, Hartmut

2014-10-01

A new monoglyceride, l',26'-bis-[(S)-2,3-dihydroxypropyl] hexacosanedioate (1a) and the new peltogynoid, entadanin (3), along with eight known compounds, were isolated from the stem bark of Entada abyssinica (Fabaceae). The structures of the new compounds were determined by detailed analyses of 1D and 2D NMR spectra, in combination with high-resolution mass spectrometry data, and by comparison with related data from the literature. The stereochemistry of la was derived by comparison of the optical rotation with reference data. Peltogynoids have been reported previously from other Fabaceae, however this is the first report ofa peltogynoid from the genus Entada.

Diversity-oriented synthesis yields novel multistage antimalarial inhibitors.

PubMed

Kato, Nobutaka; Comer, Eamon; Sakata-Kato, Tomoyo; Sharma, Arvind; Sharma, Manmohan; Maetani, Micah; Bastien, Jessica; Brancucci, Nicolas M; Bittker, Joshua A; Corey, Victoria; Clarke, David; Derbyshire, Emily R; Dornan, Gillian L; Duffy, Sandra; Eckley, Sean; Itoe, Maurice A; Koolen, Karin M J; Lewis, Timothy A; Lui, Ping S; Lukens, Amanda K; Lund, Emily; March, Sandra; Meibalan, Elamaran; Meier, Bennett C; McPhail, Jacob A; Mitasev, Branko; Moss, Eli L; Sayes, Morgane; Van Gessel, Yvonne; Wawer, Mathias J; Yoshinaga, Takashi; Zeeman, Anne-Marie; Avery, Vicky M; Bhatia, Sangeeta N; Burke, John E; Catteruccia, Flaminia; Clardy, Jon C; Clemons, Paul A; Dechering, Koen J; Duvall, Jeremy R; Foley, Michael A; Gusovsky, Fabian; Kocken, Clemens H M; Marti, Matthias; Morningstar, Marshall L; Munoz, Benito; Neafsey, Daniel E; Sharma, Amit; Winzeler, Elizabeth A; Wirth, Dyann F; Scherer, Christina A; Schreiber, Stuart L

2016-10-20

Antimalarial drugs have thus far been chiefly derived from two sources-natural products and synthetic drug-like compounds. Here we investigate whether antimalarial agents with novel mechanisms of action could be discovered using a diverse collection of synthetic compounds that have three-dimensional features reminiscent of natural products and are underrepresented in typical screening collections. We report the identification of such compounds with both previously reported and undescribed mechanisms of action, including a series of bicyclic azetidines that inhibit a new antimalarial target, phenylalanyl-tRNA synthetase. These molecules are curative in mice at a single, low dose and show activity against all parasite life stages in multiple in vivo efficacy models. Our findings identify bicyclic azetidines with the potential to both cure and prevent transmission of the disease as well as protect at-risk populations with a single oral dose, highlighting the strength of diversity-oriented synthesis in revealing promising therapeutic targets.

Design of a serotonin 4 receptor radiotracer with decreased lipophilicity for single photon emission computed tomography.

PubMed

Fresneau, Nathalie; Dumas, Noé; Tournier, Benjamin B; Fossey, Christine; Ballandonne, Céline; Lesnard, Aurélien; Millet, Philippe; Charnay, Yves; Cailly, Thomas; Bouillon, Jean-Philippe; Fabis, Frédéric

2015-04-13

With the aim to develop a suitable radiotracer for the brain imaging of the serotonin 4 receptor subtype (5-HT4R) using single photon emission computed tomography (SPECT), we synthesized and evaluated a library of di- and triazaphenanthridines with lipophilicity values which were in the range expected to favour brain penetration, and which demonstrated specific binding to the target of interest. Adding additional nitrogen atoms to previously described phenanthridine ligands exhibiting a high unspecific binding, we were able to design a radioiodinated compound [(125)I]14. This compound exhibited a binding affinity value of 0.094 nM toward human 5-HT4R and a high selectivity over other serotonin receptor subtypes (5-HTR). In vivo SPECT imaging studies and competition experiments demonstrated that the decreased lipophilicity (in comparison with our previously reported compounds 4 and 5) allowed a more specific labelling of the 5-HT4R brain-containing regions. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Insecticidal activity against Aedes aegypti of m-pentadecadienyl-phenol isolated from Myracrodruon urundeuva seeds.

PubMed

Souza, Terezinha M; Cunha, Arcelina P; Farias, Davi F; Machado, Lyeghyna K; Morais, Selene M; Ricardo, Nágila Mps; Carvalho, Ana Fu

2012-10-01

Myracrodruon urundeuva Fr. Allemao is a common tree in the Caatinga that has been widely used for various medical purposes. Previous studies showed that the ethanol seed extract of M. urundeuva has potent activity against the larval stage of the dengue vector Aedes aegypti. Given this potential insecticidal activity, bioguided separation steps were performed in order to isolate the active compound(s). The isolation process resulted in only one active chemical compound, identified by infrared spectroscopy and mass spectrometry as m-pentadecadienyl-phenol. This compound presented potent larvicidal and pupicidal activity (LC50 10.16 and 99.06 µg mL(-1) respectively) and great egg hatching inhibitory activity (IC50 49.79 µg mL(-1)). The mode of action was investigated through observations of behavioural and morphological changes performed in third-instar larvae treated with m-pentadecadienyl-phenol solution after 1, 6, 12, 16 and 20 h of exposure. Some changes were observed as flooding of the tracheal system, alterations in siphonal valves and anal gills and lethargy, probably caused by the strong anticholinesterasic activity reported previously. The compound isolated from M. urundeuva seeds, m-pentadecadienyl-phenol, showed potent activity against immature stages of dengue vector, Ae. aegypti, being considered the main larvicidal principle. Copyright © 2012 Society of Chemical Industry.

Transposed-Letter Priming across Inflectional Morpheme Boundaries

ERIC Educational Resources Information Center

Zargar, Ehsan Shafiee; Witzel, Naoko

2017-01-01

This study reports findings from two experiments testing whether a transposed-letter (TL) priming effect can be obtained when the transposition occurs across morphological boundaries. Previous studies have primarily tested derivationally complex words or compound words, but have not examined a more rule-based and productive morphological…

Antimalarial Activity and Mechanisms of Action of Two Novel 4-Aminoquinolines against Chloroquine-Resistant Parasites

PubMed Central

Aguiar, Anna Caroline Campos; Santos, Raquel de Meneses; Figueiredo, Flávio Júnior Barbosa; Cortopassi, Wilian Augusto; Pimentel, André Silva; França, Tanos Celmar Costa; Meneghetti, Mario Roberto; Krettli, Antoniana Ursine

2012-01-01

Chloroquine (CQ) is a cost effective antimalarial drug with a relatively good safety profile (or therapeutic index). However, CQ is no longer used alone to treat patients with Plasmodium falciparum due to the emergence and spread of CQ-resistant strains, also reported for P. vivax. Despite CQ resistance, novel drug candidates based on the structure of CQ continue to be considered, as in the present work. One CQ analog was synthesized as monoquinoline (MAQ) and compared with a previously synthesized bisquinoline (BAQ), both tested against P. falciparum in vitro and against P. berghei in mice, then evaluated in vitro for their cytotoxicity and ability to inhibit hemozoin formation. Their interactions with residues present in the NADH binding site of P falciparum lactate dehydrogenase were evaluated using docking analysis software. Both compounds were active in the nanomolar range evaluated through the HRPII and hypoxanthine tests. MAQ and BAQ derivatives were not toxic, and both compounds significantly inhibited hemozoin formation, in a dose-dependent manner. MAQ had a higher selectivity index than BAQ and both compounds were weak PfLDH inhibitors, a result previously reported also for CQ. Taken together, the two CQ analogues represent promising molecules which seem to act in a crucial point for the parasite, inhibiting hemozoin formation. PMID:22649514

Antimalarial activity and mechanisms of action of two novel 4-aminoquinolines against chloroquine-resistant parasites.

PubMed

Aguiar, Anna Caroline Campos; Santos, Raquel de Meneses; Figueiredo, Flávio Júnior Barbosa; Cortopassi, Wilian Augusto; Pimentel, André Silva; França, Tanos Celmar Costa; Meneghetti, Mario Roberto; Krettli, Antoniana Ursine

2012-01-01

Chloroquine (CQ) is a cost effective antimalarial drug with a relatively good safety profile (or therapeutic index). However, CQ is no longer used alone to treat patients with Plasmodium falciparum due to the emergence and spread of CQ-resistant strains, also reported for P. vivax. Despite CQ resistance, novel drug candidates based on the structure of CQ continue to be considered, as in the present work. One CQ analog was synthesized as monoquinoline (MAQ) and compared with a previously synthesized bisquinoline (BAQ), both tested against P. falciparum in vitro and against P. berghei in mice, then evaluated in vitro for their cytotoxicity and ability to inhibit hemozoin formation. Their interactions with residues present in the NADH binding site of P falciparum lactate dehydrogenase were evaluated using docking analysis software. Both compounds were active in the nanomolar range evaluated through the HRPII and hypoxanthine tests. MAQ and BAQ derivatives were not toxic, and both compounds significantly inhibited hemozoin formation, in a dose-dependent manner. MAQ had a higher selectivity index than BAQ and both compounds were weak PfLDH inhibitors, a result previously reported also for CQ. Taken together, the two CQ analogues represent promising molecules which seem to act in a crucial point for the parasite, inhibiting hemozoin formation.

Comprehensive laboratory measurements of biomass-burning emissions: 1. Emissions from Indonesian, African, and other fuels

NASA Astrophysics Data System (ADS)

Christian, T. J.; Kleiss, B.; Yokelson, R. J.; Holzinger, R.; Crutzen, P. J.; Hao, W. M.; Saharjo, B. H.; Ward, D. E.

2003-12-01

Trace gas and particle emissions were measured from 47 laboratory fires burning 16 regionally to globally significant fuel types. Instrumentation included the following: open-path Fourier transform infrared spectroscopy; proton transfer reaction mass spectrometry; filter sampling with subsequent analysis of particles with diameter <2.5 μm for organic and elemental carbon and other elements; and canister sampling with subsequent analysis by gas chromatography (GC)/flame ionization detector, GC/electron capture detector, and GC/mass spectrometry. The emissions of 26 compounds are reported by fuel type. The results include the first detailed measurements of the emissions from Indonesian fuels. Carbon dioxide, CO, CH4, NH3, HCN, methanol, and acetic acid were the seven most abundant emissions (in order) from burning Indonesian peat. Acetol (hydroxyacetone) was a major, previously unobserved emission from burning rice straw (21-34 g/kg). The emission factors for our simulated African fires are consistent with field data for African fires for compounds measured in both the laboratory and the field. However, the higher concentrations and more extensive instrumentation in this work allowed quantification of at least 10 species not previously quantified for African field fires (in order of abundance): acetaldehyde, phenol, acetol, glycolaldehyde, methylvinylether, furan, acetone, acetonitrile, propenenitrile, and propanenitrile. Most of these new compounds are oxygenated organic compounds, which further reinforces the importance of these reactive compounds as initial emissions from global biomass burning. A few high-combustion-efficiency fires emitted very high levels of elemental (black) carbon, suggesting that biomass burning may produce more elemental carbon than previously estimated.

Discovery and structural optimization of 4-(4-(benzyloxy)phenyl)-3,4-dihydropyrimidin-2(1H)-ones as RORc inverse agonists.

PubMed

Wu, Xi-Shan; Wang, Rui; Xing, Yan-Li; Xue, Xiao-Qian; Zhang, Yan; Lu, Yong-Zhi; Song, Yu; Luo, Xiao-Yu; Wu, Chun; Zhou, Yu-Lai; Jiang, Jian-Qin; Xu, Yong

2016-11-01

Retinoic acid receptor-related orphan nuclear receptors (RORs) are orphan nuclear receptors that show constitutive activity in the absence of ligands. Among 3 subtypes of RORs, RORc is a promising therapeutic target for the treatment of Th17-mediated autoimmune diseases. Here, we report novel RORc inverse agonists discovered through structure-based drug design. Based on the structure of compound 8, a previously described agonist of RORa, a series of 4-(4-(benzyloxy)phenyl)-3,4-dihydropyrimidin-2(1H)-one derivatives were designed and synthesized. The interaction between the compounds and RORc was detected at molecular level using AlphaScreen assay. The compounds were further examined in 293T cells transfected with RORc and luciferase reporter gene. Thermal stability shift assay was used to evaluate the effects of the compounds on protein stability. A total of 27 derivatives were designed and synthesized. Among them, the compound 22b was identified as the most potent RORc inverse agonist. Its IC 50 values were 2.39 μmol/L in AlphaScreen assay, and 0.82 μmol/L in inhibition of the cell-based luciferase reporter activity. Furthermore, the compound 22b displayed a 120-fold selectivity for RORc over other nuclear receptors. Moreover, a molecular docking study showed that the structure-activity relationship was consistent with the binding mode of compound 22b in RORc. 4-(4-(Benzyloxy)phenyl)-3,4-dihydropyrimidin-2(1H)-one derivatives are promising candidates for the treatment of Th17-mediated autoimmune diseases, such as rheumatoid arthritis, psoriasis, and multiple sclerosis.

Survey of Sterile Admixture Practices in Canadian Hospital Pharmacies: Part 1. Methods and Results

PubMed Central

Warner, Travis; Nishi, Cesilia; Checkowski, Ryan; Hall, Kevin W.

2009-01-01

Background: The 1996 Guidelines for Preparation of Sterile Products in Pharmacies of the Canadian Society of Hospital Pharmacists (CSHP) represent the current standard of practice for sterile compounding in Canada. However, these guidelines are practice recommendations, not enforceable standards. Previous surveys of sterile compounding practices have shown that actual practice deviates markedly from voluntary practice recommendations. In 2004, the United States Pharmacopeia (USP) published its “General Chapter <797> Pharmaceutical Compounding—Sterile Preparations”, which set a more rigorous and enforceable standard for sterile compounding in the United States. Objectives: To assess sterile compounding practices in Canadian hospital pharmacies and to compare them with current CSHP recommendations and USP chapter <797> standards. Methods: An online survey, based on previous studies of sterile compounding practices, the CSHP guidelines, and the chapter <797> standards, was created and distributed to 193 Canadian hospital pharmacies. Results: A total of 133 pharmacies completed at least part of the survey, for a response rate of 68.9%. All respondents reported the preparation of sterile products. Various degrees of deviation from the practice recommendations were noted for virtually all areas of the CSHP guidelines and the USP standards. Low levels of compliance were most notable in the areas of facilities and equipment, process validation, and product testing. Availability in the central pharmacy of a clean room facility meeting or exceeding the criteria of International Organization for Standardization (ISO) class 8 is a requirement of the chapter <797> standards, but more than 40% of responding pharmacies reported that they did not have such a facility. Higher levels of compliance were noted for policies and procedures, garbing requirements, aseptic technique, and handling of hazardous products. Part 1 of this series reports the survey methods and results relating to policies, personnel, raw materials, storage and handling, facilities and equipment, and garments. Part 2 will report results relating to preparation of aseptic products, expiry dating, labelling, process validation, product testing and release, documentation, records, and disposal of hazardous pharmaceuticals. It will also highlight some of the key areas where there is considerable opportunity for improvement. Conclusion: This survey identified numerous deficiences in sterile compounding practices in Canadian hospital pharmacies. Awareness of these deficiencies may create an impetus for critical assessment and improvements in practice. PMID:22478875

Survey of Sterile Admixture Practices in Canadian Hospital Pharmacies: Part 2. More Results and Discussion

PubMed Central

Warner, Travis; Nishi, Cesilia; Checkowski, Ryan; Hall, Kevin W

2009-01-01

Background: The 1996 Guidelines for Preparation of Sterile Products in Pharmacies of the Canadian Society of Hospital Pharmacists (CSHP) represent the current standard of practice for sterile compounding in Canada. However, these guidelines are practice recommendations, not enforceable standards. Previous surveys of sterile compounding practices have shown that actual practice deviates markedly from voluntary practice recommendations. In 2004, the United States Pharmacopeia (USP) published its “General Chapter <797> Pharmaceutical Compounding—Sterile Preparations”, which set a more rigorous and enforceable standard for sterile compounding in the United States. Objectives: To assess sterile compounding practices in Canadian hospital pharmacies and to compare them with current CSHP recommendations and USP chapter <797> standards. Methods: An online survey, based on previous studies of sterile compounding practices, the CSHP guidelines, and the chapter <797> standards, was created and distributed to 193 Canadian hospital pharmacies. Results: A total of 133 pharmacies completed at least part of the survey, for a response rate of 68.9%. All respondents reported the preparation of sterile products. Various degrees of deviation from the practice recommendations were noted for virtually all areas of the CSHP guidelines and the USP standards. Low levels of compliance were most notable in the areas of facilities and equipment, process validation, and product testing. Availability in the central pharmacy of a clean room facility meeting or exceeding the criteria of International Organization for Standardization (ISO) class 8 is a requirement of the chapter <797> standards, but more than 40% of responding pharmacies reported that they did not have such a facility. Higher levels of compliance were noted for policies and procedures, garbing requirements, aseptic technique, and handling of hazardous products. The survey methods for this study and results relating to policies, personnel, raw materials, storage and handling, facilities and equipment, and garments were reported in Part 1. Part 2 reports results relating to preparation of aseptic products, expiry dating, labelling, process validation, product testing and release, documentation, records, and disposal of hazardous pharmaceuticals. It also highlights some of the key areas where there is considerable opportunity for improvement. Conclusion: This survey identified numerous deficiencies in sterile compounding practices in Canadian hospital pharmacies. Awareness of these deficiencies may create an impetus for critical assessment and improvements in practice. PMID:22478890

Utilization of the terrestrial cyanobacteria

NASA Astrophysics Data System (ADS)

Katoh, Hiroshi; Tomita-Yokotani, Kaori; Furukawa, Jun; Kimura, Shunta; Yokoshima, Mika; Yamaguchi, Yuji; Takenaka, Hiroyuki

The terrestrial, N _{2}-fixing cyanobacterium, Nostoc commune has expected to utilize for agriculture, food and terraforming cause of its extracellular polysaccharide, desiccation tolerance and nitrogen fixation. Previously, the first author indicated that desiccation related genes were analyzed and the suggested that the genes were related to nitrogen fixation and metabolisms. In this report, we suggest possibility of agriculture, using the cyanobacterium. Further, we also found radioactive compounds accumulated N. commune (cyanobacterium) in Fukushima, Japan after nuclear accident. Thus, it is investigated to decontaminate radioactive compounds from the surface soil by the cyanobacterium and showed to accumulate radioactive compounds using the cyanobacterium. We will discuss utilization of terrestrial cyanobacteria under closed environment. Keyword: Desiccation, terrestrial cyanobacteria, bioremediation, agriculture

Development of pharmacophore models for small molecules targeting RNA: Application to the RNA repeat expansion in myotonic dystrophy type 1.

PubMed

Angelbello, Alicia J; González, Àlex L; Rzuczek, Suzanne G; Disney, Matthew D

2016-12-01

RNA is an important drug target, but current approaches to identify bioactive small molecules have been engineered primarily for protein targets. Moreover, the identification of small molecules that bind a specific RNA target with sufficient potency remains a challenge. Computer-aided drug design (CADD) and, in particular, ligand-based drug design provide a myriad of tools to identify rapidly new chemical entities for modulating a target based on previous knowledge of active compounds without relying on a ligand complex. Herein we describe pharmacophore virtual screening based on previously reported active molecules that target the toxic RNA that causes myotonic dystrophy type 1 (DM1). DM1-associated defects are caused by sequestration of muscleblind-like 1 protein (MBNL1), an alternative splicing regulator, by expanded CUG repeats (r(CUG) exp ). Several small molecules have been found to disrupt the MBNL1-r(CUG) exp complex, ameliorating DM1 defects. Our pharmacophore model identified a number of potential lead compounds from which we selected 11 compounds to evaluate. Of the 11 compounds, several improved DM1 defects both in vitro and in cells. Copyright © 2016 Elsevier Ltd. All rights reserved.

Lipophilicity assessment of basic drugs (log P(o/w) determination) by a chromatographic method.

PubMed

Pallicer, Juan M; Sales, Joaquim; Rosés, Martí; Ràfols, Clara; Bosch, Elisabeth

2011-09-16

A previously reported chromatographic method to determine the 1-octanol/water partition coefficient (log P(o/w)) of organic compounds is used to estimate the hydrophobicity of bases, mainly commercial drugs with diverse chemical nature and pK(a) values higher than 9. For that reason, mobile phases buffered at high pH to avoid the ionization of the solutes and three different columns (Phenomenex Gemini NX, Waters XTerra RP-18 and Waters XTerra MS C(18)) with appropriate alkaline-resistant stationary phases have been used. Non-ionizable substances studied in previous works were also included in the set of compounds to evaluate the consistency of the method. The results showed that all the columns provide good estimations of the log P(o/w) for most of the compounds included in this study. The Gemini NX column has been selected to calculate log P(o/w) values of the set of studied drugs, and really good correlations between the determined log P(o/w) values and those considered as reference were obtained, proving the ability of the procedure for the lipophilicity assessment of bioactive compounds with very different structures and functionalities. Copyright © 2011 Elsevier B.V. All rights reserved.

Haenamindole and fumiquinazoline analogs from a fungicolous isolate of Penicillium lanosum

USDA-ARS?s Scientific Manuscript database

Two new amino acid-derived compounds, lanosindole (1) and 2'-epi-fumiquinazoline C (2), were isolated from cultures of a fungicolous isolate of Penicillium lanosum (MYC 1813 = NRRL 66231), together with 2'-epi-fumiquinazoline D (3), previously reported only as a product of an in vitro enzymatic step...

Reduced forced vital capacity in childhood associated with exposures to petroleum-related compounds at birth residence

EPA Science Inventory

Rationale: Previous studies have reported associations of ambient air pollutant exposures with childhood decrements in lung volumes. While the current study was designed primarily to examine traffic exposures, we also examined the impact of other early life exposures on pulmonary...

Two novel dicarboxylic Acid derivatives and a new dimeric hydrolyzable tannin from walnuts.

PubMed

Ito, Hideyuki; Okuda, Takahiro; Fukuda, Toshiyuki; Hatano, Tsutomu; Yoshida, Takashi

2007-02-07

In addition to the 16 previously reported polyphenols including 3 new ellagitannins, 2 novel dicarboxylic acid derivatives, glansreginins A (1) and B (2), and a new dimeric hydrolyzable tannin, glansrin D (3), were isolated, together with 15 known compounds from walnuts, the seeds of Juglans regia. The structures of the new compounds were elucidated on the basis of 1D- and 2D-NMR analyses and chemical data. The antioxidant effect of these isolates was also evaluated by SOD-like and DPPH radical scavenging activities.

Small molecule mimics of DFTamP1, a database designed anti-Staphylococcal peptide

PubMed Central

Dong, Yuxiang; Lushnikova, Tamara; Golla, Radha M.; Wang, Xiaofang; Wang, Guangshun

2017-01-01

Antimicrobial peptides (AMPs) are important templates for developing new antimicrobial agents. Previously, we developed a database filtering technology that enabled us to design a potent anti-Staphylococcal peptide DFTamP1. Using this same design approach, we now report the discovery of a new class of bis-indole diimidazolines as AMP small molecule mimics. The best compound killed multiple S. aureus clinical strains in both planktonic and biofilm forms. The compound appeared to target bacterial membranes with antimicrobial activity and membrane permeation ability similar to daptomycin. PMID:28011203

Overcoming Chloroquine Resistance in Malaria: Design, Synthesis, and Structure-Activity Relationships of Novel Hybrid Compounds

PubMed Central

Boudhar, Aicha; Ng, Xiao Wei; Loh, Chiew Yee; Chia, Wan Ni; Tan, Zhi Ming; Nosten, Francois

2016-01-01

Resistance to antimalarial therapies, including artemisinin, has emerged as a significant challenge. Reversal of acquired resistance can be achieved using agents that resensitize resistant parasites to a previously efficacious therapy. Building on our initial work describing novel chemoreversal agents (CRAs) that resensitize resistant parasites to chloroquine (CQ), we herein report new hybrid single agents as an innovative strategy in the battle against resistant malaria. Synthetically linking a CRA scaffold to chloroquine produces hybrid compounds with restored potency toward a range of resistant malaria parasites. A preferred compound, compound 35, showed broad activity and good potency against seven strains resistant to chloroquine and artemisinin. Assessment of aqueous solubility, membrane permeability, and in vitro toxicity in a hepatocyte line and a cardiomyocyte line indicates that compound 35 has a good therapeutic window and favorable drug-like properties. This study provides initial support for CQ-CRA hybrid compounds as a potential treatment for resistant malaria. PMID:26953199

Not-from-concentrate pilot plant 'Wonderful' cultivar pomegranate juice changes: Volatiles.

PubMed

Beaulieu, John C; Obando-Ulloa, Javier M

2017-08-15

Pilot plant ultrafiltration was used to mimic the dominant U.S. commercial pomegranate juice extraction method (hydraulic pressing whole fruit), to deliver a not-from-concentrate (NFC) juice that was high-temperature short-time pasteurized and stored at 4 and 25°C. Recovered were 46 compounds, of which 38 were routinely isolated and subjected to analysis of variance to assess these NFC juices. Herein, 18 of the 21 consensus pomegranate compounds were recovered. Ultrafiltration resulted in significant decreases for many compounds. Conversely, pasteurization resulted in compound increases. Highly significant decreases in 12 consensus compounds were observed during storage. Principal component analysis demonstrated clearly which compounds were tightly associated, and how storage samples behaved very similarly, independent of temperature. Based on these data and previous work we reported, this solid-phase microextraction (SPME) method delivered a robust 'Wonderful' volatile profile in NFC juices that is likely superior qualitatively and perhaps quantitatively to typical commercial offerings. Published by Elsevier Ltd.

gem-Difluoroolefination of Diazo Compounds with TMSCF3 or TMSCF2Br: Transition-Metal-Free Cross-Coupling of Two Carbene Precursors.

PubMed

Hu, Mingyou; Ni, Chuanfa; Li, Lingchun; Han, Yongxin; Hu, Jinbo

2015-11-18

A new olefination protocol for transition-metal-free cross-coupling of two carbene fragments arising from two different sources, namely, a nonfluorinated carbene fragment resulting from a diazo compound and a difluorocarbene fragment derived from Ruppert-Prakash reagent (TMSCF3) or TMSCF2Br, has been developed. This gem-difluoroolefination proceeds through the direct nucleophilic addition of diazo compounds to difluorocarbene followed by elimination of N2. Compared to previously reported Cu-catalyzed gem-difluoroolefination of diazo compounds with TMSCF3, which possesses a narrow substrate scope due to a demanding requirement on the reactivity of diazo compounds and in-situ-generated CuCF3, this transition-metal-free protocol affords a general and efficient approach to various disubstituted 1,1-difluoroalkenes, including difluoroacrylates, diaryldifluoroolefins, as well as arylalkyldifluoroolefins. In view of the ready availability of diazo compounds and difluorocarbene reagents and versatile transformations of 1,1-difluoroalkenes, this new gem-difluoroolefination method is expected to find wide applications in organic synthesis.

First-Principles Study of the Li-Mg-N-H System: Compound Structures and Hydrogen Storage Properties

NASA Astrophysics Data System (ADS)

Michel, Kyle; Ozolins, Vidvuds

2009-03-01

The Li-Mg-N-H system is studied with the addition of the Li4Mg(NH)3, MgNH, and Li4NH compounds using first-principles density-functional theory (DFT) calculations. A structure for the mixed imide Li4Mg(NH)3 is proposed, belonging to the Imm2 space group. A new structure for Li2Mg(NH)2 is given that has Pca21 symmetry; this compound has been previously reported as having Iba2 symmetry. The stability of the Li4Mg-imide is studied with respect to its decomposition reactions. The static, zero-point (ZPE), and vibrational energies of all relevant compounds belonging to this system are reported along with their predicted lowest-energy structures. Dehydrogenation reactions are presented that involve these phases and which are found to be spontaneously occurring within 400 K of room temperature. It is predicted that mixing LiH, LiNH2, and Li2Mg(NH)2 at 505 K will form Li4Mg(NH)3 with the release of 2.04 wt. % H2.

Antimicrobial cholic acid derivatives from the Pitch Lake bacterium Bacillus amyloliquefaciens UWI-W23.

PubMed

Dobson, Tresha E; Maxwell, Anderson R; Ramsubhag, Adesh

2018-07-01

Six cholic acid derivatives (1-6) were isolated from broth cultures of Bacillus amyloliquefaciens UWI-W23, an isolate from the Trinidad Pitch Lake. The compounds were extracted via solvent extraction and/or XAD resin adsorption and purified using silica gel column chromatography. Their structures were elucidated using 1D, 2D NMR and ESI-MS spectrometry and FT-IR spectrophotometry. One of the compounds, taurodeoxycholate (2) is for the first time being reported from a bacterial source while deoxycholate (4) is for the first time being reported from a Gram-positive bacterium. The other compounds have not been previously isolated from Bacillus spp. viz. cholate (1), taurocholic acid (3); glycodeoxycholic acid (5) and glycocholic acid (6). All six compounds exhibited antimicrobial activity against P. aeruginosa and B. cereus with MICs ranging from 7 to 250 µg/mL. Cholate (1) also showed activity against MRSA (MICs = 125 µg/mL) and glycocholic acid (6) against S. cerevisiae (MICs = 15.6 µg/mL). Copyright © 2018 Elsevier Inc. All rights reserved.

Exploration and Pharmacokinetic Profiling of Phenylalanine Based Carbamates as Novel Substance P 1–7 Analogues

PubMed Central

2014-01-01

The bioactive metabolite of Substance P, the heptapeptide SP1–7 (H-Arg-Pro-Lys-Pro-Gln-Gln-Phe-OH), has been shown to attenuate signs of hyperalgesia in diabetic mice, which indicate a possible use of compounds targeting the SP1–7 binding site as analgesics for neuropathic pain. Aiming at the development of drug-like SP1–7 peptidomimetics we have previously reported on the discovery of H-Phe-Phe-NH2 as a high affinity lead compound. Unfortunately, the pharmacophore of this compound was accompanied by a poor pharmacokinetic (PK) profile. Herein, further lead optimization of H-Phe-Phe-NH2 by substituting the N-terminal phenylalanine for a benzylcarbamate group giving a new type of SP1–7 analogues with good binding affinities is reported. Extensive in vitro as well as in vivo PK characterization is presented for this compound. Evaluation of different C-terminal functional groups, i.e., hydroxamic acid, acyl sulfonamide, acyl cyanamide, acyl hydrazine, and oxadiazole, suggested hydroxamic acid as a bioisosteric replacement for the original primary amide. PMID:25516784

Exploration and pharmacokinetic profiling of phenylalanine based carbamates as novel substance p 1-7 analogues.

PubMed

Fransson, Rebecca; Nordvall, Gunnar; Bylund, Johan; Carlsson-Jonsson, Anna; Kratz, Jadel M; Svensson, Richard; Artursson, Per; Hallberg, Mathias; Sandström, Anja

2014-12-11

The bioactive metabolite of Substance P, the heptapeptide SP1-7 (H-Arg-Pro-Lys-Pro-Gln-Gln-Phe-OH), has been shown to attenuate signs of hyperalgesia in diabetic mice, which indicate a possible use of compounds targeting the SP1-7 binding site as analgesics for neuropathic pain. Aiming at the development of drug-like SP1-7 peptidomimetics we have previously reported on the discovery of H-Phe-Phe-NH2 as a high affinity lead compound. Unfortunately, the pharmacophore of this compound was accompanied by a poor pharmacokinetic (PK) profile. Herein, further lead optimization of H-Phe-Phe-NH2 by substituting the N-terminal phenylalanine for a benzylcarbamate group giving a new type of SP1-7 analogues with good binding affinities is reported. Extensive in vitro as well as in vivo PK characterization is presented for this compound. Evaluation of different C-terminal functional groups, i.e., hydroxamic acid, acyl sulfonamide, acyl cyanamide, acyl hydrazine, and oxadiazole, suggested hydroxamic acid as a bioisosteric replacement for the original primary amide.

Unexpected Magnetic Ordering on the Cr Substructure in UCr2Si2C and Structural Relationships in Quaternary U-Cr-Si-C Compounds.

PubMed

Lemoine, Pierric; Vernière, Anne; Pasturel, Mathieu; Venturini, Gérard; Malaman, Bernard

2018-03-05

Previous experimental and theoretical studies revealed that carbon insertion into the RCr 2 Si 2 compounds drastically affects the magnetic behavior, since chromium does not carry any magnetic moment in RCr 2 Si 2 C (R = Y, La-Sm, Gd-Er) compounds in contrast to RCr 2 Si 2 (R = Y, Sm, Gd-Lu, Th) compounds. In this study, we report on the unexpected magnetic ordering of chromium atoms in the isotype quaternary UCr 2 Si 2 C compound. While specific heat and magnetic measurements suggest a Pauli paramagnetic behavior, neutron powder diffraction reveals an antiferromagnetic ordering of the chromium substructure at high temperature ( T N > 300 K), while that of uranium remains nonmagnetically ordered down to 2 K. Its magnetic behavior, inverse in comparison to the RCr 2 Si 2 C carbides involving a magnetic lanthanide, is discussed in relation with the singularity of its crystal structure among the series. Moreover, the crystallographic structures and the structural stability of UCr 2 Si 2 C and of two other quaternary U-Cr-Si-C compounds (i.e., UCr 3 Si 2 C and U 2 Cr 3 Si 2 C 3 ), based on the full occupancy of interstitial sites by carbon atoms, are discussed and compared to those of the related ternary intermetallics. Finally, the low-temperature form of UCr 2 Si 2 , corresponding to a displacive transformation around 210 K of the ThCr 2 Si 2 -type structure, is reinvestigated by considering a higher symmetry monoclinic unit cell ( C2/ m) instead of the previously reported triclinic cell ( P1̅). The antiferromagnetic ordering at low temperature ( T N = 30(2) K) of the uranium substructure is confirmed, and its magnetic structure is reanalyzed and discussed considering the monoclinic crystal structure.

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

NASA Astrophysics Data System (ADS)

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

2016-09-01

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

A charged aerosol detector/chemiluminescent nitrogen detector/liquid chromatography/mass spectrometry system for regular and fragment compound analysis in drug discovery.

PubMed

Jiang, Yutao; Hascall, Daniel; Li, Delia; Pease, Joseph H

2015-09-11

In this paper, we introduce a high throughput LCMS/UV/CAD/CLND system that improves upon previously reported systems by increasing both the quantitation accuracy and the range of compounds amenable to testing, in particular, low molecular weight "fragment" compounds. This system consists of a charged aerosol detector (CAD) and chemiluminescent nitrogen detector (CLND) added to a LCMS/UV system. Our results show that the addition of CAD and CLND to LCMS/UV is more reliable for concentration determination for a wider range of compounds than either detector alone. Our setup also allows for the parallel analysis of each sample by all four detectors and so does not significantly increase run time per sample. Copyright © 2015 Elsevier B.V. All rights reserved.

Dammarane-type triterpenes from the Brazilian medicinal plant Cordia multispicata.

PubMed

Kuroyanagi, Masanori; Kawahara, Nobuo; Sekita, Setsuko; Satake, Motoyoshi; Hayashi, Tatsuo; Takase, Yoichi; Masuda, Kazuo

2003-10-01

From the Brazilian medicinal plant Carucaá (Cordia multispicata), oleanane- and ursane-type triterpenoids were previously reported as anti-androgenic constituents of the plant. In this study, purification of the polar elements of the EtOAc-soluble fraction of the plant revealed nine novel dammarane-type triterpenes, named cordianols A-I (1-9) along with the known compound cordialin A (10). The structures of these new compounds were elucidated by means of spectral methods including HRFABMS, (1)H NMR, (13)C NMR, and 2D NMR (HMQC, HMBC, NOESY). Absolute configuration at C-23 of compound 7 was determined by an excitone chirality method. Some of these new compounds revealed a hemiketal structure on the A ring and a hydroxylated or epoxidated 20(22)-(E)-ene side chain and showed weak anti-androgenic activity.

Pancreatic Agenesis due to Compound Heterozygosity for a Novel Enhancer and Truncating Mutation in the PTF1A Gene.

PubMed

Gabbay, Monica; Ellard, Sian; De Franco, Elisa; Moisés, Regina S

2017-09-01

Neonatal diabetes, defined as the onset of diabetes within the first six months of life, is very rarely caused by pancreatic agenesis. Homozygous truncating mutations in the PTF1A gene, which encodes a transcriptional factor, have been reported in patients with pancreatic and cerebellar agenesis, whilst mutations located in a distal pancreatic-specific enhancer cause isolated pancreatic agenesis. We report an infant, born to healthy non-consanguineous parents, with neonatal diabetes due to pancreatic agenesis. Initial genetic investigation included sequencing of KCNJ11, ABCC8 and INS genes, but no mutations were found. Following this, 22 neonatal diabetes associated genes were analyzed by a next generation sequencing assay. We found compound heterozygous mutations in the PTF1A gene: A frameshift mutation in exon 1 (c.437_462 del, p.Ala146Glyfs*116) and a mutation affecting a highly conserved nucleotide within the distal pancreatic enhancer (g.23508442A>G). Both mutations were confirmed by Sanger sequencing. Isolated pancreatic agenesis resulting from compound heterozygosity for truncating and enhancer mutations in the PTF1A gene has not been previously reported. This report broadens the spectrum of mutations causing pancreatic agenesis.

Pancreatic Agenesis due to Compound Heterozygosity for a Novel Enhancer and Truncating Mutation in the PTF1A Gene

PubMed Central

Gabbay, Monica; Ellard, Sian; De Franco, Elisa; Moisés, Regina S.

2017-01-01

Neonatal diabetes, defined as the onset of diabetes within the first six months of life, is very rarely caused by pancreatic agenesis. Homozygous truncating mutations in the PTF1A gene, which encodes a transcriptional factor, have been reported in patients with pancreatic and cerebellar agenesis, whilst mutations located in a distal pancreatic-specific enhancer cause isolated pancreatic agenesis. We report an infant, born to healthy non-consanguineous parents, with neonatal diabetes due to pancreatic agenesis. Initial genetic investigation included sequencing of KCNJ11, ABCC8 and INS genes, but no mutations were found. Following this, 22 neonatal diabetes associated genes were analyzed by a next generation sequencing assay. We found compound heterozygous mutations in the PTF1A gene: A frameshift mutation in exon 1 (c.437_462 del, p.Ala146Glyfs*116) and a mutation affecting a highly conserved nucleotide within the distal pancreatic enhancer (g.23508442A>G). Both mutations were confirmed by Sanger sequencing. Isolated pancreatic agenesis resulting from compound heterozygosity for truncating and enhancer mutations in the PTF1A gene has not been previously reported. This report broadens the spectrum of mutations causing pancreatic agenesis. PMID:28663161

Potential impurities in drug substances: Compound-specific toxicology limits for 20 synthetic reagents and by-products, and a class-specific toxicology limit for alkyl bromides.

PubMed

Bercu, J P; Galloway, S M; Parris, P; Teasdale, A; Masuda-Herrera, M; Dobo, K; Heard, P; Kenyon, M; Nicolette, J; Vock, E; Ku, W; Harvey, J; White, A; Glowienke, S; Martin, E A; Custer, L; Jolly, R A; Thybaud, V

2018-04-01

This paper provides compound-specific toxicology limits for 20 widely used synthetic reagents and common by-products that are potential impurities in drug substances. In addition, a 15 μg/day class-specific limit was developed for monofunctional alkyl bromides, aligning this with the class-specific limit previously defined for monofunctional alkyl chlorides. Both the compound- and class-specific toxicology limits assume a lifetime chronic exposure for the general population (including sensitive subpopulations) by all routes of exposure for pharmaceuticals. Inhalation-specific toxicology limits were also derived for acrolein, formaldehyde, and methyl bromide because of their localized toxicity via that route. Mode of action was an important consideration for a compound-specific toxicology limit. Acceptable intake (AI) calculations for certain mutagenic carcinogens assumed a linear dose-response for tumor induction, and permissible daily exposure (PDE) determination assumed a non-linear dose-response. Several compounds evaluated have been previously incorrectly assumed to be mutagenic, or to be mutagenic carcinogens, but the evidence reported here for such compounds indicates a lack of mutagenicity, and a non-mutagenic mode of action for tumor induction. For non-mutagens with insufficient data to develop a toxicology limit, the ICH Q3A qualification thresholds are recommended. The compound- and class-specific toxicology limits described here may be adjusted for an individual drug substance based on treatment duration, dosing schedule, severity of the disease and therapeutic indication. Copyright © 2018. Published by Elsevier Inc.

Symmetrical choline-derived dications display strong anti-kinetoplastid activity

PubMed Central

Ibrahim, Hasan M. S.; Al-Salabi, Mohammed I.; El Sabbagh, Nasser; Quashie, Neils B.; Alkhaldi, Abdulsalam A. M.; Escale, Roger; Smith, Terry K.; Vial, Henri J.; de Koning, Harry P.

2011-01-01

Objectives To investigate the anti-kinetoplastid activity of choline-derived analogues with previously reported antimalarial efficacy. Methods From an existing choline analogue library, seven antimalarial compounds, representative of the first-, second- and third-generation analogues previously developed, were assessed for activity against Trypanosoma and Leishmania spp. Using a variety of techniques, the effects of choline analogue exposure on the parasites were documented and a preliminary investigation of their mode of action was performed. Results The activities of choline-derived compounds against Trypanosoma brucei and Leishmania mexicana were determined. The compounds displayed promising anti-kinetoplastid activity, particularly against T. brucei, to which 4/7 displayed submicromolar EC50 values for the wild-type strain. Low micromolar concentrations of most compounds cleared trypanosome cultures within 24–48 h. The compounds inhibit a choline transporter in Leishmania, but their entry may not depend only on this carrier; T. b. brucei lacks a choline carrier and the mode of uptake remains unclear. The compounds had no effect on the overall lipid composition of the cells, cell cycle progression or cyclic adenosine monophosphate production or short-term effects on intracellular calcium levels. However, several of the compounds, displayed pronounced effects on the mitochondrial membrane potential; this action was not associated with production of reactive oxygen species but rather with a slow rise of intracellular calcium levels and DNA fragmentation. Conclusions The choline analogues displayed strong activity against kinetoplastid parasites, particularly against T. b. brucei. In contrast to their antimalarial activity, they did not act on trypanosomes by disrupting choline salvage or phospholipid metabolism, instead disrupting mitochondrial function, leading to chromosomal fragmentation. PMID:21078603

Fenofibrate Metabolism in the Cynomolgus Monkey using Ultraperformance Liquid Chromatography-Quadrupole Time-of-Flight Mass Spectrometry-Based MetabolomicsS⃞

PubMed Central

Liu, Aiming; Patterson, Andrew D.; Yang, Zongtao; Zhang, Xinying; Liu, Wei; Qiu, Fayang; Sun, He; Krausz, Kristopher W.; Idle, Jeffrey R.; Gonzalez, Frank J.; Dai, Renke

2009-01-01

Fenofibrate, widely used for the treatment of dyslipidemia, activates the nuclear receptor, peroxisome proliferator-activated receptor α. However, liver toxicity, including liver cancer, occurs in rodents treated with fibrate drugs. Marked species differences occur in response to fibrate drugs, especially between rodents and humans, the latter of which are resistant to fibrate-induced cancer. Fenofibrate metabolism, which also shows species differences, has not been fully determined in humans and surrogate primates. In the present study, the metabolism of fenofibrate was investigated in cynomolgus monkeys by ultraperformance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-QTOFMS)-based metabolomics. Urine samples were collected before and after oral doses of fenofibrate. The samples were analyzed in both positive-ion and negative-ion modes by UPLC-QTOFMS, and after data deconvolution, the resulting data matrices were subjected to multivariate data analysis. Pattern recognition was performed on the retention time, mass/charge ratio, and other metabolite-related variables. Synthesized or purchased authentic compounds were used for metabolite identification and structure elucidation by liquid chromatographytandem mass spectrometry. Several metabolites were identified, including fenofibric acid, reduced fenofibric acid, fenofibric acid ester glucuronide, reduced fenofibric acid ester glucuronide, and compound X. Another two metabolites (compound B and compound AR), not previously reported in other species, were characterized in cynomolgus monkeys. More importantly, previously unknown metabolites, fenofibric acid taurine conjugate and reduced fenofibric acid taurine conjugate were identified, revealing a previously unrecognized conjugation pathway for fenofibrate. PMID:19251819

Analysis of Odorants in Marking Fluid of Siberian Tiger (Panthera tigris altaica) Using Simultaneous Sensory and Chemical Analysis with Headspace Solid-Phase Microextraction and Multidimensional Gas Chromatography-Mass Spectrometry-Olfactometry.

PubMed

Soso, Simone B; Koziel, Jacek A

2016-06-25

Scent-marking is the most effective method of communication in the presence or absence of a signaler. These complex mixtures result in a multifaceted interaction triggered by the sense of smell. The objective was to identify volatile organic compound (VOC) composition and odors emitted by total marking fluid (MF) associated with Siberian tigers (Panthera tigris altaica). Siberian tiger, an endangered species, was chosen because its MF had never been analyzed. Solid phase microextraction (SPME) for headspace volatile collection combined with multidimensional gas chromatography-mass spectrometry-olfactometry for simultaneous chemical and sensory analyses were used. Thirty-two VOCs emitted from MF were identified. 2-acetyl-1-pyrroline, the sole previously identified compound responsible for the "characteristic" odor of P. tigris MF, was identified along with two additional compounds confirmed with standards (urea, furfural) and four tentatively identified compounds (3-methylbutanamine, (R)-3-methylcyclopentanone, propanedioic acid, and 3-hydroxybutanal) as being responsible for the characteristic aroma of Siberian tiger MF. Simultaneous chemical and sensory analyses improved characterization of scent-markings and identified compounds not previously reported in MF of other tiger species. This research will assist animal ecologists, behaviorists, and zookeepers in understanding how scents from specific MF compounds impact tiger and wildlife communication and improve management practices related to animal behavior. Simultaneous chemical and sensory analyses is applicable to unlocking scent-marking information for other species.

Anthelmintic, Antibacterial and Cytotoxicity Activity of Imidazole Alkaloids from Pilocarpus microphyllus Leaves.

PubMed

Rocha, Jefferson A; Andrade, Ivanilza M; Véras, Leiz M C; Quelemes, Patrick V; Lima, David F; Soares, Maria J S; Pinto, Pedro L S; Mayo, Simon J; Ivanova, Galya; Rangel, Maria; Correia, Manuela; Mafud, Ana Carolina; Mascarenhas, Yvonne P; Delerue-Matos, Cristina; de Moraes, Josué; Eaton, Peter; Leite, José R S A

2017-04-01

Pilocarpus microphyllus Stapf ex Wardlew (Rutaceae), popularly known as jaborandi, is a plant native to the northern and northeastern macroregions of Brazil. Several alkaloids from this species have been isolated. There are few reports of antibacterial and anthelmintic activities for these compounds. In this work, we report the antibacterial and anthelmintic activity of five alkaloids found in P. microphyllus leaves, namely, pilosine, epiisopilosine, isopilosine, epiisopiloturine and macaubine. Of these, only anthelmintic activity of one of the compounds has been previously reported. Nuclear magnetic resonance, HPLC and mass spectrometry were combined and used to identify and confirm the structure of the five compounds. As regards the anthelmintic activity, the alkaloids were studied using in vitro assays to evaluate survival time and damaged teguments for Schistosoma mansoni adult worms. We found epiisopilosine to have anthelmintic activity at very low concentrations (3.125 μg mL -1 ); at this concentration, it prevented mating, oviposition, reducing motor activity and altered the tegument of these worms. In contrast, none of the alkaloids showed antibacterial activity. Additionally, alkaloids displayed no cytotoxic effect on vero cells. The potent anthelmintic activity of epiisopilosine indicates the potential of this natural compound as an antiparasitic agent. Copyright © 2017 John Wiley & Sons, Ltd. Copyright © 2017 John Wiley & Sons, Ltd.

Antioxidant and Anti-Osteoporotic Activities of Aromatic Compounds and Sterols from Hericium erinaceum.

PubMed

Li, Wei; Lee, Sang Hyun; Jang, Hae Dong; Ma, Jin Yeul; Kim, Young Ho

2017-01-11

Hericium erinaceum , commonly called lion's mane mushroom, is a traditional edible mushroom widely used in culinary applications and herbal medicines in East Asian countries. In this study, a new sterol, cerevisterol 6-cinnamate ( 6 ), was isolated from the fruiting bodies of H. erinaceum together with five aromatic compounds 1 - 5 and five sterols 7 - 11 . The chemical structures of these compounds were elucidated using chemical and physical methods and comparison of HRESIMS, ¹D-NMR (¹H, 13 C, and DEPT) and 2D-NMR (COSY, HMQC, HMBC, and NOESY) spectra with previously reported data. The antioxidant and anti-osteoporotic activities of extracts and the isolated compounds 1 - 11 were investigated. All compounds exhibited peroxyl radical-scavenging capacity but only compounds 1 , 3 , and 4 showed potent reducing capacity. Moreover, compounds 1 , 2 , 4 , and 5 showed moderate effects on cellular antioxidant activity and inhibited the receptor activator of nuclear factor κB ligand (RANKL)-induced osteoclastic differentiation. These results suggested that H. erinaceum could be utilized in the development of natural antioxidant and anti-osteoporotic nutraceuticals and functional foods.

Discovery and structural optimization of 4-(4-(benzyloxy)phenyl)-3,4-dihydropyrimidin-2(1H)-ones as RORc inverse agonists

PubMed Central

Wu, Xi-shan; Wang, Rui; Xing, Yan-li; Xue, Xiao-qian; Zhang, Yan; Lu, Yong-zhi; Song, Yu; Luo, Xiao-yu; Wu, Chun; Zhou, Yu-lai; Jiang, Jian-qin; Xu, Yong

2016-01-01

Aim: Retinoic acid receptor-related orphan nuclear receptors (RORs) are orphan nuclear receptors that show constitutive activity in the absence of ligands. Among 3 subtypes of RORs, RORc is a promising therapeutic target for the treatment of Th17-mediated autoimmune diseases. Here, we report novel RORc inverse agonists discovered through structure-based drug design. Methods: Based on the structure of compound 8, a previously described agonist of RORa, a series of 4-(4-(benzyloxy)phenyl)-3,4-dihydropyrimidin-2(1H)-one derivatives were designed and synthesized. The interaction between the compounds and RORc was detected at molecular level using AlphaScreen assay. The compounds were further examined in 293T cells transfected with RORc and luciferase reporter gene. Thermal stability shift assay was used to evaluate the effects of the compounds on protein stability. Results: A total of 27 derivatives were designed and synthesized. Among them, the compound 22b was identified as the most potent RORc inverse agonist. Its IC50 values were 2.39 μmol/L in AlphaScreen assay, and 0.82 μmol/L in inhibition of the cell-based luciferase reporter activity. Furthermore, the compound 22b displayed a 120-fold selectivity for RORc over other nuclear receptors. Moreover, a molecular docking study showed that the structure-activity relationship was consistent with the binding mode of compound 22b in RORc. Conclusion: 4-(4-(Benzyloxy)phenyl)-3,4-dihydropyrimidin-2(1H)-one derivatives are promising candidates for the treatment of Th17-mediated autoimmune diseases, such as rheumatoid arthritis, psoriasis, and multiple sclerosis. PMID:27374490

Recent Trends in WRN Gene Mutation Patterns in Individuals with Werner Syndrome.

PubMed

Yamaga, Masaya; Takemoto, Minoru; Takada-Watanabe, Aki; Koizumi, Naoko; Kitamoto, Takumi; Sakamoto, Kenichi; Ishikawa, Takahiro; Koshizaka, Masaya; Maezawa, Yoshiro; Yokote, Koutaro

2017-08-01

To determine recent trends in mutation patterns in the WRN gene, which cause Werner syndrome (WS), a rare, inheritable progeroid syndrome in Japan. Retrospective cohort. Longitudinal survey of WS and literature search for case reports. Individuals whose genetic testing their facilities had requested between 2009 and October 2016 (N = 67). A nationwide epidemiological study was conducted from 2009 to 2011 to improve understanding of the pathology of WS and develop therapeutic guidelines. Since 2009, Chiba University Hospital consecutively evaluated the WRN gene in 67 individuals throughout Japan who had requested genetic testing. A literature search was also conducted for case reports on Japanese WS reported since 1997. A definitive diagnosis of WS was confirmed genetically in 50 of 67 participants. Through the literature search, 16 individuals diagnosed genetically with WS were identified. Of these 66 individuals with WS, 42 were homozygous for a WRN mutation, and 21 were compound heterozygotes. One novel mutant allele was identified in an individual with the compound heterozygous genotype. The proportion of compound heterozygotes (31.8%) was significantly greater than reported previously (14.2%), indicating that the incidence of consanguineous marriage of parents has decreased. The increased frequency of individuals with WS with the compound heterozygous genotype is a recent trend in Japan. A long-term follow-up study on WRN homozygotes and compound heterozygotes will allow the relationship between WRN genotype and clinical severity of WS to be evaluated in the future. © 2017, Copyright the Authors Journal compilation © 2017, The American Geriatrics Society.

ANALYSIS OF MOTOR VEHICLE EMISSIONS IN A HOUSTON TUNNEL DURING THE TEXAS AIR QUALITY STUDY 2000

EPA Science Inventory

Measurements from a Houston tunnel were used to develop fuel consumption based emission factors for CO, NOx, and Non-Methane Organic Compound (NMOC) for on-road gasoline vehicles. The Houston NOx emission factor was at the low range of emission factors reported in previous (pr...

Predicting binding modes of reversible peptide-based inhibitors of falcipain-2 consistent with structure-activity relationships.

PubMed

Hernández González, Jorge Enrique; Hernández Alvarez, Lilian; Pascutti, Pedro Geraldo; Valiente, Pedro A

2017-09-01

Falcipain-2 (FP-2) is a major hemoglobinase of Plasmodium falciparum, considered an important drug target for the development of antimalarials. A previous study reported a novel series of 20 reversible peptide-based inhibitors of FP-2. However, the lack of tridimensional structures of the complexes hinders further optimization strategies to enhance the inhibitory activity of the compounds. Here we report the prediction of the binding modes of the aforementioned inhibitors to FP-2. A computational approach combining previous knowledge on the determinants of binding to the enzyme, docking, and postdocking refinement steps, is employed. The latter steps comprise molecular dynamics simulations and free energy calculations. Remarkably, this approach leads to the identification of near-native ligand conformations when applied to a validation set of protein-ligand structures. Overall, we proposed substrate-like binding modes of the studied compounds fulfilling the structural requirements for FP-2 binding and yielding free energy values that correlated well with the experimental data. Proteins 2017; 85:1666-1683. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Identification of TRAIL-inducing compounds highlights small molecule ONC201/TIC10 as a unique anti-cancer agent that activates the TRAIL pathway.

PubMed

Allen, Joshua E; Krigsfeld, Gabriel; Patel, Luv; Mayes, Patrick A; Dicker, David T; Wu, Gen Sheng; El-Deiry, Wafik S

2015-05-01

We previously reported the identification of ONC201/TIC10, a novel small molecule inducer of the human TRAIL gene that improves efficacy-limiting properties of recombinant TRAIL and is in clinical trials in advanced cancers based on its promising safety and antitumor efficacy in several preclinical models. We performed a high throughput luciferase reporter screen using the NCI Diversity Set II to identify TRAIL-inducing compounds. Small molecule-mediated induction of TRAIL reporter activity was relatively modest and the majority of the hit compounds induced low levels of TRAIL upregulation. Among the candidate TRAIL-inducing compounds, TIC9 and ONC201/TIC10 induced sustained TRAIL upregulation and apoptosis in tumor cells in vitro and in vivo. However, ONC201/TIC10 potentiated tumor cell death while sparing normal cells, unlike TIC9, and lacked genotoxicity in normal fibroblasts. Investigating the effects of TRAIL-inducing compounds on cell signaling pathways revealed that TIC9 and ONC201/TIC10, which are the most potent inducers of cell death, exclusively activate Foxo3a through inactivation of Akt/ERK to upregulate TRAIL and its pro-apoptotic death receptor DR5. These studies reveal the selective activity of ONC201/TIC10 that led to its selection as a lead compound for this novel class of antitumor agents and suggest that ONC201/TIC10 is a unique inducer of the TRAIL pathway through its concomitant regulation of the TRAIL ligand and its death receptor DR5.

Volatile organic compounds associated with Plasmodium falciparum infection in vitro.

PubMed

Correa, Ricardo; Coronado, Lorena M; Garrido, Anette C; Durant-Archibold, Armando A; Spadafora, Carmenza

2017-05-02

In order to identify new ways to prevent transmission of vector-borne diseases such as malaria, efforts have been made to understand how insects are attracted to humans. Vector-host interaction studies have shown that several volatile compounds play an important role in attracting mosquitoes to human targets. A headspace solid-phase micro-extraction/gas chromatography-mass spectrometry (HSPME GC-MS) analysis of the volatile organic composition of extracellular vesicles (EVs) and supernatants of ultracentrifugation (SNUs) was carried out in Plasmodium falciparum-infected cultures with high and low parasitemias. A list of 18 volatile organic compounds (VOCs) was obtained from the EVs of both infected and uninfected RBCs with 1,2,3-Propanetriol, diacetate (diacetin) increased in the infected EVs, regardless of the parasitemia of the culture. The supernatant analysis, however, gave off 56 VOCs, with pentane 2,2,4-trimethyl being present in all the SNUs of uninfected erythrocytes but absent from the parasite-infected ones. Standing out in this study was hexanal, a reported insect attractant, which was the only VOC present in all samples from SNUs from infected erythrocytes and absent from uninfected ones, suggesting that it originates during parasite infection. The hexanal compound, reportedly a low-level component found in healthy human samples such as breath and plasma, had not been found in previous analyses of P. falciparum-infected patients or cultures. This compound has been reported as an Anopheles gambiae attractant in plants. While the compound could be produced during infection by the malaria parasite in human erythrocytes, the A. gambiae attraction could be used by the parasite as a strategy for transmission.

Structure-Based Design and Synthesis of a Small Molecule that Exhibits Anti-inflammatory Activity by Inhibition of MyD88-mediated Signaling to Bacterial Toxin Exposure.

PubMed

Alam, Shahabuddin; Javor, Sacha; Degardin, Melissa; Ajami, Dariush; Rebek, Mitra; Kissner, Teri L; Waag, David M; Rebek, Julius; Saikh, Kamal U

2015-08-01

Both Gram-positive and Gram-negative pathogens or pathogen-derived components, such as staphylococcal enterotoxins (SEs) and endotoxin (LPS) exposure, activate MyD88-mediated pro-inflammatory cellular immunity for host defense. However, dysregulated MyD88-mediated signaling triggers exaggerated immune response that often leads to toxic shock and death. Previously, we reported a small molecule compound 1 mimicking BB-loop structure of MyD88 was capable of inhibiting pro-inflammatory response to SEB exposure in mice. In this study, we designed a dimeric structure compound 4210 covalently linked with compound 1 by a non-polar cyclohexane linker which strongly inhibited the production of pro-inflammatory cytokines in human primary cells to SEB (IC50 1-50 μm) or LPS extracted from Francisella tularensis, Escherichia coli, or Burkholderia mallei (IC50 10-200 μm). Consistent with cytokine inhibition, in a ligand-induced cell-based reporter assay, compound 4210 inhibited Burkholderia mallei or LPS-induced MyD88-mediated NF-kB-dependent expression of reporter activity (IC50 10-30 μm). Furthermore, results from a newly expressed MyD88 revealed that 4210 inhibited MyD88 dimer formation which is critical for pro-inflammatory signaling. Importantly, a single administration of compound 4210 in mice showed complete protection from lethal toxin challenge. Collectively, these results demonstrated that compound 4210 inhibits toxin-induced inflated pro-inflammatory immune signaling, thus displays a potential bacterial toxin therapeutic. © 2014 John Wiley & Sons A/S.

Fragmentation pathways of O-alkyl methylphosphonothionocyanidates in the gas phase: toward unambiguous structural characterization of chemicals in the Chemical Weapons Convention framework.

PubMed

Saeidian, Hamid; Babri, Mehran; Ashrafi, Davood; Sarabadani, Mansour; Naseri, Mohammad Taghi

2013-08-01

The electron-impact (EI) mass spectra of a series of O-alkyl methylphosphonothionocyanidates were studied for Chemical Weapons Convention (CWC) purposes. General EI fragmentation pathways were constructed and discussed, and collision-induced dissociation studies of the major EI ions were performed to confirm proposed fragment structures by analyzing fragment ions of deuterated analogs and by use of density functional theory (DFT) calculations. Thiono-thiolo rearrangement, McLafferty-type rearrangement, and a previously unknown intramolecular electrophilic aromatic substitution reaction were observed and confirmed. The study also focused on differentiation of isomeric compounds. Retention indices for all compounds, and an electrophilicity index for several compounds, are reported and interpreted.

Electronic, phonon and superconducting properties of LaPtBi half-Heusler compound

NASA Astrophysics Data System (ADS)

Shrivastava, Deepika; Sanyal, Sankar P.

2018-05-01

In the framework of density functional theory based on plane wave pseudopotential method and linear response technique, we have studied the electronic, phonon and superconducting properties of LaPtBi half-Heusler compound. The electronic band structure and density of states show that it is gapless semiconductor which is consistent with previous results. The positive phonon frequencies confirm the stability of this compound in cubic MgAgAs phase. Superconductivity is studied in terms of Eliashberg spectral function (α2F(ω)), electron-phonon coupling constants (λ). The value of electron-phonon coupling parameter is found to be 0.41 and the superconducting transition temperature is calculated to be 0.76 K, in excellent agreement with the experimentally reported values.

Characterization of a Case of Pigmentary Retinopathy in Sanfilippo Syndrome Type IIIA Associated with Compound Heterozygous Mutations in the SGSH Gene.

PubMed

Wilkin, Justin; Kerr, Natalie C; Byrd, Kathryn W; Ward, Jewell C; Iannaccone, Alessandro

2016-06-01

To report longitudinal phenotypic findings in a patient with Sanfilippo syndrome type IIIA, harboring SGSH mutations, one of which is novel. Heparan-N-sulfatidase enzyme function testing in skin fibroblasts and white blood cells and SGSH gene sequencing were obtained. Clinical office examinations, examinations under anesthesia, electroretinogram, spectral domain optical coherence tomography (SD-OCT), and fundus photography were performed over a 5-year period. Fundus examination revealed a progressive breadcrumb-like pigmentary retinopathy with perifoveal pigmentary involvement. SD-OCT showed loss of normal neuroretinal lamination and cystic macular changes responsive to treatment with carbonic anhydrase inhibitors. Electroretinography exhibited complex characteristics indicative of a generalized retinal rod > cone dysfunction with significant ON > OFF postreceptoral response compromise. Sequencing revealed compound heterozygous mutations in the SGSH gene, the novel c.88G > C (p.A30P) change and a second, previously reported one (c.734G > A, p.R245H). We have identified ocular features of a patient with Sanfilippo syndrome type IIIA harboring a novel SGHS mutation that were not previously known to occur in this disease - namely, a progressive retinopathy with distinctive features, cystic macular changes responsive to carbonic anhydrase inhibitors, and complex electroretinographic abnormalities consistent with postreceptoral dysfunction. SD-OCT imaging revealed retinal lamination changes consistent with previously reported histologic studies. Both the SD-OCT and the electroretinogram changes appear attributable to intraretinal deposition of heparan sulfate.

Design and chemical synthesis of iodine-containing molecules for application to solar-pumped I* lasers

NASA Technical Reports Server (NTRS)

Shiner, C. S.

1986-01-01

The design and chemical synthesis of new media for solar pumped iodine molecule lasers are explored. In an effort to prepare an iodo fluorocarbon compound absorbing strongly at 300 nm or above, the synthesis of perfluoro allylic iodides was investigated. These compounds furnish especially stable allylic radicals upon photodissociation. The desired red shift is anticipated in the absorption maximum could correlate with increasing radical stability. This expectation was based upon the analysis, previously reported, of the structures and absorption maxima of compounds studied earlier. A previously unknown substance was prepared, a prototypical target molecule, perfluoro-3-iodocyclopent-1-ene. It was obtained by reaction of perfluorocyclopentene with sulfur trioxide under the influence of antimony pentafluoride catalyst, followed by treatment of the resulting allylic fluorosulfonate with sodium iodide in sulfoland solvent. Preliminary data indicate that the absorption maximum for the iodo fluorocarbon is not shifted significantly to longer wavelength. It is not certain whether this result reflects an unexpected influence of the cyclic structure upon the position of the absorption maximum.

Small-molecule inhibitors of FABP4/5 ameliorate dyslipidemia but not insulin resistance in mice with diet-induced obesity

PubMed Central

Lan, Hong; Cheng, Cliff C.; Kowalski, Timothy J.; Pang, Ling; Shan, Lixin; Chuang, Cheng-Chi; Jackson, James; Rojas-Triana, Alberto; Bober, Loretta; Liu, Li; Voigt, Johannes; Orth, Peter; Yang, Xianshu; Shipps, Gerald W.; Hedrick, Joseph A.

2011-01-01

Fatty acid binding protein-4 (FABP4) and FABP5 are two closely related FA binding proteins expressed primarily in adipose tissue and/or macrophages. The small-molecule FABP4 inhibitor BMS309403 was previously reported to improve insulin sensitivity in leptin-deficient Lepob/Lepob (ob/ob) mice. However, this compound was not extensively characterized in the more physiologically relevant animal model of mice with diet-induced obesity (DIO). Here, we report the discovery and characterization of a novel series of FABP4/5 dual inhibitors represented by Compounds 1–3. Compared with BMS309403, the compounds had significant in vitro potency toward both FABP4 and FABP5. In cell-based assays, Compounds 2 and 3 were more potent than BMS309403 to inhibit lipolysis in 3T3-L1 adipocytes and in primary human adipocytes. They also inhibited MCP-1 release from THP-1 macrophages as well as from primary human macrophages. When chronically administered to DIO mice, BMS309403 and Compound 3 reduced plasma triglyceride and free FA levels. Compound 3 reduced plasma free FAs at a lower dose level than BMS309403. However, no significant change was observed in insulin, glucose, or glucose tolerance. Our results indicate that the FABP4/5 inhibitors ameliorate dyslipidemia but not insulin resistance in DIO mice. PMID:21296956

Small-molecule inhibitors of FABP4/5 ameliorate dyslipidemia but not insulin resistance in mice with diet-induced obesity.

PubMed

Lan, Hong; Cheng, Cliff C; Kowalski, Timothy J; Pang, Ling; Shan, Lixin; Chuang, Cheng-Chi; Jackson, James; Rojas-Triana, Alberto; Bober, Loretta; Liu, Li; Voigt, Johannes; Orth, Peter; Yang, Xianshu; Shipps, Gerald W; Hedrick, Joseph A

2011-04-01

Fatty acid binding protein-4 (FABP4) and FABP5 are two closely related FA binding proteins expressed primarily in adipose tissue and/or macrophages. The small-molecule FABP4 inhibitor BMS309403 was previously reported to improve insulin sensitivity in leptin-deficient Lep(ob)/Lep(ob) (ob/ob) mice. However, this compound was not extensively characterized in the more physiologically relevant animal model of mice with diet-induced obesity (DIO). Here, we report the discovery and characterization of a novel series of FABP4/5 dual inhibitors represented by Compounds 1-3. Compared with BMS309403, the compounds had significant in vitro potency toward both FABP4 and FABP5. In cell-based assays, Compounds 2 and 3 were more potent than BMS309403 to inhibit lipolysis in 3T3-L1 adipocytes and in primary human adipocytes. They also inhibited MCP-1 release from THP-1 macrophages as well as from primary human macrophages. When chronically administered to DIO mice, BMS309403 and Compound 3 reduced plasma triglyceride and free FA levels. Compound 3 reduced plasma free FAs at a lower dose level than BMS309403. However, no significant change was observed in insulin, glucose, or glucose tolerance. Our results indicate that the FABP4/5 inhibitors ameliorate dyslipidemia but not insulin resistance in DIO mice.

Isolation and Total Synthesis of Stolonines A–C, Unique Taurine Amides from the Australian Marine Tunicate Cnemidocarpa stolonifera

PubMed Central

Tran, Trong D.; Pham, Ngoc B.; Ekins, Merrick; Hooper, John N. A.; Quinn, Ronald J.

2015-01-01

Cnemidocarpa stolonifera is an underexplored marine tunicate that only occurs on the tropical to subtropical East Coast of Australia, with only two pyridoacridine compounds reported previously. Qualitative analysis of the lead-like enhanced fractions of C. stolonifera by LC-MS dual electrospray ionization coupled with PDA and ELSD detectors led to the identification of three new natural products, stolonines A–C (1–3), belonging to the taurine amide structure class. Structures of the new compounds were determined by NMR and MS analyses and later verified by total synthesis. This is the first time that the conjugates of taurine with 3-indoleglyoxylic acid, quinoline-2-carboxylic acid and β-carboline-3-carboxylic acid present in stolonines A–C (1–3), respectively, have been reported. An immunofluorescence assay on PC3 cells indicated that compounds 1 and 3 increased cell size, induced mitochondrial texture elongation, and caused apoptosis in PC3 cells. PMID:26204949

Antibacterial activities of plant-derived compounds and essential oils toward Cronobacter sakazakii and Cronobacter malonaticus.

PubMed

Fraňková, Adéla; Marounek, Milan; Mozrová, Věra; Weber, Jaroslav; Klouček, Pavel; Lukešová, Daniela

2014-10-01

Cronobacter sakazakii and C. malonaticus are opportunistic pathogens that cause infections in children and immunocompromised adults. In the present study, the antibacterial activity of 19 plant-derived compounds, 5 essential oils, and an extract of propolis were assessed against C. sakazakii and C. malonaticus. The effects of most of these antimicrobials have not been reported previously. Both strains were susceptible to thymol, carvacrol, thymoquinone, p-cymene, linalool, camphor, citral, eugenol, and trans-cinnamaldehyde as well as cinnamon, lemongrass, oregano, clove, and laurel essential oils; their minimum inhibitory concentrations varied between 0.1 and 2.0 mg/mL. As an alternative treatment method, vapors of the volatiles were tested as an indirect treatment. Vapors of trans-cinnamaldehyde, eugenol, oregano, and cinnamon essential oils inhibited both tested strains, while vapors of linalool were only active against C. sakazakii. To our knowledge, this study is the first time that the inhibitory activity of the vapors of these compounds and essential oils has been reported against Cronobacter spp.

Evaluation of the Allelopathic Potential of Leaf, Stem, and Root Extracts of Ocotea pulchella Nees et Mart.

PubMed

Candido, Lafayette P; Varela, Rosa M; Torres, Ascensión; Molinillo, José M G; Gualtieri, Sonia C J; Macías, Francisco A

2016-08-01

Despite the increase in recent decades in herbicide research on the potential of native plants, current knowledge is considered to be low. Very few studies have been carried out on the chemical profile or the biological activity of the Brazilian savanna (Cerrado) species. In the study reported here, the allelopathic activity of AcOEt and MeOH extracts of leaves, stems, and roots from Ocotea pulchella Nees was evaluated. The extracts were assayed on etiolated wheat coleoptiles. The AcOEt leaf extract was the most active and this was tested on standard target species (STS). Lycopersicon esculentum and Lactuca sativa were the most sensitive species in this test. A total of eleven compounds have been isolated and characterized. Compounds 1, 2, 4, and 6 have not been identified previously from O. pulchella and ocoteol (9) is reported for the first time in the literature. Eight compounds were tested on wheat coleoptile growth, and spathulenol, benzyl salicylate, and benzyl benzoate showed the highest activities. These compounds showed inhibitory activity on L. esculentum. The values obtained correspond to the activity exhibited by the extract and these compounds may therefore be responsible for the allelopathic activity shown by O. pulchella. © 2016 Wiley-VHCA AG, Zürich.

Groundwater geochemical and selected volatile organic compound data, Operable Unit 1, Naval Undersea Warfare Center, Division Keyport, Washington, June 2011

USGS Publications Warehouse

Huffman, Raegan L.; Frans, L.M.

2012-01-01

Previous investigations indicate that concentrations of chlorinated volatile organic compounds are substantial in groundwater beneath the 9-acre former landfill at Operable Unit 1, Naval Undersea Warfare Center, Division Keyport, Washington. Phytoremediation combined with ongoing natural attenuation processes was the preferred remedy selected by the U.S. Navy, as specified in the Record of Decision for the site. The U.S. Navy planted two hybrid poplar plantations on the landfill in spring 1999 to remove and to control the migration of chlorinated volatile organic compounds in shallow groundwater. The U.S. Geological Survey has continued to monitor groundwater geochemistry to ensure that conditions remain favorable for contaminant biodegradation as specified in the Record of Decision. This report presents groundwater geochemical and selected volatile organic compound data collected at Operable Unit 1 by the U.S. Geological Survey during June 20-22, 2011, in support of long-term monitoring for natural attenuation. In 2011, groundwater samples were collected from 13 wells and 9 piezometers. Samples from all wells and piezometers were analyzed for redox sensitive constituents and dissolved gases, and samples from 5 of 13 wells and all piezometers also were analyzed for chlorinated volatile organic compounds. Concentrations of redox sensitive constituents measured in 2011 were consistent with previous years, with dissolved oxygen concentrations all at 0.4 milligram per liter or less; little to no detectable nitrate; abundant dissolved manganese, iron, and methane; and commonly detected sulfide. The reductive declorination byproducts - methane, ethane, and ethene - were either not detected in samples collected from the upgradient wells in the landfill and the upper aquifer beneath the northern phytoremediation plantation or were detected at concentrations less than those measured in 2010. Chlorinated volatile organic compound concentrations in 2011 at most piezometers were similar to or slightly less than chlorinated volatile organic compound concentrations measured in previous years. For the upper aquifer beneath the southern phytoremediation plantation, chlorinated volatile organic compound concentrations in 2011 in groundwater from the piezometers were extremely high and continued to vary considerably over space and between years. At piezometer P1-9, the total chlorinated volatile organic compound concentrations increased from 9,500 micrograms per liter in 2010 to more than 44,000 micrograms per liter in 2011. Total chlorinated volatile organic compound concentrations decreased at piezometers P1-6, P1-7, and P1-10 compared to the concentrations measured in 2010. One or both of the reductive dechlorination byproducts ethane and ethene were detected at all piezometers and three of the four wells in the southern plantation. For the intermediate aquifer, concentrations of redox sensitive constituents and chlorinated volatile organic compounds in 2011 were consistent with concentrations measured in previous years, with the exception of notable decreases in sulfate and chloride concentrations at well MW1-28. Concentrations of the reductive dechlorination byproducts ethane and ethene decreased at wells MW1-25 and MW1-28 compared to previously measured concentrations.

Safety Assessment of Diethanolamine and Its Salts as Used in Cosmetics.

PubMed

Fiume, Monice M; Heldreth, Bart; Bergfeld, Wilma F; Belsito, Donald V; Hill, Ronald A; Klaassen, Curtis D; Liebler, Daniel C; Marks, James G; Shank, Ronald C; Slaga, Thomas J; Snyder, Paul W; Andersen, F Alan

The Cosmetic Ingredient Review (CIR) Expert Panel assessed the safety of diethanolamine and its salts as used in cosmetics. Diethanolamine functions as a pH adjuster; the 16 salts included in this rereview reportedly function as surfactants, emulsifying agents, viscosity increasing agents, hair or skin conditioning agents, foam boosters, or antistatic agents. The Panel reviewed available animal and clinical data, as well as information from previous CIR reports. Since data were not available for each individual ingredient, and since the salts dissociate freely in water, the Panel extrapolated from previous reports to support safety. The Panel concluded that diethanolamine and its salts are safe for use when formulated to be nonirritating. These ingredients should not be used in cosmetic products in which N-nitroso compounds can be formed.

Investigation of thermoelectricity in KScSn half-Heusler compound

NASA Astrophysics Data System (ADS)

Shrivastava, Deepika; Acharya, Nikita; Sanyal, Sankar P.

2018-05-01

The electronic and transport properties of KScSn half-Heusler (HH) compound have been investigated using first-principles density functional theory and semi classical Boltzmann transport theory. The electronic band structure and density of states (total and partial) show semiconducting nature of KScSn with band gap 0.48 eV which agree well with previously reported results. The transport coefficient such as electrical conductivity, Seebeck coefficient, electronic thermal conductivity and power factor as a function of chemical potential are evaluated. KScSn has high power factor for p-type doping and is a potential candidate for thermoelectric applications.

Snythesis and characterization of the first main group oxo-centered trinuclear carboxylate

NASA Technical Reports Server (NTRS)

Duraj, Stan A.

1994-01-01

The synthesis and structural characterization of the first main group oxo-centered, trinuclear carboxylato-bridged species is reported, namely (Ga3(mu(sub 3)-O) (mu-O2CC6H5)6 (4-Mepy)3) GaCl4 center dot 4-Mepy (compound 1), where 4-Mepy is 4-methylpyridine. Compound 1 is a main group example of a well-established class of complexes, referred to as 'basic carboxylates' of the general formula (M3(mu(sub 3)-O)(mu-O2CR)6L3)(+), previously observed only for transition metals.

Discrimination of different geographic varieties of Gymnema sylvestre, an anti-sweet plant used for the treatment of type 2 diabetes.

PubMed

Pham, Ha Thanh Tung; Hoang, Minh Chau; Ha, Thi Kim Quy; Dang, Lan Huong; Tran, Van On; Nguyen, Thi Bich Thu; Lee, Chul Ho; Oh, Won Keun

2018-06-01

Gymnema sylvestre (Retz.) R.Br. ex Sm. (Asclepiadaceae) is a well-known Ayurvedic anti-sweet plant for the treatment of type 2 diabetes mellitus. Although it was previously proposed that G. sylvestre exhibits chemical variation based on geography, most research on G. sylvestre has used material originating from India. Morphological and anatomical descriptions, ITS1-5.8S-ITS2 DNA sequencing, and acid hydrolysis analyses showed that G. sylvestre samples from Vietnam are distinguishable from those of Indian origin and thus suggest a dissimilarity among G. sylvestre samples with different geographic distributions. An LC-MS-guided strategy targeting 3β-glucuronide oleane-triterpenes in the Vietnamese G. sylvestre variety led to the isolation of four known compounds and nine previously undescribed compounds, named gymnemosides ND1-ND9. None of the isolated compounds were reported in the Indian sample, further supporting the geo-diversity of G. sylvestre. Three compounds, gymnemosides ND7-9, exerted significant stimulatory effects on the uptake of 2-NBDG in 3T3-L1 adipocyte cells and thus have potential as lead molecules for anti-diabetes agents. Copyright © 2018 Elsevier Ltd. All rights reserved.

Chemical Analysis of the Chinese Liquor Luzhoulaojiao by Comprehensive Two-Dimensional Gas Chromatography/Time-of-Flight Mass Spectrometry

PubMed Central

Yao, Feng; Yi, Bin; Shen, Caihong; Tao, Fei; Liu, Yumin; Lin, Zhixin; Xu, Ping

2015-01-01

Luzhoulaojiao liquor is a type of Chinese liquor that dates back hundreds of years, but whose precise chemical composition remains unknown. This paper describes the screening of the liquor and the identification of its compounds using comprehensive two-dimensional gas chromatography/time-of-flight mass spectrometry (GC × GC/TOF-MS). Samples were prepared by both liquid-liquid extraction and solid-phase microextraction, which facilitated the detection of thousands of compounds in the liquor, thus demonstrating the superior performance of the proposed method over those reported in previous studies. A total of 320 compounds were common to all 18 types of Luzhoulaojiao liquor studied here, and 13 abundant and potentially bioactive compounds were further quantified. The results indicated that the high-performance method presented here is well suited for the detection and identification of compounds in liquors. This study also contributes to enriching our knowledge of the contents of Chinese liquors. PMID:25857434

Bioactive Hydantoin Alkaloids from the Red Sea Marine Sponge Hemimycale arabica.

PubMed

Youssef, Diaa T A; Shaala, Lamiaa A; Alshali, Khalid Z

2015-10-28

In the course of our continuing efforts to identify bioactive secondary metabolites from Red Sea marine invertebrates, we have investigated the sponge Hemimycale arabica. The antimicrobial fraction of an organic extract of the sponge afforded two new hydantoin alkaloids, hemimycalins A and B (2 and 3), together with the previously reported compound (Z)-5-(4-hydroxybenzylidene)imidazolidine-2,4-dione (1). The structures of the compounds were determined by extensive 1D and 2D NMR (COSY, HSQC and HMBC) studies and high-resolution mass spectral determinations. Hemimycalins A (2) and B (3) represent the first examples of the natural N-alkylated hydantoins from the sponge Hemimycale arabica. Compounds 1-3 displayed variable antimicrobial activities against E. coli, S. aureus, and C. albicans. In addition, compound 1 displayed moderate antiproliferative activity against the human cervical carcinoma (HeLa) cell line. These findings provide further insight into the chemical diversity as well as the biological activity of this class of compounds.

2-acetylphenol analogs as potent reversible monoamine oxidase inhibitors.

PubMed

Legoabe, Lesetja J; Petzer, Anél; Petzer, Jacobus P

2015-01-01

Based on a previous report that substituted 2-acetylphenols may be promising leads for the design of novel monoamine oxidase (MAO) inhibitors, a series of C5-substituted 2-acetylphenol analogs (15) and related compounds (two) were synthesized and evaluated as inhibitors of human MAO-A and MAO-B. Generally, the study compounds exhibited inhibitory activities against both MAO-A and MAO-B, with selectivity for the B isoform. Among the compounds evaluated, seven compounds exhibited IC50 values <0.01 µM for MAO-B inhibition, with the most selective compound being 17,000-fold selective for MAO-B over the MAO-A isoform. Analyses of the structure-activity relationships for MAO inhibition show that substitution on the C5 position of the 2-acetylphenol moiety is a requirement for MAO-B inhibition, and the benzyloxy substituent is particularly favorable in this regard. This study concludes that C5-substituted 2-acetylphenol analogs are potent and selective MAO-B inhibitors, appropriate for the design of therapies for neurodegenerative disorders such as Parkinson's disease.

Lead Optimization Studies of Cinnamic Amide EP2 Antagonists

PubMed Central

2015-01-01

Prostanoid receptor EP2 can play a proinflammatory role, exacerbating disease pathology in a variety of central nervous system and peripheral diseases. A highly selective EP2 antagonist could be useful as a drug to mitigate the inflammatory consequences of EP2 activation. We recently identified a cinnamic amide class of EP2 antagonists. The lead compound in this class (5d) displays anti-inflammatory and neuroprotective actions. However, this compound exhibited moderate selectivity to EP2 over the DP1 prostanoid receptor (∼10-fold) and low aqueous solubility. We now report compounds that display up to 180-fold selectivity against DP1 and up to 9-fold higher aqueous solubility than our previous lead. The newly developed compounds also display higher selectivity against EP4 and IP receptors and a comparable plasma pharmacokinetics. Thus, these compounds are useful for proof of concept studies in a variety of models where EP2 activation is playing a deleterious role. PMID:24773616

Chemical Analysis of the Chinese Liquor Luzhoulaojiao by Comprehensive Two-Dimensional Gas Chromatography/Time-of-Flight Mass Spectrometry

NASA Astrophysics Data System (ADS)

Yao, Feng; Yi, Bin; Shen, Caihong; Tao, Fei; Liu, Yumin; Lin, Zhixin; Xu, Ping

2015-04-01

Luzhoulaojiao liquor is a type of Chinese liquor that dates back hundreds of years, but whose precise chemical composition remains unknown. This paper describes the screening of the liquor and the identification of its compounds using comprehensive two-dimensional gas chromatography/time-of-flight mass spectrometry (GC × GC/TOF-MS). Samples were prepared by both liquid-liquid extraction and solid-phase microextraction, which facilitated the detection of thousands of compounds in the liquor, thus demonstrating the superior performance of the proposed method over those reported in previous studies. A total of 320 compounds were common to all 18 types of Luzhoulaojiao liquor studied here, and 13 abundant and potentially bioactive compounds were further quantified. The results indicated that the high-performance method presented here is well suited for the detection and identification of compounds in liquors. This study also contributes to enriching our knowledge of the contents of Chinese liquors.

Contact toxicities of anuran skin alkaloids against the fire ant ( Solenopsis invicta)

NASA Astrophysics Data System (ADS)

Weldon, Paul J.; Cardoza, Yasmin J.; Vander Meer, Robert K.; Hoffmann, W. Clint; Daly, John W.; Spande, Thomas F.

2013-02-01

Nearly 500 alkaloids, representing over 20 structural classes, have been identified from the skin of neotropical poison frogs (Dendrobatidae). These cutaneous compounds, which are derived from arthropod prey of the frogs, generally are believed to deter predators. We tested the red imported fire ant ( Solenopsis invicta) for toxicosis following contact with 20 alkaloids (12 structural classes) identified from dendrobatids or other anurans. Individual ants forced to contact the dried residues of 13 compounds exhibited convulsions and/or reduced ambulation. We estimated the cutaneous concentrations of several compounds based on their reported recoveries from skin extracts of free-ranging frogs and our measurements of the skin surface areas of museum specimens. Pumiliotoxin 251D exhibited contact toxicity below its estimated cutaneous concentration in the Ecuadorian frog, Epipedobates anthonyi, an observation consistent with the hypothesized role of this compound in anuran chemical defense. Our results and those of a previous study of mosquitoes indicate that some anuran skin compounds function defensively as contact toxins against arthropods, permeating their exoskeleton.

Cytotoxic cassaine diterpenoid-diterpenoid amide dimers and diterpenoid amides from the leaves of Erythrophleum fordii.

PubMed

Du, Dan; Qu, Jing; Wang, Jia-Ming; Yu, Shi-Shan; Chen, Xiao-Guang; Xu, Song; Ma, Shuang-Gang; Li, Yong; Ding, Guang-Zhi; Fang, Lei

2010-10-01

Detailed phytochemical investigation from the leaves of Erythrophleum fordii resulted in the isolation of 13 compounds, including three cassaine diterpenoid-diterpenoid amide dimers (1, 3 and 5), and seven cassaine diterpenoid amides (6 and 8-13), together with three previously reported ones, erythrophlesins D (2), C (4) and 3beta-hydroxynorerythrosuamide (7). Compounds 1, 3 and 5 are further additions to the small group of cassaine diterpenoid dimers represented by erythrophlesins A-D. Their structures were determined by analysis of extensive one- and two-dimensional NMR experiments and ESIMS methods. Cytotoxic activities of the isolated compounds were tested against HCT-8, Bel-7402, BGC-823, A549 and A2780 human cancer cell lines in the MTT test. Results showed that compounds 1 and 3-5 exhibited significantly selective cytotoxic activities (IC(50)<10 microM) against these cells, respectively. Copyright © 2010 Elsevier Ltd. All rights reserved.

Facile preparation of bioactive seco-guaianolides and guaianolides from Artemisia gorgonum and evaluation of their phytotoxicity.

PubMed

Macías, Francisco A; Santana, Alejandro; Yamahata, Azusa; Varela, Rosa M; Fronczek, Frank R; Molinillo, José M G

2012-11-26

Commercially available santonin was used to synthesize seven sesquiterpene lactones using a facile strategy that involved a high-yielding photochemical reaction. Three natural products from Artemisia gorgonum were synthesized in good yields, and in the case of two compounds, absolute configurations were determined from X-ray quality crystals. The structures previously reported for these compounds were revised. Sesquiterpene lactones were tested using the etiolated wheat coleoptile bioassay, and the most active compounds were assayed in standard target species. seco-Guaianolide (4) showed higher phytotoxic activities than the known herbicide Logran. This high activity could be due to the presence of a cyclopentenedione ring. These results suggest that compound 4 should be involved in defense of A. gorgorum, displaying a wide range of activities that allow proposing them as new leads for development of a natural herbicide model with a seco-guaianolide skeleton.

Cytotoxic components of Pereskia bleo (Kunth) DC. (Cactaceae) leaves.

PubMed

Malek, Sri Nurestri Abdul; Shin, Sim Kae; Wahab, Norhanom Abdul; Yaacob, Hashim

2009-05-06

Dihydroactinidiolide (1) and a mixture of sterols [campesterol (2), stigmasterol (3) and beta-sitosterol (4)], together with the previously isolated individual compounds beta-sitosterol (4), 2,4-di-tert-butylphenol (5), alpha-tocopherol (6), phytol (7) were isolated from the active ethyl acetate fraction of Pereskia bleo (Kunth) DC. (Cactaceae) leaves. Cytotoxic activities of the above mentioned compounds against five human carcinoma cell lines, namely the human nasopharyngeal epidermoid carcinoma cell line (KB), human cervical carcinoma cell line (CasKi), human colon carcinoma cell line (HCT 116), human hormone-dependent breast carcinoma cell line (MCF7) and human lung carcinoma cell line (A549); and non-cancer human fibroblast cell line (MRC-5) were investigated. Compound 5 possessed very remarkable cytotoxic activity against KB cells, with an IC(50 )value of 0.81microg/mL. This is the first report on the cytotoxic activities of the compounds isolated from Pereskia bleo.

Zunyimycins B and C, New Chloroanthrabenzoxocinones Antibiotics against Methicillin-Resistant Staphylococcus aureus and Enterococci from Streptomyces sp. FJS31-2.

PubMed

Lü, Yuhong; Shao, Meiyun; Wang, Yinyin; Qian, Shengyan; Wang, Miao; Wang, Yingquan; Li, Xiaoqian; Bao, Yuxin; Deng, Chengmin; Yue, Changwu; Liu, Daishun; Liu, Ning; Liu, Minghao; Huang, Ying; Chen, Zehui; Hu, Yonglin

2017-02-08

This study performed an optimization of the fermentation conditions to activate the expression of the zunyimycin family biosynthesis genes of the zunyimycin-producing streptomycetes strain Streptomyces sp. FJS31-2. Bioassay-guided isolation and purification by varied chromatographic methods yielded two new compounds of the zunyimycin derivatives, namely, 31-2-7 and 31-2-8, accompanied with three known anthrabenzoxocinones family members of zunyimycin A, BE24566B, and chloroanthrabenzoxocinone. Their structures were elucidated by NMR, HRESIMS, IR, UV, and CD. Results showed that these two compounds were structurally similar to the previously reported compound zunyimycin A but differed in positions and number of chlorine atom substitution. The two novel compounds were called zunyimycins B and C. Antibacterial activity assay indicated that zunyimycin C showed a good inhibitory effect on the methicillin-resistant Staphylococcus aureus and Enterococci .

Ionic Liquids and Solids with Paramagnetic Anions

DOE Office of Scientific and Technical Information (OSTI.GOV)

Castner, Jr., E.W.; Wishart, J.; Krieger, B.M.

2010-06-18

Four paramagnetic ionic compounds have been prepared and their magnetic, structural and thermal properties have been investigated. The four compounds are methylbutylpyrrolidinium tetrachloroferrate(III) ([Pyrr{sub 14}]{sup +}/[FeCl{sub 4}]{sup -}), methyltributylammonium tetrachloroferrate(III) ([N{sub 1444}]{sup +}/[FeCl{sub 4}]{sup -}), butylmethylimidazolium tetrachloroferrate(III) ([bmim]{sup +}/[FeCl{sub 4}]{sup -}) and tetrabutylammonium bromotrichloroferrate(III) ([N{sub 4444}]{sup +}/[FeBrCl{sub 3}]{sup -}). Temperature-dependent studies of their magnetic behaviors show that all four compounds are paramagnetic at ambient temperatures. Glass transitions are observed for only two of the four compounds, [Pyrr{sub 14}]{sup +}/[FeCl{sub 4}]{sup -} and [bmim]{sup +}/[FeCl{sub 4}]{sup -}. Crystal structures for [Pyrr{sub 14}]{sup +}/[FeCl{sub 4}]{sup -} and [N{sub 1444}]{sup +}/[FeCl{sub 4}]{sup -}more » are compared with the previously reported [N{sub 4444}]{sup +}/[FeBrCl{sub 3}]{sup -}.« less

Identification of anti-inflammatory constituents in Hypericum perforatum and Hypericum gentianoides extracts using RAW 264.7 mouse macrophages

PubMed Central

Huang, Nan; Rizshsky, Ludmila; Hauck, Cathy; Nikolau, Basil J.; Murphy, Patricia A.; Birt, Diane F.

2011-01-01

Hypericum perforatum (St. John’s wort) is an herb widely used as supplement for mild to moderate depression. Our prior studies revealed synergistic anti-inflammatory activity associated with 4 bioactive compounds in a fraction of H. perforatum ethanol extract. Whether these 4 compounds also contributed to the ethanol extract activity was addressed in the research reported here. Despite the popularity of H. perforatum, other Hypericum species with different phytochemical profiles could have their anti-inflammatory potentials attributed to these or other compounds. In the current study, ethanol extracts of different Hypericum species were compared for their inhibitory effect on LPS-induced prostaglandin E2 (PGE2) and nitric oxide (NO) production in RAW 264.7 mouse macrophages. Among these extracts, those made from H. perforatum and H. gentianoides demonstrated stronger overall efficacy. LC-MS analysis indicated the 4 compounds in H. perforatum extract and pseudohypericin in all active fractions. The 4 compounds accounted for a significant part of the extract’s inhibitory activity on PGE2, NO, tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β) in RAW 264.7 as well as peritoneal macrophages. Pseudohypericin was the most important contributor of the anti-inflammatory potential among the 4 compounds. The lipophilic fractions of H. gentianoides extract, which did not contain the previously identified active constituents, decreased PGE2 and NO potently. These fractions were rich in acylphloroglucinols, including uliginosin A that accounted for a proportion of the anti-inflammatory activity observed with the active fractions. Overall, the current study revealed a different group of major anti-inflammatory constituents in H. gentianoides, while showing that a previously identified 4 compounds combination was important for H. perforatum’s anti-inflammatory potential. PMID:21855951

Antiprotozoal and antimicrobial compounds from the plant pathogen Septoria pistaciarum.

PubMed

Kumarihamy, Mallika; Khan, Shabana I; Jacob, Melissa; Tekwani, Babu L; Duke, Stephen O; Ferreira, Daneel; Nanayakkara, N P Dhammika

2012-05-25

Four new 1,4-dihydroxy-5-phenyl-2-pyridinone alkaloids, 17-hydroxy-N-(O-methyl)septoriamycin A (1), 17-acetoxy-N-(O-methyl)septoriamycin A (2), 13-(S)-hydroxy-N-(O-methyl)septoriamycin A (3), and 13-(R)-hydroxy-N-(O-methyl)septoriamycin A (4), together with the known compounds (+)-cercosporin (5), (+)-14-O-acetylcercosporin (6), (+)-di-O-acetylcercosporin (7), lumichrome, and brassicasterol, were isolated from an ethyl acetate extract of a culture medium of Septoria pistaciarum. Methylation of septoriamycin A (8) with diazomethane yielded three di-O-methyl analogues, two of which existed as mixtures of rotamers. We previously reported antimalarial activity of septoriamycin A. This compound also exhibited significant activity against Leishmania donovani promastigotes. Compounds 5-7 showed moderate in vitro activity against L. donovani promastigotes and chloroquine-sensitive (D6) and -resistant (W2) strains of Plasmodium falciparum, whereas compound 5 was fairly active against methicillin-sensitive and methicillin-resistant strains of Staphylococcus aureus. Compounds 5-7 also displayed moderate phytotoxic activity against both a dicot (lettuce, Lactuca sativa) and a monocot (bentgrass, Agrostis stolonifera) and cytotoxicity against a panel of cell lines.

Time-dependent VOC-profile of decomposed human and animal remains in laboratory environment.

PubMed

Rosier, E; Loix, S; Develter, W; Van de Voorde, W; Tytgat, J; Cuypers, E

2016-09-01

A validated method using a thermal desorber combined with a gas chromatograph coupled to a mass spectrometer was used to identify the volatile organic compounds released in decomposed human and animal remains after 9 and 12 months in glass jars in a laboratory environment. This is a follow-up study on a previous report where the first 6 months of decomposition of 6 human and 26 animal remains was investigated. In the first report, out of 452 identified compounds, a combination of 8 compounds was proposed as human and pig specific. The goal of the current study was to investigate if these 8 compounds were still released after 9 and 12 months. The next results were noticed: 287 compounds were identified; only 9 new compounds were detected and 173 were no longer seen. Sulfur-containing compounds were less prevalent as compared to the first month of decomposition. The appearance of nitrogen-containing compounds and alcohols was increasingly evident during the first 6 months, and the same trend was seen in the following 6 months. Esters became less important after 6 months. From the proposed human and pig specific compounds, diethyl disulfide was only detected during the first months of decomposition. Interestingly, the 4 proposed human and pig specific esters, as well as pyridine, 3-methylthio-1-propanol and methyl(methylthio)ethyl disulfide were still present after 9 and 12 months of decomposition. This means that these 7 human and pig specific markers can be used in the development of training aids for cadaver dogs during the whole decomposition process. Diethyl disulfide can be used in training aids for the first month of decomposition. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

FORMATION OF REACTIVE GASEOUS MERCURY IN THE ARCTIC: EVIDENCE OF OXIDATION OF HG0 TO GAS-PHASE HG-II COMPOUNDS AFTER ARCTIC SUNRISE

EPA Science Inventory

We have measured total gaseous mercury concentrations (Hgo) at Point Barrow, Alaska since September 1998 in an effort to determine the geographic extent and reaction mechanism of the so-called mercury depletion events (MDE) previously reported in the high Arctic at Alert, Canad...

The biosynthetic gene cluster for the cyanogenic glucoside dhurrin in Sorghum bicolor contains its co-expressed vacuolar MATE transporter

PubMed Central

Darbani, Behrooz; Motawia, Mohammed Saddik; Olsen, Carl Erik; Nour-Eldin, Hussam H.; Møller, Birger Lindberg; Rook, Fred

2016-01-01

Genomic gene clusters for the biosynthesis of chemical defence compounds are increasingly identified in plant genomes. We previously reported the independent evolution of biosynthetic gene clusters for cyanogenic glucoside biosynthesis in three plant lineages. Here we report that the gene cluster for the cyanogenic glucoside dhurrin in Sorghum bicolor additionally contains a gene, SbMATE2, encoding a transporter of the multidrug and toxic compound extrusion (MATE) family, which is co-expressed with the biosynthetic genes. The predicted localisation of SbMATE2 to the vacuolar membrane was demonstrated experimentally by transient expression of a SbMATE2-YFP fusion protein and confocal microscopy. Transport studies in Xenopus laevis oocytes demonstrate that SbMATE2 is able to transport dhurrin. In addition, SbMATE2 was able to transport non-endogenous cyanogenic glucosides, but not the anthocyanin cyanidin 3-O-glucoside or the glucosinolate indol-3-yl-methyl glucosinolate. The genomic co-localisation of a transporter gene with the biosynthetic genes producing the transported compound is discussed in relation to the role self-toxicity of chemical defence compounds may play in the formation of gene clusters. PMID:27841372

Inhibition of Nuclear Transcription Factor-κB and Activation of Peroxisome Proliferator-Activated Receptors in HepG2 Cells by Cucurbitane-Type Triterpene Glycosides from Momordica charantia

PubMed Central

Nhiem, Nguyen Xuan; Yen, Pham Hai; Ngan, Nguyen Thi Thanh; Quang, Tran Hong; Kiem, Phan Van; Minh, Chau Van; Tai, Bui Huu; Cuong, Nguyen Xuan; Song, Seok Bean

2012-01-01

Abstract Momordica charantia: is used to treat various diseases, including inflammatory conditions. Previous reports indicated that the extract of this plant inhibits activation of nuclear transcription factor-κB (NF-κB) but activates peroxisome proliferator-activated receptor (PPAR). Additionally, cucurbitane-type triterpene glycosides are the main bioactive components of the fruit of M. charantia. Therefore, we investigated the anti-inflammatory activity of 17 cucurbitane-type triterpene glycosides (1–17) isolated from this plant. Their inhibition of NF-κB and activation of PPAR activities in HepG2 cells were measured using luciferase reporter and PPAR subtype transactivation assays. Compounds 6 and 8 were found to inhibit NF-κB activation stimulated by tumor necrosis factor-α (TNFα) in a dose-dependent manner. With 50% inhibition concentration (IC50) values of 0.4 μM, compounds 6 and 8 were more potent inhibitors than the positive control, sulfasalazine (IC50=0.9 μM). Compounds 4, 6, and 8 also inhibited TNFα-induced expressions of inducible nitric oxide synthase and cyclooxygenase-2 mRNA. However, only compound 13 significantly increased PPARγ transactivation. PMID:22248180

Long-term ground-water monitoring program and performance-evaluation plan for the extraction system at the former Nike Missile Battery Site, Aberdeen Proving Ground, Maryland

USGS Publications Warehouse

Senus, Michael P.; Tenbus, Frederick J.

2000-01-01

This report presents lithologic and ground-water-quality data collected during April and May 2000 in the remote areas of the tidal wetland of West Branch Canal Creek, Aberdeen Proving Ground, Maryland. Contamination of the Canal Creek aquifer with volatile organic compounds has been documented in previous investigations of the area. This study was conducted to investigate areas that were previously inaccessible because of deep mud and shallow water, and to support ongoing investigations of the fate and transport of volatile organic compounds in the Canal Creek aquifer. A unique vibracore drill rig mounted on a hovercraft was used for drilling and ground-water sampling. Continuous cores of the wetland sediment and of the Canal Creek aquifer were collected at five sites. Attempts to sample ground water were made by use of a continuous profiler at 12 sites, without well installation, at a total of 81 depths within the aquifer. Of those 81 attempts, only 34 sampling depths produced enough water to collect samples. Ground-water samples from two sites had the highest concentrations of volatile organic compounds?with total volatile organic compound concentrations in the upper part of the aquifer ranging from about 15,000 to 50,000 micrograms per liter. Ground-water samples from five sites had much lower total volatile organic compound concentrations (95 to 2,100 micrograms per liter), whereas two sites were essentially not contaminated, with total volatile organic compound concentrations less than or equal to 5 micrograms per liter.

Lithologic and ground-water-quality data collected using Hoverprobe drilling techniques at the West Branch Canal Creek wetland, Aberdeen Proving Ground, Maryland, April-May 2000

USGS Publications Warehouse

Phelan, Daniel J.; Senus, Michael P.; Olsen, Lisa D.

2001-01-01

This report presents lithologic and groundwater- quality data collected during April and May 2000 in the remote areas of the tidal wetland of West Branch Canal Creek, Aberdeen Proving Ground, Maryland. Contamination of the Canal Creek aquifer with volatile organic compounds has been documented in previous investigations of the area. This study was conducted to investigate areas that were previously inaccessible because of deep mud and shallow water, and to support ongoing investigations of the fate and transport of volatile organic compounds in the Canal Creek aquifer. A unique vibracore drill rig mounted on a hovercraft was used for drilling and groundwater sampling. Continuous cores of the wetland sediment and of the Canal Creek aquifer were collected at five sites. Attempts to sample ground water were made by use of a continuous profiler at 12 sites, without well installation, at a total of 81 depths within the aquifer. Of those 81 attempts, only 34 sampling depths produced enough water to collect samples. Ground-water samples from two sites had the highest concentrations of volatile organic compounds?with total volatile organic compound concentrations in the upper part of the aquifer ranging from about 15,000 to 50,000 micrograms per liter. Ground-water samples from five sites had much lower total volatile organic compound concentrations (95 to 2,100 micrograms per liter), whereas two sites were essentially not contaminated, with total volatile organic compound concentrations less than or equal to 5 micrograms per liter.

Chemical characterisation of Nigerian red propolis and its biological activity against Trypanosoma Brucei.

PubMed

Omar, Ruwida M K; Igoli, John; Gray, Alexander I; Ebiloma, Godwin Unekwuojo; Clements, Carol; Fearnley, James; Ebel, Ru Angeli Edrada; Zhang, Tong; De Koning, Harry P; Watson, David G

2016-01-01

A previous study showed the unique character of Nigerian red propolis from Rivers State, Nigeria (RSN), with regards to chemical composition and activity against Trypanosoma brucei in comparison with other African propolis. To carry out fractionation and biological testing of Nigerian propolis in order to isolate compounds with anti-trypanosomal activity. To compare the composition of the RSN propolis with the composition of Brazilian red propolis. Profiling was carried out using HPLC-UV-ELSD and HPLC-Orbitrap-FTMS on extracts of two samples collected from RSN with data extraction using MZmine software. Isolation was carried out by normal phase and reversed phase MPLC. Elucidation of the compounds with a purity > 95% was performed by 1D/2D NMR HRMS and HRLC-MS(n) . Ten phenolic compounds were isolated or in the case of liquiritigenin partially purified. Data for nine of these correlated with literature reports of known compounds i.e. one isoflavanone, calycosin (1); two flavanones, liquiritigenin (2) and pinocembrin (5); an isoflavan, vestitol (3); a pterocarpan, medicarpin (4); two prenylflavanones, 8-prenylnaringenin (7) and 6-prenylnaringenin (8); and two geranyl flavonoids, propolin D (9) and macarangin (10). The tenth was elucidated as a previously undescribed dihydrobenzofuran (6). The isolated compounds were tested against Trypanosoma brucei and displayed moderate to high activity. Some of the compounds tested had similar activity against wild type T. brucei and two strains displaying pentamidine resistance. Nigerian propolis from RSN has some similarities with Brazilian red propolis. The propolis displayed anti-trypanosomal activity at a potentially useful level. Copyright © 2015 John Wiley & Sons, Ltd.

The thermodynamic properties of benzothiazole and benzoxazole

NASA Astrophysics Data System (ADS)

Steele, W. V.; Chirico, R. D.; Knipmeyer, S. E.; Nguyen, A.

1991-08-01

This research program, funded by the Department of Energy, Office of Fossil Energy, Advanced Extraction and Process Technology, provides accurate experimental thermochemical and thermophysical properties for key organic diheteroatom-containing compounds present in heavy petroleum feedstocks, and applies the experimental information to thermodynamic analyses of key hydrodesulfurization, hydrodenitrogenation, and hydrodeoxygenation reaction networks. Thermodynamic analyses, based on accurate information, provide insights for the design of cost-effective methods of heteroatom removal. The results reported here, and in a companion report to be completed, will point the way to the development of new methods of heteroatom removal from heavy petroleum. Measurements leading to the calculation of the ideal-gas thermodynamic properties are reported for benzothiazole and benzoxazole. Experimental methods included combustion calorimetry, adiabatic heat-capacity calorimetry, comparative ebulliometry, inclinded-piston gauge manometry, and differential-scanning calorimetry (d.s.c). Critical property estimates are made for both compounds. Entropies, enthalpies, and Gibbs energies of formation were derived for the ideal gas for both compounds for selected temperatures between 280 K and near 650 K. The Gibbs energies of formation will be used in a subsequent report in thermodynamic calculations to study the reaction pathways for the removal of the heteratoms by hydrogenolysis. The results obtained in this research are compared with values present in the literature. The failure of a previous adiabatic heat capacity study to see the phase transition in benzothiazole is noted. Literature vibrational frequency assignments were used to calculate ideal gas entropies in the temperature range reported here for both compounds. Resulting large deviations show the need for a revision of those assignments.

Iodine(III) Derivatives as Halogen Bonding Organocatalysts.

PubMed

Heinen, Flemming; Engelage, Elric; Dreger, Alexander; Weiss, Robert; Huber, Stefan M

2018-03-26

Hypervalent iodine(III) derivatives are known as versatile reagents in organic synthesis, but there is only one previous report on their use as Lewis acidic organocatalysts. Herein, we present first strong indications for the crucial role of halogen bonding in this kind of catalyses. To this end, the solvolysis of benzhydryl chloride and the Diels-Alder reaction of cyclopentadiene with methyl vinyl ketone served as benchmark reactions for halide abstraction and the activation of neutral compounds. Iodolium compounds (cyclic diaryl iodonium species) were used as activators or catalysts, and we were able to markedly reduce or completely switch off their activity by sterically blocking one or two of their electrophilic axes. Compared with previously established bidentate cationic halogen bond donors, the monodentate organoiodine derivatives used herein are at least similarly active (in the Diels-Alder reaction) or even decidedly more active (in benzhydryl chloride solvolysis). © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Synthetic Cannabinoids-Further Evidence Supporting the Relationship Between Cannabinoids and Psychosis.

PubMed

Fattore, Liana

2016-04-01

Consumption of synthetic mind-altering compounds, also known as "new psychoactive substances," is increasing globally at an alarming rate. Synthetic cannabinoids (SCs) are among the most commonly used new psychoactive substances. They are usually purchased as marijuana-like drugs, marketed as herbal blends and perceived as risk-free by inexperienced users. Yet, contrary to Δ(9)-tetrahydrocannabinol, SCs may lead to severe health consequences, including anxiety, tachycardia, hallucinations, violent behavior, and psychosis. This review focuses on the latest (2010-2015) evidence of psychotic symptoms induced by ingestion of products containing SCs. Reports suggesting that SCs may either exacerbate previously stable psychotic symptoms (in vulnerable individuals) or trigger new-onset psychosis (in individuals with no previous history of psychosis) are reviewed. Pharmacology and toxicology of these compounds are discussed, with particular reference to their psychoactive effects. Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Estrogenic and serotonergic butenolides from the leaves of Piper hispidum Swingle (Piperaceae)

PubMed Central

Michel, Joanna L; Chen, Yegao; Zhang, Hongjie; Huang, Yue; Krunic, Alecjev; Orjala, Jimmy; Veliz, Mario; Soni, Kapil K.; Soejarto, Djaja Doel; Caceres, Armando; Perez, Alice; Mahady, Gail B

2010-01-01

Ethnopharmacological relevance Our previous work has demonstrated that several plants in the Piperaceae family are commonly used by the Q’eqchi Maya of Livingston, Guatemala to treat amenorrhea, dysmenorrhea, and pain. Extracts of Piper hispidum Swingle (Piperaceae), bound to the estrogen (ER) and serotonin (5-HT7) receptors. Aim of the study To investigate the estrogenic and serotonergic activities of P. hispidum extracts in functionalized assays, identify the active chemical constituents in the leaf extract, and test these compounds as agonists or antagonists of ER and 5-HT7. Materials and methods The effects of the P. hispidum leaf extracts were investigated in estrogen reporter gene and endogenous gene assays in MCF-7 cells to determine if the extracts acted as an estrogen agonist or antagonist. In addition, the active compounds were isolated using ER- and 5-HT7 receptor bioassay-guided fractionation. The structures of the purified compounds were identified using high-resolution LC-MS and NMR spectroscopic methods. The ER- and 5-HT7-agonist effects of the purified chemical constituents were tested in a 2ERE-reporter gene assay in MCF-7 cells and in serotonin binding and functionalized assays. Results Three butenolides including one new compound (1) were isolated from the leaves of P. hispidum, and their structures were determined. Compound 1 bound to the serotonin receptor 5-HT7 with IC50 values of 16.1 and 8.3 μM, respectively, and using GTP shift assays, compound 1 was found to be a partial agonist of the 5-HT7 receptor. The P. hispidum leaf extracts, as well as compounds 2 and 3 enhanced the expression of estrogen responsive reporter and endogenous genes in MCF-7 cells, demonstrating estrogen agonist effects. Conclusions Extracts of P. hispidum act as agonists of the ER and 5-HT7 receptors. Compound 1, a new natural product, identified as 9, 10-methylenedioxy-5,6-Z-fadyenolide, was isolated as the 5-HT7 agonist. Compounds 2 and 3 are reported for the first time in P. hispidum, and identified as the estrogen agonists. No inhibition of CYP450 was observed for any of these compounds in concentrations up to 1 μM. These activities are consistent with the Q’eqchi traditional use of the plant for the treatment of disorders associated with the female reproductive cycle. PMID:20304039

Estrogenic and serotonergic butenolides from the leaves of Piper hispidum Swingle (Piperaceae).

PubMed

Michel, Joanna L; Chen, Yegao; Zhang, Hongjie; Huang, Yue; Krunic, Aleksej; Orjala, Jimmy; Veliz, Mario; Soni, Kapil K; Soejarto, Djaja Doel; Caceres, Armando; Perez, Alice; Mahady, Gail B

2010-05-27

Our previous work has demonstrated that several plants in the Piperaceae family are commonly used by the Q'eqchi Maya of Livingston, Guatemala to treat amenorrhea, dysmenorrhea, and pain. Extracts of Piper hispidum Swingle (Piperaceae), bound to the estrogen (ER) and serotonin (5-HT7) receptors. To investigate the estrogenic and serotonergic activities of Piper hispidum extracts in functionalized assays, identify the active chemical constituents in the leaf extract, and test these compounds as agonists or antagonists of ER and 5-HT7. The effects of the Piper hispidum leaf extracts were investigated in estrogen reporter gene and endogenous gene assays in MCF-7 cells to determine if the extracts acted as an estrogen agonist or antagonist. In addition, the active compounds were isolated using ER- and 5-HT7 receptor bioassay-guided fractionation. The structures of the purified compounds were identified using high-resolution LC-MS and NMR spectroscopic methods. The ER- and 5-HT7-agonist effects of the purified chemical constituents were tested in a 2ERE-reporter gene assay in MCF-7 cells and in serotonin binding and functionalized assays. Three butenolides including one new compound (1) were isolated from the leaves of Piper hispidum, and their structures were determined. Compound 1 bound to the serotonin receptor 5-HT(7) with IC(50) values of 16.1 and 8.3 microM, respectively, and using GTP shift assays, Compound 1 was found to be a partial agonist of the 5-HT(7) receptor. The Piper hispidum leaf extracts, as well as Compounds 2 and 3 enhanced the expression of estrogen responsive reporter and endogenous genes in MCF-7 cells, demonstrating estrogen agonist effects. Extracts of Piper hispidum act as agonists of the ER and 5-HT(7) receptors. Compound 1, a new natural product, identified as 9,10-methylenedioxy-5,6-Z-fadyenolide, was isolated as the 5-HT(7) agonist. Compounds 2 and 3 are reported for the first time in Piper hispidum, and identified as the estrogen agonists. No inhibition of CYP450 was observed for any of these compounds in concentrations up to 1 microM. These activities are consistent with the Q'eqchi traditional use of the plant for the treatment of disorders associated with the female reproductive cycle. Copyright 2010 Elsevier Ireland Ltd. All rights reserved.

Safety Assessment of Ethanolamine and Ethanolamine Salts as Used in Cosmetics.

PubMed

Fiume, Monice M; Heldreth, Bart A; Bergfeld, Wilma F; Belsito, Donald V; Hill, Ronald A; Klaassen, Curtis D; Liebler, Daniel C; Marks, James G; Shank, Ronald C; Slaga, Thomas J; Snyder, Paul W; Andersen, F Alan

2015-09-01

The Cosmetic Ingredient Review (CIR) Expert Panel (Panel) assessed the safety of ethanolamine and 12 salts of ethanolamine as used in cosmetics. Ethanolamine functions as a pH adjuster. The majority of the salts are reported to function as surfactants, and the others are reported to function as pH adjusters, hair fixatives, or preservatives. The Panel reviewed available animal and clinical data, as well as information from previous relevant CIR reports. Because data were not available for each individual ingredient and because the salts dissociate freely in water, the Panel extrapolated from those previous reports to support safety. The Panel concluded that these ingredients are safe in the present practices of use and concentrations (rinse-off products only) when formulated to be nonirritating, and these ingredients should not be used in cosmetic products in which N-nitroso compounds may be formed. © The Author(s) 2015.

Classification of octet AB-type binary compounds using dynamical charges: A materials informatics perspective

DOE PAGES

Pilania, G.; Gubernatis, J. E.; Lookman, T.

2015-12-03

The role of dynamical (or Born effective) charges in classification of octet AB-type binary compounds between four-fold (zincblende/wurtzite crystal structures) and six-fold (rocksalt crystal structure) coordinated systems is discussed. We show that the difference in the dynamical charges of the fourfold and sixfold coordinated structures, in combination with Harrison’s polarity, serves as an excellent feature to classify the coordination of 82 sp–bonded binary octet compounds. We use a support vector machine classifier to estimate the average classification accuracy and the associated variance in our model where a decision boundary is learned in a supervised manner. Lastly, we compare the out-of-samplemore » classification accuracy achieved by our feature pair with those reported previously.« less

Characterizing the Smell of Marijuana by Odor Impact of Volatile Compounds: An Application of Simultaneous Chemical and Sensory Analysis

PubMed Central

2015-01-01

Recent US legislation permitting recreational use of marijuana in certain states brings the use of marijuana odor as probable cause for search and seizure to the forefront of forensic science, once again. This study showed the use of solid-phase microextraction with multidimensional gas chromatography—mass spectrometry and simultaneous human olfaction to characterize the total aroma of marijuana. The application of odor activity analysis offers an explanation as to why high volatile chemical concentration does not equate to most potent odor impact of a certain compound. This suggests that more attention should be focused on highly odorous compounds typically present in low concentrations, such as nonanal, decanol, o-cymene, benzaldehyde, which have more potent odor impact than previously reported marijuana headspace volatiles. PMID:26657499

Crystal field effect in light actinide dioxides and oxychalcogenides-a unified phenomenological description

NASA Astrophysics Data System (ADS)

Gajek, Z.

2004-05-01

The electronic properties of the actinide ions in the series of semi-conducting, antiferromagnetic compounds: dioxides, AnO2 and oxychalcogenides, AnOY, where An=U, Np and Y=S, Se, are re-examined from the point of view of the consistency of the crystal field (CF) model. The discussion is based on the supposition that the effective metal-ligand interaction solely determines the net CF effect in non-metallic compounds. The main question we address here is, whether a reliable, consistent description of the CF effect in terms of the intrinsic parameters can be achieved for this particular family of compounds. Encouraging calculations reported previously for the AnO2 and UOY series serve as a reference data in the present estimation of electronic structure parameters for neptunium oxychalcogenides.

Boric Acid and Commercial Organoboron Products as Inhibitors of Drug-Resistant Candida albicans.

PubMed

Larsen, Bryan; Petrovic, Marija; De Seta, Francesco

2018-04-01

Clinical use of boric acid as a topical antifungal in women who have failed standard antifungal therapy with azole drugs has been used sporadically for decades. Our previous in vitro work showing inhibition of Candida albicans growth was conducted on clinical isolates without antifungal drug susceptibility profiling. Here, we report that boric acid restricts growth of drug-resistant Candida albicans and inhibits hyphal growth and diminishes cell volume. The availability of over-the-counter organoboron compounds intended for use as oral nutritional supplements led us to determine if these also were inhibitory toward resistant Candida and show here that they also possess antifungal activity. Candida glabrata was also found to be inhibited by boric acid and organoboron compounds. Further development of organoboron compounds as topical therapeutics is of potential value.

Ab-initio calculations of the Ruddlesden Popper phases CaMnO3, CaO(CaMnO3) and CaO(CaMnO3)2

NASA Astrophysics Data System (ADS)

Cardoso, C.; Borges, R. P.; Gasche, T.; Godinho, M.

2008-01-01

The present work reports ab-initio density functional theory calculations for the Ruddlesden-Popper phase CaO(CaMnO3)n compounds. In order to study the evolution of the properties with the number of perovskite layers, a detailed analysis of the densities of states calculated for each compound and for several magnetic configurations was performed. The effect of distortions of the crystal structure on the magnetic ground state is also analysed and the exchange constants and transition temperatures are calculated for the three compounds using a mean field model. The calculated magnetic ground state structures and magnetic moments are in good agreement with experimental results and previous calculations.

Optofluidic Single-Cell Genome Amplification of Sub-micron Bacteria in the Ocean Subsurface

PubMed Central

Landry, Zachary C.; Vergin, Kevin; Mannenbach, Christopher; Block, Stephen; Yang, Qiao; Blainey, Paul; Carlson, Craig; Giovannoni, Stephen

2018-01-01

Optofluidic single-cell genome amplification was used to obtain genome sequences from sub-micron cells collected from the euphotic and mesopelagic zones of the northwestern Sargasso Sea. Plankton cells were visually selected and manually sorted with an optical trap, yielding 20 partial genome sequences representing seven bacterial phyla. Two organisms, E01-9C-26 (Gammaproteobacteria), represented by four single cell genomes, and Opi.OSU.00C, an uncharacterized Verrucomicrobia, were the first of their types retrieved by single cell genome sequencing and were studied in detail. Metagenomic data showed that E01-9C-26 is found throughout the dark ocean, while Opi.OSU.00C was observed to bloom transiently in the nutrient-depleted euphotic zone of the late spring and early summer. The E01-9C-26 genomes had an estimated size of 4.76–5.05 Mbps, and contained “O” and “W”-type monooxygenase genes related to methane and ammonium monooxygenases that were previously reported from ocean metagenomes. Metabolic reconstruction indicated E01-9C-26 are likely versatile methylotrophs capable of scavenging C1 compounds, methylated compounds, reduced sulfur compounds, and a wide range of amines, including D-amino acids. The genome sequences identified E01-9C-26 as a source of “O” and “W”-type monooxygenase genes related to methane and ammonium monooxygenases that were previously reported from ocean metagenomes, but are of unknown function. In contrast, Opi.OSU.00C genomes encode genes for catabolizing carbohydrate compounds normally associated with eukaryotic phytoplankton. This exploration of optofluidics showed that it was effective for retrieving diverse single-cell bacterioplankton genomes and has potential advantages in microbiology applications that require working with small sample volumes or targeting cells by their morphology.

Chemical and biological study of Manilkara zapota (L.) Van Royen leaves (Sapotaceae) cultivated in Egypt

PubMed Central

Fayek, Nesrin M.; Monem, Azza R. Abdel; Mossa, Mohamed Y.; Meselhy, Meselhy R.; Shazly, Amani H.

2012-01-01

Background: Manilkara zapota (L.) Van Royen is an evergreen tree, native to the tropical Americas and introduced to Egypt as a fruiting tree in 2002. No previous study was reported on the plant cultivated in Egypt. Materials and Methods: In this study, the leaves of the plant cultivated in Egypt were subjected to phytochemical and biological investigations. The lipoidal matter was analyzed by GLC. Five compounds were isolated from the petroleum ether and ethyl acetate fractions of the alcoholic extract of the leaves by chromatographic fractionation on silica gel and sephadex, the structures of these compounds were identified using IR, UV, MS, 1H-NMR and 13C-NMR. The LD50 of the alcoholic and aqueous extracts of the leaves was determined and their antihyperglycemic, hypocholesterolemic and antioxidant activities were tested by enzymatic colorimetric methods using specific kits. Results: Unsaturated fatty acids represent 32.32 % of the total fatty acids, oleic acid (13.95%), linoleidic acid (10.18 %) and linoleic acid (5.96 %) were the major ones. The isolated compounds were identified as lupeol acetate, oleanolic acid, apigenin-7-O-α-L-rhamnoside, myricetin-3-O-α-L-rhamnoside and caffeic acid. This is the first report about isolation of these compounds from Manilkara zapota except myricetin-3-O-α-L-rhamnoside, which was previously isolated from the plant growing abroad. The LD50 recorded 80 g/Kg b. wt. for both the tested extracts, so they could be considered to be safe. They exhibited antihyperglycemic, hypocholesterolemic and antioxidant activities. Conclusion: The observed biological activities were attributed to the different chemical constituents present in the plant mainly its phenolic constituents. PMID:22518080

Progress report on new antiepileptic drugs: A summary of the Thirteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XIII).

PubMed

Bialer, Meir; Johannessen, Svein I; Levy, René H; Perucca, Emilio; Tomson, Torbjörn; White, H Steve

2017-02-01

The Thirteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XIII) took place in Madrid, Spain, on June 26-29, 2016, and was attended by >200 delegates from 31 countries. The present Progress Report provides an update on experimental and clinical results for drugs presented at the Conference. Compounds for which summary data are presented include an AED approved in 2016 (brivaracetam), 12 drugs in phase I-III clinical development (adenosine, allopregnanolone, bumetanide, cannabidiol, cannabidivarin, 2-deoxy-d-glucose, everolimus, fenfluramine, huperzine A, minocycline, SAGE-217, and valnoctamide) and 6 compounds or classes of compounds for which only preclinical data are available (bumetanide derivatives, sec-butylpropylacetamide, FV-082, 1OP-2198, NAX 810-2, and SAGE-689). Overall, the results presented at the Conference show that considerable efforts are ongoing into discovery and development of AEDs with potentially improved therapeutic profiles compared with existing agents. Many of the drugs discussed in this report show innovative mechanisms of action and many have shown promising results in patients with pharmacoresistant epilepsies, including previously neglected rare and severe epilepsy syndromes. Wiley Periodicals, Inc. © 2017 International League Against Epilepsy.

Quellenin, a new anti-Saprolegnia compound isolated from the deep-sea fungus, Aspergillus sp. YK-76.

PubMed

Takahashi, Konami; Sakai, Kazunari; Fukasawa, Wataru; Nagano, Yuriko; Sakaguchi, Sakiko Orui; Lima, Andre O; Pellizari, Vivian H; Iwatsuki, Masato; Takishita, Kiyotaka; Yoshida, Takao; Nonaka, Kenichi; Fujikura, Katsunori; Ōmura, Satoshi

2018-04-23

Saprolegnia parasitica, belonging to oomycetes, is one of virulent pathogen of fishes such as salmon and trout, and causes tremendous damage and losses in commercial aquacultures by saprolegniasis. Previously, malachite green, an effective medicine, had been used to control saprolegniasis. However, this drug has been banned around the world due to its mutagenicity. Therefore, novel anti-saprolegniasis compounds are urgently needed. As a new frontier to discover bioactive compounds, we focused on the deep-sea fungi for the isolation of anti-saprolegniasis compounds. In this paper, on the course of anti-saprolegniasis agents from 546 cultured broths of 91 deep-sea fungal strains, we report a new compound, named quellenin (1) together with three known compounds, diorcinol (2), violaceol-I (3) and violaceol-II (4), from deep-sea fungus Aspergillus sp. YK-76. This strain was isolated from an Osedax sp. annelid, commonly called bone-eating worm, collected at the São Paulo Ridge in off Brazil. Compounds 2, 3 and 4 showed anti-S. parasitica activity. Our results suggest that diorcinol and violaceol analogs and could be good lead candidates for the development of novel agents to prevent saprolegniasis.

Geobacter metallireducens gen. nov. sp. nov., a microorganism capable of coupling the complete oxidation of organic compounds to the reduction of iron and other metals

USGS Publications Warehouse

Lovley, D.R.; Giovannoni, S.J.; White, D.C.; Champine, J.E.; Phillips, E.J.P.; Gorby, Y.A.; Goodwin, S.

1993-01-01

The gram-negative metal-reducing microorganism, previously known as strain GS-15, was further characterized. This strict anaerobe oxidizes several short-chain fatty acids, alcohols, and monoaromatic compounds with Fe(III) as the sole electron acceptor. Furthermore, acetate is also oxidized with the reduction of Mn(IV), U(VI), and nitrate. In whole cell suspensions, the c-type cytochrome(s) of this organism was oxidized by physiological electron acceptors and also by gold, silver, mercury, and chromate. Menaquinone was recovered in concentrations comparable to those previously found in gram-negative sulfate reducers. Profiles of the phospholipid ester-linked fatty acids indicated that both the anaerobic desaturase and the branched pathways for fatty acid biosynthesis were operative. The organism contained three lipopolysaccharide hydroxy fatty acids which have not been previously reported in microorganisms, but have been observed in anaerobic freshwater sediments. The 16S rRNA sequence indicated that this organism belongs in the delta proteobacteria. Its closest known relative is Desulfuromonas acetoxidans. The name Geobacter metallireducens is proposed.

Concentrations and co-occurrence correlations of 88 volatile organic compounds (VOCs) in the ambient air of 13 semi-rural to urban locations in the United States

USGS Publications Warehouse

Pankow, J.F.; Luo, W.; Bender, D.A.; Isabelle, L.M.; Hollingsworth, J.S.; Chen, C.; Asher, W.E.; Zogorski, J.S.

2003-01-01

The ambient air concentrations of 88 volatile organic compounds were determined in samples taken at 13 semi-rural to urban locations in Maine, Massachusetts, New Jersey, Pennsylvania, Ohio, Illinois, Louisiana, and California. The sampling periods ranged from 7 to 29 months, yielding a large data set with a total of 23,191 individual air concentration values, some of which were designated "ND" (not detected). For each compound at each sampling site, the air concentrations (ca, ppbV) are reported in terms of means, medians, and means of the detected values. The analytical method utilized adsorption/thermal desorption with air-sampling cartridges. The analytes included numerous halogenated alkanes, halogenated alkenes, ethers, alcohols, nitriles, esters, ketones, aromatics, a disulfide, and a furan. At some sites, the air concentrations of the gasoline-related aromatic compounds and the gasoline additive methyl tert-butyl ether were seasonally dependent, with concentrations that maximized in the winter. For each site studied here, the concentrations of some compounds were highly correlated one with another (e.g., the BTEX group (benzene, toluene, ethylbenzene, and the xylenes). Other aromatic compounds were also all generally correlated with one another, while the concentrations of other compound pairs were not correlated (e.g., benzene was not correlated with CFC-12). The concentrations found for the BTEX group were generally lower than the values that have been previously reported for urbanized and industrialized areas of other nations. ?? 2003 Elsevier Ltd. All rights reserved.

Isolation and characterization of novel endogenous digitalis-like factors in the ovary of the giant toad, Bufo marinus.

PubMed

Matsukawa, M; Mukai, T; Akizawa, T; Miyatake, S; Yoshioka, M; Morris, J F; Butler, V P

1998-12-01

We have previously described the structures of four novel unconjugated bufadienolides in the ovary of the toad, Bufo marinus. In this study, we report the separation and characterization of three novel bufadienolide conjugates. These compounds were purified by HPLC, and their structures were determined to be 11alpha, 19-dihydroxytelocinobufagin-3-(12-hydroxydodecanoic acid) ester, 11alpha,19-dihydroxytelocinobufagin-3-(14-hydroxy-7-tetra decenoic acid) ester, and 11alpha, 19-dihydroxytelocinobufagin-3-(14-hydroxytetradecanoic acid) ester on the basis of NMR and MS data. Numerous dicarboxylic acid esters of bufadienolides have previously been described, but the three bufadienolide conjugates described in this report differ from previously described esters in that they contain hydroxylated monocarboxylic acids. The function of these three conjugates is not known but they are, like bufotoxins, potent inhibitors of Na+, K+-ATPase and may play a developmental role in the differentiation of toad oocytes.

Pseudomonas fluorescens SBW25 produces furanomycin, a non-proteinogenic amino acid with selective antimicrobial properties.

PubMed

Trippe, Kristin; McPhail, Kerry; Armstrong, Donald; Azevedo, Mark; Banowetz, Gary

2013-05-20

Pseudomonas fluorescens SBW25 has been extensively studied because of its plant growth promoting properties and potential as a biocontrol agent. The genome of SBW25 has been sequenced, and among sequenced strains of pseudomonads, SBW25 appears to be most closely related to P. fluorescens WH6. In the authors' laboratories, WH6 was previously shown to produce and secrete 4-formylaminooxyvinylglycine (FVG), a non-proteinogenic amino acid with selective herbicidal and antimicrobial activity. Although SBW25 does not have the genetic capacity to produce FVG, we were interested in determining whether this pseudomonad might produce some other type of non-proteinogenic amino acid. P. fluorescens SBW25 was found to produce and secrete a ninhydrin-reactive compound with selective antimicrobial properties. This compound was purified from SBW25 culture filtrate and identified as the non-proteinogenic amino acid L-furanomycin [2S,2'R,5'S)-2-amino-2-(5'methyl-2',5'-dihydrofuran-2'-yl)acetic acid]. The identification of furanomycin as a secondary metabolite of SBW25 is the first report of the production of furanomycin by a pseudomonad. This compound was known previously only as a natural product produced by a strain of Streptomyces. This report adds furanomycin to the small list of non-proteinogenic amino acids that have been identified as secondary products of pseudomonads. This study also extends the list of bacteria that are inhibited by furanomycin to include several plant pathogenic bacteria.

Compound K induced apoptosis via endoplasmic reticulum Ca2+ release through ryanodine receptor in human lung cancer cells.

PubMed

Shin, Dong-Hyun; Leem, Dong-Gyu; Shin, Ji-Sun; Kim, Joo-Il; Kim, Kyung-Tack; Choi, Sang Yoon; Lee, Myung-Hee; Choi, Jung-Hye; Lee, Kyung-Tae

2018-04-01

Extended endoplasmic reticulum (ER) stress may initiate apoptotic pathways in cancer cells, and ER stress has been reported to possibly increase tumor death in cancer therapy. We previously reported that caspase-8 played an important role in compound K-induced apoptosis via activation of caspase-3 directly or indirectly through Bid cleavage, cytochrome c release, and caspase-9 activation in HL-60 human leukemia cells. The mechanisms leading to apoptosis in A549 and SK-MES-1 human lung cancer cells and the role of ER stress have not yet been understood. The apoptotic effects of compound K were analyzed using flow cytometry, and the changes in protein levels were determined using Western blot analysis. The intracellular calcium levels were monitored by staining with Fura-2/AM and Fluo-3/AM. Compound K-induced ER stress was confirmed through increased phosphorylation of eIF2α and protein levels of GRP78/BiP, XBP-1S, and IRE1α in human lung cancer cells. Moreover, compound-K led to the accumulation of intracellular calcium and an increase in m-calpain activities that were both significantly inhibited by pretreatment either with BAPTA-AM (an intracellular Ca 2+ chelator) or dantrolene (an RyR channel antagonist). These results were correlated with the outcome that compound K induced ER stress-related apoptosis through caspase-12, as z-ATAD-fmk (a specific inhibitor of caspase-12) partially ameliorated this effect. Interestingly, 4-PBA (ER stress inhibitor) dramatically improved the compound K-induced apoptosis. Cell survival and intracellular Ca 2+ homeostasis during ER stress in human lung cancer cells are important factors in the induction of the compound K-induced apoptotic pathway.

Sensory irritating potency of some microbial volatile organic compounds (MVOCs) and a mixture of five MVOCs.

PubMed

Korpi, A; Kasanen, J P; Alarie, Y; Kosma, V M; Pasanen, A L

1999-01-01

The authors investigated the ability/potencies of 3 microbial volatile organic compounds and a mixture of 5 microbial volatile organic compounds to cause eye and upper respiratory tract irritation (i.e., sensory irritation), with an animal bioassay. The authors estimated potencies by determining the concentration capable of decreasing the respiratory frequency of mice by 50% (i.e., the RD50 value). The RD50 values for 1-octen-3-ol, 3-octanol, and 3-octanone were 182 mg/m3 (35 ppm), 1359 mg/m3 (256 ppm), and 17586 mg/m3 (3360 ppm), respectively. Recommended indoor air levels calculated from the individual RD50 values for 1-octen-3-ol, 3-octanol, and 3-octanone were 100, 1000, and 13000 microg/m3, respectively-values considerably higher than the reported measured indoor air levels for these compounds. The RD50 value for a mixture of 5 microbial volatile organic compounds was also determined and found to be 3.6 times lower than estimated from the fractional concentrations and the respective RD50s of the individual components. The data support the conclusion that a variety of microbial volatile organic compounds may have some synergistic effects for the sensory irritation response, which constrains the interpretation and application of recommended indoor air levels of individual microbial volatile organic compounds. The results also showed that if a particular component of a mixture was much more potent than the other components, it may dominate the sensory irritation effect. With respect to irritation symptoms reported in moldy houses, the results of this study indicate that the contribution of microbial volatile organic compounds to these symptoms seems less than previously supposed.

Phase diagram and electrical behavior of silicon-rich iridium silicide compounds

NASA Technical Reports Server (NTRS)

Allevato, C. E.; Vining, Cronin B.

1992-01-01

The iridium-silicon phase diagram on the silicon-rich side was investigated by means of X-ray powder diffraction, density, differential thermal analysis, metalography, microprobe analysis, and electrical resistivity. Attempts were made to prepare eight previously reported silicon-rich iridium silicide compounds by arc melting and Bridgman-like growth. However, microprobe analysis identified only four distinct compositions: IrSi, Ir3Si4, Ir3Si5 and IrSi sub about 3. The existence of Ir4Si5 could not be confirmed in this study, even though the crystal structure has been previously reported. Differential thermal analysis (DTA) in conjunction with X-ray powder diffraction confirm polymorphism in IrSi sub about 3, determined to have orthorhombic and monoclinic unit cells in the high and low temperature forms. A eutectic composition alloy of 83 +/- 1 atomic percent silicon was observed between IrSi sub about 3 and silicon. Ir3Si4 exhibits distinct metallic behavior while Ir3Si5 is semiconducting. Both and IrSi and IrSi sub about 3 exhibit nearly temperature independent electrical resistivities on the order of 5-10 x 10 exp -6 ohms-m.

Two new karlotoxins found in Karlodinium veneficum (strain GM2) from the East China Sea.

PubMed

Cai, Pengjie; He, Shan; Zhou, Chengxu; Place, Allen R; Haq, Saddef; Ding, Lijian; Chen, Haimin; Jiang, Ying; Guo, Cheng; Xu, Yaru; Zhang, Jinrong; Yan, Xiaojun

2016-09-01

The dinoflagellate Karlodinium veneficum is a harmful algal bloom species with a worldwide distribution. This small athecate dinoflagellate makes a family of polyketide toxins that are hemolytic, cytotoxic and ichthyotoxic. The first chemical structure for karlotoxins from East China Sea (ECS) is reported here. The two new karlotoxins, namely 4,5-dihydro-KmTx 2 (compound 1) and 4,5-dihydro-dechloro-KmTx 2 (compound 2), were isolated and purified from monoalgal cultures of K. veneficum strain GM2. Their structures were determined by spectroscopic analysis, including tandem mass spectrometry as well as 1D and 2D NMR experiments. These new karlotoxin congeners feature a saturated polyol arm different from previously reported for KmTx 2 that appears to increase hemolytic activity. Copyright © 2016 Elsevier B.V. All rights reserved.

A combined ultra-wideline solid-state NMR and DFT study of 137Ba electric field gradient tensors in barium compounds

NASA Astrophysics Data System (ADS)

O'Dell, Luke A.; Moudrakovski, Igor L.

2013-04-01

Ultra-wideline 137Ba solid-state (SS) NMR spectra have been obtained from a series of five barium compounds (BaSO4, BaMoO4, Ba(CH3COO)2, Ba(OH)2·8H2O and α-Ba2P2O7), using the broadband WURST-QCPMG pulse sequence and magnetic field of 21.1 T. The signals from the two distinct crystallographic sites in α-Ba2P2O7 are resolved, with one of them demonstrating a CQ of 42.3 ± 0.3 MHz, the largest obtained for 137Ba in a powder. The quadrupolar parameters reported in this work are in excellent agreement with the DFT calculations and correlate well with those previously reported by Hamaed et al. (2010) [24].

Algicidal metabolites produced by Bacillus sp. strain B1 against Phaeocystis globosa.

PubMed

Zhao, Ling; Chen, Lina; Yin, Pinghe

2014-03-01

The bloom of Phaeocystis globosa has broken out frequently in the coastal areas of China in recent years, which has led to substantial economic losses. This study shows that Bacillus sp. strain B1, which was previously identified by our group, is effective in regulating P. globosa by excreting active metabolites. Heat stability, pH stability and molecular weight range of the algicidal compounds from strain B1 were measured and the results demonstrated that the algicidal activities of these compounds were not affected by pH or temperature variation. The algicidal compounds extracted with methanol were isolated and purified by ODS-A column chromatography and HPLC. The algicidal compounds corresponding to peaks 2-5 eluted from HPLC were further analysed by quadrupole time-of-flight mass spectrometry (Q-TOF-MS). PeakView™ Software determined the compounds corresponding to peaks 2-5 to be L-histidine, o-tyrosine, N-acetylhistamine and urocanic acid on the basis of the accurate mass information, the isotopic pattern and MS-MS spectra. Furthermore, these compounds were also able to eliminate Skeletonema costatum, Prorocentrum donghaiense and Heterosigma akashiwo. This is the first report of bacteria-derived algicidal compounds being identified only by Q-TOF-MS and PeakView™ Software, and these compounds may be used as the constituents of algicides in the future.

The oxidation of 2,6-di-tert-butyl-4-methylphenol

USGS Publications Warehouse

Yohe, G.R.; Dunbar, J.E.; Pedrotti, R.L.; Scheidt, F.M.; Lee, F.G.H.; Smith, E.C.

1956-01-01

The products formed in the oxidation of 2,6-di-tert-butyl-4-methylphenol with oxygen and sodium hydroxide at about 100?? are 3,5-di-tert-butyl-4-hydroxybenzaldehyde, trimethylacetic acid, an acidic compound C14H22O3, and probably 2,6-di-tert-butylbenzoquinone (which was actually isolated in the similar oxidation of the above-named benzaldehyde), in addition to compounds previously reported. Some of the properties of C14H22O3 are given, and the oxidation of it to 2,3-di-tert-butylsuccinic anhydride is described, but assignment of structure is reserved pending the completion of more experimental work.

A novel small-molecule compound of lithium iodine and 3-hydroxypropionitride as a solid-state electrolyte for lithium–air batteries

DOE PAGES

Liu, Fang -Chao; Shadike, Zulipiya; Wang, Xiao -Fang; ...

2016-06-16

A novel small-molecule compound of lithium iodine and 3-hydroxypropionitrile (HPN) has been successfully synthesized. Our combined experimental and theoretical studies indicated that LiIHPN is a Li-ion conductor, which is utterly different from the I–-anion conductor of LiI(HPN) 2 reported previously. Solid-state lithium–air batteries based on LiIHPN as the electrolyte exhibit a reversible discharge capacity of more than 2100 mAh g –1 with a cyclic performance over 10 cycles. Lastly, our findings provide a new way to design solid-state electrolytes toward high-performance lithium–air batteries.

Polyoxygenated steroids from the gorgonian Menella woodin with capabilities to modulate ROS levels in macrophages at response to LPS.

PubMed

Tu, Vu A; Lyakhova, Ekaterina G; Diep, Chau N; Kalinovsky, Anatoly I; Dmitrenok, Pavel S; Cuong, Nguyen X; Thanh, Nguyen V; Menchinskaya, Ekaterina S; Pislyagin, Evgeny A; Nam, Nguyen H; Kiem, Phan V; Stonik, Valentin A; Minh, Chau V

2015-12-01

Four new polyoxygenated sterol derivatives (1-4) along with the compounds (5-7) previously known from other biological sources were isolated from the gorgonian Menella woodin, collected from the Vietnamese waters. Structures of 1-4 were elucidated by the detailed NMR spectroscopic and mass-spectrometric analyses as well as comparison with those reported in literature data. Compounds 1, 4, and 6 decrease the production of reactive oxygen species (ROS) by the murine macrophages of RAW 264.7 line at induction by endotoxic lipopolysaccharide (LPS) from Escherichia coli. Copyright © 2015 Elsevier Inc. All rights reserved.

Comparative study on the antioxidant activities of the different extracts and the composition of the oil extracted by n-hexane from Iranian Vitex pseudo-negundo.

PubMed

Mozdianfard, Mohammadreza; Akhbari, Maryam; Batooli, Hossein

2012-01-01

Antioxidant activities of different extracts obtained from the aerial parts of Vitex pseudo-negundo from Kashan, central Iran, were evaluated for the first time in this study using β-carotene/linoleic acid and scavenging of free-radical (DPPH) assays. Water extract showed the highest activity in both assays. GC-MS analysis of the oil extracted by n-hexane revealed 46 compounds with trans-β-farnesene being the main component. Several new compounds, not reported in the previous literature, were identified in the essential oil of this chemo-type.

Achiral-to-chiral transition in benzil solidification: analogies with racemic conglomerates systems showing deracemization.

PubMed

El-Hachemi, Zoubir; Arteaga, Oriol; Canillas, Adolf; Crusats, Joaquim; Sorrenti, Alessandro; Veintemillas-Verdaguer, Sabino; Ribo, Josep M

2013-07-01

Experimental results show that benzil (1,2-diphenyl-1,2-ethanedione), an achiral compound that crystallizes as a racemic conglomerate, yields by solidification polycrystalline scalemic mixtures of high enantiomeric excesses. These results are related to those previously reported in this type of compounds on deracemizations of racemic mixtures of crystal enantiomorphs obtained by wet grinding. However, the present results strongly suggest that these experiments cannot be explained without taking into account chiral recognition interactions at the level of precritical clusters. The conditions that would define a general thermodynamic scenario for such deracemizations are discussed. © 2013 Wiley Periodicals, Inc.

Phytochemical Investigations of Three Rhodocodon (Hyacinthaceae Sensu APG II) Species.

PubMed

Schwikkard, Sianne; Alqahtani, Alaa; Knirsch, Walter; Wetschnig, Wolfgang; Jaksevicius, Andrius; Opara, Elizabeth I; Langat, Moses K; Andriantiana, Jackie L; Mulholland, Dulcie A

2017-01-27

The genus Rhodocodon (Hyacinthaceae sensu APG II) is endemic to Madagascar, and its phytochemistry has not been described previously. The phytochemistry of three species in this genus has been investigated, and eight compounds, including three bufadienolides (compounds 1, 4, and 5), a norlignan (2), and four homoisoflavonoids (compounds 3 and 6-8), have been isolated and identified. Compounds 1-3 and 6-8 have not been described previously. The COX-2 inhibitory activity of compound 6 and compound 7 acetate (compound 7A) was investigated on isolated colorectal cancer cells. Compounds 6 and 7A inhibited COX-2 by 10% and 8%, respectively, at a concentration of 12.5 μM compared to 12% for 1 mM aspirin (the positive control).

2004 Toxic Chemical Release Inventory Report for the Emergency Planning and Community Right-to-Know Act of 1986, Title III, Section 313

DOE Office of Scientific and Technical Information (OSTI.GOV)

M. Stockton

2006-01-15

Section 313 of Emergency Planning and Community Right-to-Know Act (EPCRA) specifically requires facilities to submit a Toxic Chemical Release Inventory Report (Form R) to the U.S. Environmental Protection Agency (EPA) and state agencies if the owners and operators manufacture, process, or otherwise use any of the listed toxic chemicals above listed threshold quantities. EPA compiles this data in the Toxic Release Inventory database. Form R reports for each chemical over threshold quantities must be submitted on or before July 1 each year and must cover activities that occurred at the facility during the previous year. For reporting year 2004, Losmore » Alamos National Laboratory (LANL or the Laboratory) submitted Form R reports for lead compounds, nitric acid, and nitrate compounds as required under the EPCRA Section 313. No other EPCRA Section 313 chemicals were used in 2004 above the reportable thresholds. This document provides a description of the evaluation of EPCRA Section 313 chemical use and threshold determinations for LANL for calendar year 2004, as well as background information about data included on the Form R reports.« less

HPLC-based activity profiling for antiplasmodial compounds in the traditional Indonesian medicinal plant Carica papaya L.

PubMed

Julianti, Tasqiah; De Mieri, Maria; Zimmermann, Stefanie; Ebrahimi, Samad N; Kaiser, Marcel; Neuburger, Markus; Raith, Melanie; Brun, Reto; Hamburger, Matthias

2014-08-08

Leaf decoctions of Carica papaya have been traditionally used in some parts of Indonesia to treat and prevent malaria. Leaf extracts and fraction have been previously shown to possess antiplasmodial activity in vitro and in vivo. Antiplasmodial activity of extracts was confirmed and the active fractions in the extract were identified by HPLC-based activity profiling, a gradient HPLC fractionation of a single injection of the extract, followed by offline bioassay of the obtained microfractions. For preparative isolation of compounds, an alkaloidal fraction was obtained via adsorption on cationic ion exchange resin. Active compounds were purified by HPLC-MS and MPLC-ELSD. Structures were established by HR-ESI-MS and NMR spectroscopy. For compounds 5 and 7 absolute configuration was confirmed by comparison of experimental and calculated electronic circular dichroism (ECD) spectroscopy data, and by X-ray crystallography. Compounds were tested for bioactivity in vitro against four parasites (Trypanosoma brucei rhodesiense, Trypanosoma cruzi, Leishmania donovani, and Plasmodium falciparum), and in the Plasmodium berghei mouse model. Profiling indicated flavonoids and alkaloids in the active time windows. A total of nine compounds were isolated. Four were known flavonols--manghaslin, clitorin, rutin, and nicotiflorin. Five compounds isolated from the alkaloidal fraction were piperidine alkaloids. Compounds 5 and 6 were inactive carpamic acid and methyl carpamate, while three alkaloids 7-9 showed high antiplasmodial activity and low cytotoxicity. When tested in the Plasmodium berghei mouse model, carpaine (7) did not increase the survival time of animals. The antiplasmodial activity of papaya leaves could be linked to alkaloids. Among these, carpaine was highly active and selective in vitro. The high in vitro activity could not be substantiated with the in vivo murine model. Further investigations are needed to clarify the divergence between our negative in vivo results for carpaine, and previous reports of in vivo activity with papaya leaf extracts. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Astrobiological Implications of Titan Tholin in Methane Lakes

NASA Astrophysics Data System (ADS)

Khare, Bishun N.; McKay, C. P.; McPherson, S.; Cruikshank, D.; Nna-Mvondo, D.; Sekine, Y.

2010-10-01

We report here on our ongoing research in the Laboratory for Planetary Studies at NASA Ames Research Center dedicated to determine the degree of solubility of Titan tholin in the methane-ethane lakes. Our work is also directed toward confirming the presence of any astrobiologically significant molecules via hydrolysis and pyrolysis of a simulated lake sample. Our previous work conducted at Cornell University and subsequently in the Laboratory for Planetary Studies at NASA Ames Research Center has established that Titan tholin produces amino acids (Khare et al. Icarus 1986) on hydrolysis, and many compounds including adenine on pyrolysis (Khare et al. Adv. Space Res. 1984). Also, our previous work by Thompson et al. (Icarus 1991) has clearly indicated that when energy is supplied to Titan's atmospheric composition (methane and nitrogen), tholin results from hundreds of contemporary compounds, including highly reactive compounds such as azides and isocyanides. Cassini showed that photolysis of methane produces benzene and many polycyclic aromatic hydrocarbons, along with compounds with very high molecular weights (up to 10000 amu), resulting from the photolytic reactions of CH4 with nitrogen. These heavy aerosols, termed "tholins” by Sagan and Khare (Nature 1979), are also synthesized when Titan intercepts charged particles from the magnetosphere of Saturn. Tholins resulting from both of these syntheses eventually descend to the surface of Titan, where some quantity collects in the methane-ethane lakes. This research is supported by a grant from Planetary Atmospheres.

Homozygous and compound heterozygous mutations in the FBN1 gene: unexpected findings in molecular diagnosis of Marfan syndrome.

PubMed

Arnaud, Pauline; Hanna, Nadine; Aubart, Mélodie; Leheup, Bruno; Dupuis-Girod, Sophie; Naudion, Sophie; Lacombe, Didier; Milleron, Olivier; Odent, Sylvie; Faivre, Laurence; Bal, Laurence; Edouard, Thomas; Collod-Beroud, Gwenaëlle; Langeois, Maud; Spentchian, Myrtille; Gouya, Laurent; Jondeau, Guillaume; Boileau, Catherine

2017-02-01

Marfan syndrome (MFS) is an autosomal-dominant connective tissue disorder usually associated with heterozygous mutations in the gene encoding fibrillin-1 (FBN1). Homozygous and compound heterozygous cases are rare events and have been associated with a clinical severe presentation. Report unexpected findings of homozygosity and compound heterozygosity in the course of molecular diagnosis of heterozygous MFS and compare the findings with published cases. In the context of molecular diagnosis of heterozygous MFS, systematic sequencing of the FBN1 gene was performed in 2500 probands referred nationwide. 1400 probands carried a heterozygous mutation in this gene. Unexpectedly, among them four homozygous cases (0.29%) and five compound heterozygous cases (0.36%) were identified (total: 0.64%). Interestingly, none of these cases carried two premature termination codon mutations in the FBN1 gene. Clinical features for these carriers and their families were gathered and compared. There was a large spectrum of severity of the disease in probands carrying two mutated FBN1 alleles, but none of them presented extremely severe manifestations of MFS in any system compared with carriers of only one mutated FBN1 allele. This observation is not in line with the severe clinical features reported in the literature for four homozygous and three compound heterozygous probands. Homozygotes and compound heterozygotes were unexpectedly identified in the course of molecular diagnosis of MFS. Contrary to previous reports, the presence of two mutated alleles was not associated with severe forms of MFS. Although homozygosity and compound heterozygosity are rarely found in molecular diagnosis, they should not be overlooked, especially among consanguineous families. However, no predictive evaluation of severity should be provided. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

2002 Toxic Chemical Release Inventory Report for the Emergency Planning and Community Right-to-Know Act of 1986, Title III, Section 313

DOE Office of Scientific and Technical Information (OSTI.GOV)

M. Stockton

2003-11-01

For reporting year 2002, Los Alamos National Laboratory (LANL or the Laboratory) submitted Form R reports for lead compounds and mercury as required under the Emergency Planning and Community Right-to-Know Act (EPCRA), Section 313. No other EPCRA Section 313 chemicals were used in 2002 above the reportable thresholds. This document was prepared to provide a description of the evaluation of EPCRA Section 313 chemical usage and threshold determinations for LANL for calendar year 2002 as well as provide background information about the data included on the Form R reports. Section 313 of EPCRA specifically requires facilities to submit a Toxicmore » Chemical Release Inventory report (Form R) to the U.S. Environmental Protection Agency (EPA) and state agencies if the owners and operators manufacture, process, or otherwise use any of the listed toxic chemicals above listed threshold quantities. EPA compiles this data in the Toxic Release Inventory database. Form R reports for each chemical over threshold quantities must be submitted on or before July 1 each year and must cover activities that occurred at the facility during the previous year. In 1999 EPA promulgated a final rule on Persistent Bioaccumulative Toxics (PBTs). This rule added several chemicals to the EPCRA Section 313 list of toxic chemicals and established lower reporting thresholds for these and other PBT chemicals that were already reportable under EPCRA Section 313. These lower thresholds became applicable in reporting year 2000. In 2001, EPA expanded the PBT rule to include a lower reporting threshold for lead and lead compounds. Facilities that manufacture, process, or otherwise use more than 100 lb of lead or lead compounds must submit a Form R.« less

Identification of Human Semiochemicals Attractive to the Major Vectors of Onchocerciasis

PubMed Central

Young, Ryan M.; Burkett-Cadena, Nathan D.; McGaha, Tommy W.; Rodriguez-Perez, Mario A.; Toé, Laurent D.; Adeleke, Monsuru A.; Sanfo, Moussa; Soungalo, Traore; Katholi, Charles R.; Noblet, Raymond; Fadamiro, Henry; Torres-Estrada, Jose L.; Salinas-Carmona, Mario C.; Baker, Bill; Unnasch, Thomas R.; Cupp, Eddie W.

2015-01-01

Background Entomological indicators are considered key metrics to document the interruption of transmission of Onchocerca volvulus, the etiological agent of human onchocerciasis. Human landing collection is the standard employed for collection of the vectors for this parasite. Recent studies reported the development of traps that have the potential for replacing humans for surveillance of O. volvulus in the vector population. However, the key chemical components of human odor that are attractive to vector black flies have not been identified. Methodology/Principal Findings Human sweat compounds were analyzed using GC-MS analysis and compounds common to three individuals identified. These common compounds, with others previously identified as attractive to other hematophagous arthropods were evaluated for their ability to stimulate and attract the major onchocerciasis vectors in Africa (Simulium damnosum sensu lato) and Latin America (Simulium ochraceum s. l.) using electroantennography and a Y tube binary choice assay. Medium chain length carboxylic acids and aldehydes were neurostimulatory for S. damnosum s.l. while S. ochraceum s.l. was stimulated by short chain aliphatic alcohols and aldehydes. Both species were attracted to ammonium bicarbonate and acetophenone. The compounds were shown to be attractive to the relevant vector species in field studies, when incorporated into a formulation that permitted a continuous release of the compound over time and used in concert with previously developed trap platforms. Conclusions/Significance The identification of compounds attractive to the major vectors of O. volvulus will permit the development of optimized traps. Such traps may replace the use of human vector collectors for monitoring the effectiveness of onchocerciasis elimination programs and could find use as a contributing component in an integrated vector control/drug program aimed at eliminating river blindness in Africa. PMID:25569240

Identification of human semiochemicals attractive to the major vectors of onchocerciasis.

PubMed

Young, Ryan M; Burkett-Cadena, Nathan D; McGaha, Tommy W; Rodriguez-Perez, Mario A; Toé, Laurent D; Adeleke, Monsuru A; Sanfo, Moussa; Soungalo, Traore; Katholi, Charles R; Noblet, Raymond; Fadamiro, Henry; Torres-Estrada, Jose L; Salinas-Carmona, Mario C; Baker, Bill; Unnasch, Thomas R; Cupp, Eddie W

2015-01-01

Entomological indicators are considered key metrics to document the interruption of transmission of Onchocerca volvulus, the etiological agent of human onchocerciasis. Human landing collection is the standard employed for collection of the vectors for this parasite. Recent studies reported the development of traps that have the potential for replacing humans for surveillance of O. volvulus in the vector population. However, the key chemical components of human odor that are attractive to vector black flies have not been identified. Human sweat compounds were analyzed using GC-MS analysis and compounds common to three individuals identified. These common compounds, with others previously identified as attractive to other hematophagous arthropods were evaluated for their ability to stimulate and attract the major onchocerciasis vectors in Africa (Simulium damnosum sensu lato) and Latin America (Simulium ochraceum s. l.) using electroantennography and a Y tube binary choice assay. Medium chain length carboxylic acids and aldehydes were neurostimulatory for S. damnosum s.l. while S. ochraceum s.l. was stimulated by short chain aliphatic alcohols and aldehydes. Both species were attracted to ammonium bicarbonate and acetophenone. The compounds were shown to be attractive to the relevant vector species in field studies, when incorporated into a formulation that permitted a continuous release of the compound over time and used in concert with previously developed trap platforms. The identification of compounds attractive to the major vectors of O. volvulus will permit the development of optimized traps. Such traps may replace the use of human vector collectors for monitoring the effectiveness of onchocerciasis elimination programs and could find use as a contributing component in an integrated vector control/drug program aimed at eliminating river blindness in Africa.

Structural Optimizations of Thieno[3,2-b]pyrrole Derivatives for the Development of Metabolically Stable Inhibitors of Chikungunya Virus.

PubMed

Ching, Kuan-Chieh; Tran, Thi Ngoc Quy; Amrun, Siti Naqiah; Kam, Yiu-Wing; Ng, Lisa F P; Chai, Christina L L

2017-04-13

Chikungunya virus (CHIKV) is a re-emerging vector-borne alphavirus, and there is no approved effective antiviral treatment currently available for CHIKV. We previously reported the discovery of thieno[3,2-b]pyrrole 1b that displayed good antiviral activity against CHIKV infection in vitro. However, it has a short half-life in the presence of human liver microsomes (HLMs) (T 1/2 = 2.91 min). Herein, we report further optimization studies in which potential metabolically labile sites on compound 1b were removed or modified, resulting in the identification of thieno[3,2-b]pyrrole 20 and pyrrolo[2,3-d]thiazole 23c possessing up to 17-fold increase in metabolic half-lives in HLMs and good in vivo pharmacokinetic properties. Compound 20 not only attenuated viral RNA production and displayed broad-spectrum antiviral activity against other alphaviruses and CHIKV isolates but also exhibited limited cytotoxic liability (CC 50 > 100 μM). These studies have identified two compounds that have the potential for further development as antiviral drugs against CHIKV infection.

Changing patterns of cow's milk contamination with organochlorine compounds in Israel (1976-1986)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pines, A.; Cucos, S.; Grafstein, O.

1988-01-01

Environmental pollution with organochlorine insecticides (OCIs) and polychlorinated biphenyls (PCGs) has decreased due to restriction and/or banning of these compounds. However, several recent reports indicate that pollution with OCIs and PCBs still does exist, and may be of public and environmental health significance even in developed countries. Cow's milk is one of the most important media where organochlorine compound (OCC) levels are monitored. On the one hand, milk and its products play a central role in human nutrition and, on the other, highly lipophilic OCCs can accumulate in fat-rich milk products. In a previous study, the authors reported a significantmore » decrease in OCC content in both farm and market milk in Israel between the mid-1970s and early 1980s. The clearest decrease was seen in the cases of DDT, dieldrin and lindane, but not as much as for heptachlor epoxide (HE) and PCBs. The present study was undertaken to follow up the observed trends and to determine whether cow's milk contamination with OCC presently poses a public health problem in Israel.« less

Discovery of a Pederin Family Compound in a Nonsymbiotic Bloom-Forming Cyanobacterium.

PubMed

Kust, Andreja; Mareš, Jan; Jokela, Jouni; Urajová, Petra; Hájek, Jan; Saurav, Kumar; Voráčová, Kateřina; Fewer, David P; Haapaniemi, Esa; Permi, Perttu; Řeháková, Klára; Sivonen, Kaarina; Hrouzek, Pavel

2018-05-18

The pederin family includes a number of bioactive compounds isolated from symbiotic organisms of diverse evolutionary origin. Pederin is linked to beetle-induced dermatitis in humans, and pederin family members possess potent antitumor activity caused by selective inhibition of the eukaryotic ribosome. Their biosynthesis is accomplished by a polyketide/nonribosomal peptide synthetase machinery employing an unusual trans-acyltransferase mechanism. Here, we report a novel pederin type compound, cusperin, from the free-living cyanobacterium Cuspidothrix issatschenkoi (earlier Aphanizomenon). The chemical structure of cusperin is similar to that of nosperin recently isolated from the lichen cyanobiont Nostoc sharing the tehrahydropyran moiety and major part of the linear backbone. However, the cusperin molecule is extended by a glycine residue and lacks one hydroxyl substituent. Pederins were previously thought to be exclusive to symbiotic relationships. However, C. issatschenkoi is a nonsymbiotic planktonic organism and a frequent component of toxic water blooms. Cusperin is devoid of the cytotoxic activity reported for other pederin family members. Hence, our findings raise questions about the role of pederin analogues in cyanobacteria and broaden the knowledge of ecological distribution of this group of polyketides.

Solid-Phase Microextraction Coupled to Capillary Atmospheric Pressure Photoionization-Mass Spectrometry for Direct Analysis of Polar and Nonpolar Compounds.

PubMed

Mirabelli, Mario F; Zenobi, Renato

2018-04-17

A novel capillary ionization source based on atmospheric pressure photoionization (cAPPI) was developed and used for the direct interfacing between solid-phase microextraction (SPME) and mass spectrometry (MS). The efficiency of the source was evaluated for direct and dopant-assisted photoionization, analyzing both polar (e.g., triazines and organophosphorus pesticides) and nonpolar (polycyclic aromatic hydrocarbons, PAHs) compounds. The results show that the range of compound polarity, which can be addressed by direct SPME-MS can be substantially extended by using cAPPI, compared to other sensitive techniques like direct analysis in real time (DART) and dielectric barrier discharge ionization (DBDI). The new source delivers a very high sensitivity, down to sub parts-per-trillion (ppt), making it a viable alternative when compared to previously reported and less comprehensive direct approaches.

Cardanols, long chain cyclohexenones and cyclohexenols from Lannea schimperi (Anacardiaceae).

PubMed

Okoth, Dorothy A; Koorbanally, Neil A

2015-01-01

Alkenyl cyclohexenones (1a-d), alkenyl cyclohexenols (2a-c and 3b-d) and cardanols (4a-d) were isolated from the stem bark and root of Lannea schimperi. The alkenyl cyclohexenones (1a and 1d) and cardanols (4a and 4d) have side chains which have not been reported previously, in combination with the core skeletal structures. In addition, compounds 2a-c and 3b-d are all new cyclohexenols. Also isolated were the triterpenes, taraxerone and taraxerol, and sitosterol. The suite of compounds isolated (cyclohexenones and cyclohexenols) make up a nice biosynthetic pathway to the cardanols. The 5-[alkenyl]-4,5- dihydroxycyclohex-2-enone mixture (1a-d) exhibited good in vitro cytotoxicity against the Chinese Hamster Ovarian mammalian cell-line. The compounds were identified mainly from GCMS and NMR spectroscopic techniques.

Partial least squares analysis of rocket propulsion fuel data using diaphragm valve-based comprehensive two-dimensional gas chromatography coupled with flame ionization detection.

PubMed

Freye, Chris E; Fitz, Brian D; Billingsley, Matthew C; Synovec, Robert E

2016-06-01

The chemical composition and several physical properties of RP-1 fuels were studied using comprehensive two-dimensional (2D) gas chromatography (GC×GC) coupled with flame ionization detection (FID). A "reversed column" GC×GC configuration was implemented with a RTX-wax column on the first dimension ((1)D), and a RTX-1 as the second dimension ((2)D). Modulation was achieved using a high temperature diaphragm valve mounted directly in the oven. Using leave-one-out cross-validation (LOOCV), the summed GC×GC-FID signal of three compound-class selective 2D regions (alkanes, cycloalkanes, and aromatics) was regressed against previously measured ASTM derived values for these compound classes, yielding root mean square errors of cross validation (RMSECV) of 0.855, 0.734, and 0.530mass%, respectively. For comparison, using partial least squares (PLS) analysis with LOOCV, the GC×GC-FID signal of the entire 2D separations was regressed against the same ASTM values, yielding a linear trend for the three compound classes (alkanes, cycloalkanes, and aromatics), yielding RMSECV values of 1.52, 2.76, and 0.945 mass%, respectively. Additionally, a more detailed PLS analysis was undertaken of the compounds classes (n-alkanes, iso-alkanes, mono-, di-, and tri-cycloalkanes, and aromatics), and of physical properties previously determined by ASTM methods (such as net heat of combustion, hydrogen content, density, kinematic viscosity, sustained boiling temperature and vapor rise temperature). Results from these PLS studies using the relatively simple to use and inexpensive GC×GC-FID instrumental platform are compared to previously reported results using the GC×GC-TOFMS instrumental platform. Copyright © 2016 Elsevier B.V. All rights reserved.

Development of propidium iodide as a fluorescence probe for the on-line screening of non-specific DNA-intercalators in Fufang Banbianlian Injection.

PubMed

Niu, Yanyan; Li, Sensen; Lin, Zongtao; Liu, Meixian; Wang, Daidong; Wang, Hong; Chen, Shizhong

2016-09-09

Fufang Banbianlian Injection (FBI) has been widely used as an anti-inflammatory and anti-tumor prescription. To understand the relationships between its bioactive ingredients and pharmacological efficacies, our previous study has been successfully identified some DNA-binding compounds in FBI using an established on-line screening system, in which 4',6-diamidino-2-phenylindole (DAPI) was developed as a probe. However, DAPI can be only used to screen ATT-specific DNA minor groove binders, leaving the potential active intercalators unknown in FBI. As a continuation of our studies on FBI, here we present a sensitive analytical method for rapid identification and evaluation of DNA-intercalators using propidium iodide (PI) as a fluorescent probe. We have firstly established the technique of high-performance liquid chromatography-diode-array detector-multistage mass spectrometry-deoxyribonucleic acid-propidium iodide-fluorescence detector (HPLC-DAD-MS(n)-DNA-PI-FLD) system. As a result, 38 of 58 previously identified compounds in FBI were DNA-intercalation active. Interestingly, all previously reported DNA-binders also showed intercalative activities, suggesting they are dual-mode DNA-binders. Quantitative study showed that flavonoid glycosides and chlorogenic acids were the main active compounds in FBI, and displayed similar DNA-binding ability using either DAPI or PI. In addition, 13 active compounds were used to establish the structure-activity relationships. In this study, PI was developed into an on-line method for identifying DNA-intercalators for the first time, and thus it will be a useful high-throughput screening technique for other related samples. Copyright © 2016 Elsevier B.V. All rights reserved.

Monoterpenes with antibacterial activities from a Cameroonian medicinal plant Canthium Multiflorum (Rubiaceae).

PubMed

Kouam, Simeon Fogue; Ngouonpe, Alain Wembe; Bullach, Anke; Lamshöft, Marc; Kuigoua, Guy Merlin; Spiteller, Michael

2013-12-01

Investigation of the crude extract obtained from the aerial parts of Canthium multiflorum led to the isolation of a new iridoid (1) together with twelve known compounds. The structures of these compounds were elucidated by interpretation of 1D and 2D NMR spectroscopic data, accurate mass measurements and comparison with analytical data of previously known analogues. Most of the isolated compounds have been reported for the first time from C. multiflorium. The antimicrobial activities of the isolated compounds were evaluated on five different bacterial strains using agar diffusion technique. The Gram-positive bacterium Staphylococcus aureus subsp. aureus (DSM 799), and the Gram-negative bacteria Actinobacter calco-aceticus (DSM 30006), Serratia plymuthica (DSM 4540), Pseudomonas stutzeri (DSM 4166) and Escherichia coli (DSM 1116) were employed for this purpose. The new iridoid, named 6-oxo-genipin (1), demonstrated significant inhibitory activity against all microbial strains tested, especially the pathogen Staphylococcus aureus. In addition, the compounds 3, 4 and 9 exhibited antiplasmodial activity against Plasmodium falciparum strain K1 and weak cytotoxicity against L6 cell lines. © 2013 Elsevier B.V. All rights reserved.

Turning Defense into Offense: Defensin Mimetics as Novel Antibiotics Targeting Lipid II

PubMed Central

Ateh, Eugene; Oashi, Taiji; Lu, Wuyuan; Huang, Jing; Diepeveen-de Buin, Marlies; Bryant, Joseph; Breukink, Eefjan; MacKerell, Alexander D.; de Leeuw, Erik P. H.

2013-01-01

We have previously reported on the functional interaction of Lipid II with human alpha-defensins, a class of antimicrobial peptides. Lipid II is an essential precursor for bacterial cell wall biosynthesis and an ideal and validated target for natural antibiotic compounds. Using a combination of structural, functional and in silico analyses, we present here the molecular basis for defensin-Lipid II binding. Based on the complex of Lipid II with Human Neutrophil peptide-1, we could identify and characterize chemically diverse low-molecular weight compounds that mimic the interactions between HNP-1 and Lipid II. Lead compound BAS00127538 was further characterized structurally and functionally; it specifically interacts with the N-acetyl muramic acid moiety and isoprenyl tail of Lipid II, targets cell wall synthesis and was protective in an in vivo model for sepsis. For the first time, we have identified and characterized low molecular weight synthetic compounds that target Lipid II with high specificity and affinity. Optimization of these compounds may allow for their development as novel, next generation therapeutic agents for the treatment of Gram-positive pathogenic infections. PMID:24244161

Insights into the Key Compounds of Durian (Durio zibethinus L. 'Monthong') Pulp Odor by Odorant Quantitation and Aroma Simulation Experiments.

PubMed

Li, Jia-Xiao; Schieberle, Peter; Steinhaus, Martin

2017-01-25

Sixteen compounds, previously identified as potent odorants by application of an aroma extract dilution analysis and the gas chromatography-olfactometry analysis of static headspace samples, were quantitated in the pulp of durians, variety Monthong, and odor activity values (OAVs) were calculated by dividing the concentrations obtained by the odor thresholds of the compounds in water. In combination with data recently reported for hydrogen sulfide and short-chain alkanethiols, OAVs > 1 were obtained for 19 compounds, among which ethyl (2S)-2-methylbutanoate (fruity; OAV 1700000), ethanethiol (rotten onion; OAV 480000), and 1-(ethylsulfanyl)ethane-1-thiol (roasted onion; OAV 250000) were the most potent, followed by methanethiol (rotten, cabbage; OAV 45000), ethane-1,1-dithiol (sulfury, durian; OAV 23000), and ethyl 2-methylpropanoate (fruity; OAV 22000). Aroma simulation and omission experiments revealed that the overall odor of durian pulp could be mimicked by only two compounds, namely, ethyl (2S)-2-methylbutanoate and 1-(ethylsulfanyl)ethane-1-thiol, when combined in their natural concentrations.

Obtusifoliol related steroids from Euphorbia sogdiana with cell growth inhibitory activity and apoptotic effects on breast cancer cells (MCF-7 and MDA-MB231).

PubMed

Aghaei, Mahmoud; Yazdiniapour, Zeinab; Ghanadian, Mustafa; Zolfaghari, Behzad; Lanzotti, Virginia; Mirsafaee, Vahid

2016-11-01

From the aerial parts of Euphorbia sogdiana Popov, obtusifoliol (1) and two related steroids (2-3) have been isolated and characterized along with a known cycloartane derivative (4). The chemical structure of the obtusifoliol-related compounds, obtained by 1D and 2D NMR, and MS measurements, have been determined as: 3β,7α-dihydroxy-4α,14α-dimethyl-5α-ergosta-8,24(28)-diene-11-one (2) and 3β-hydroxy-4α,14α-dimethyl-5α-ergosta-8,24(28)-diene-1-one (3). Compound 2 has been previously isolated from Euphorbia chamaesyce while compound 3 was never reported before. The isolated compounds 1-4 were subjected to cytotoxic tests on the breast cancer cells, MCF-7 and MDA-MB231. Further pharmacological tests on the more active compounds 2 and 3 indicated their action to be related to cell growth inhibitory activity and apoptotic effects on the tested cells. Copyright © 2016 Elsevier Inc. All rights reserved.

Chemical Characterization and in Vitro Cytotoxicity on Squamous Cell Carcinoma Cells of Carica papaya Leaf Extracts.

PubMed

Nguyen, Thao T; Parat, Marie-Odile; Hodson, Mark P; Pan, Jenny; Shaw, Paul N; Hewavitharana, Amitha K

2015-12-24

In traditional medicine, Carica papaya leaf has been used for a wide range of therapeutic applications including skin diseases and cancer. In this study, we investigated the in vitro cytotoxicity of aqueous and ethanolic extracts of Carica papaya leaves on the human oral squamous cell carcinoma SCC25 cell line in parallel with non-cancerous human keratinocyte HaCaT cells. Two out of four extracts showed a significantly selective effect towards the cancer cells and were found to contain high levels of phenolic and flavonoid compounds. The chromatographic and mass spectrometric profiles of the extracts obtained with Ultra High Performance Liquid Chromatography-Quadrupole Time of Flight-Mass Spectrometry were used to tentatively identify the bioactive compounds using comparative analysis. The principal compounds identified were flavonoids or flavonoid glycosides, particularly compounds from the kaempferol and quercetin families, of which several have previously been reported to possess anticancer activities. These results confirm that papaya leaf is a potential source of anticancer compounds and warrant further scientific investigation to validate the traditional use of papaya leaf to treat cancer.

Chemical Characterization and in Vitro Cytotoxicity on Squamous Cell Carcinoma Cells of Carica Papaya Leaf Extracts

PubMed Central

Nguyen, Thao T.; Parat, Marie-Odile; Hodson, Mark P.; Pan, Jenny; Shaw, Paul N.; Hewavitharana, Amitha K.

2015-01-01

In traditional medicine, Carica papaya leaf has been used for a wide range of therapeutic applications including skin diseases and cancer. In this study, we investigated the in vitro cytotoxicity of aqueous and ethanolic extracts of Carica papaya leaves on the human oral squamous cell carcinoma SCC25 cell line in parallel with non-cancerous human keratinocyte HaCaT cells. Two out of four extracts showed a significantly selective effect towards the cancer cells and were found to contain high levels of phenolic and flavonoid compounds. The chromatographic and mass spectrometric profiles of the extracts obtained with Ultra High Performance Liquid Chromatography-Quadrupole Time of Flight-Mass Spectrometry were used to tentatively identify the bioactive compounds using comparative analysis. The principal compounds identified were flavonoids or flavonoid glycosides, particularly compounds from the kaempferol and quercetin families, of which several have previously been reported to possess anticancer activities. These results confirm that papaya leaf is a potential source of anticancer compounds and warrant further scientific investigation to validate the traditional use of papaya leaf to treat cancer. PMID:26712788

Bis[2-(hy-droxy-imino-meth-yl)phenolato]nickel(II): a second monoclinic polymorph.

PubMed

Rusanova, Julia A; Buvaylo, Elena A; Rusanov, Eduard B

2011-01-15

The title compound, [Ni(C(7)H(6)NO(2))(2)], (I), is a second monoclinic polymorph of the compound, (II), reported by Srivastava et al. [Acta Cryst. (1967), 22, 922] and Mereiter [Private communication (2002) CCDC refcode NISALO01]. The bond lengths and angles are similar in both structures. The mol-ecule in both structures lies on a crystallographic inversion center and both have an inter-nal hydrogen bond. The title compound crystallizes in the space group P2(1)/c (Z = 2), whereas compound (II) is in the space group P2(1)/n (Z = 2) with a similar cell volume but different cell parameters. In both polymorphs, mol-ecules are arranged in the layers but in contrast to the previously published compound (II) where the dihedral angle between the layers is 86.3°, in the title polymorph the same dihedral angle is 29.4°. The structure of (I) is stabilized by strong intra-molecular O-H⋯O hydrogen bonding between the O-H group and the phenolate O atom.

Biological evaluation and molecular docking of some chromenyl-derivatives as potential antimicrobial agents.

PubMed

Ionuţ, Ioana; Vodnar, Dan Cristian; Oniga, Ilioara; Oniga, Ovidiu; Tiperciuc, Brînduşa; Tamaian, Radu

2016-01-01

Various thiosemicarbazones (TSCs) and their heterocyclic thiadiazolines (TDZ) possess important biological effects. In addition, chromenyl derivatives exhibit a wide range of pharmacological activities. Based on these findings and as a continuation of our research on nitrogen and sulfur containing compounds, we investigated a series of previously reported chromenyl-TSCs (1a-j) and chromenyl-TDZs (2a-j) for their in vitro antimicrobial activities against two bacterial and four fungal strains. MIC and MBC/MFC (µg/mL) values of these compounds were evaluated and compared to those of Spectinomycin, Moxifloxacin and Fluconazole, used as reference drugs. For a better understanding of the drug-receptor interactions, all the compounds were further subjected to molecular docking against four targets that were chosen based on the specific mechanism of action of the reference drugs used in the antimicrobial screening. All compounds tested showed equal or higher antibacterial/antifungal activities relative to the used reference drugs. In silico studies (molecular docking) revealed that all the investigated compounds showed good binding energies towards four receptor protein targets and supported their antimicrobial properties.

Synthesis, crystal structure determination, biological screening and docking studies of N1-substituted derivatives of 2,3-dihydroquinazolin-4(1H)-one as inhibitors of cholinesterases.

PubMed

Sultana, Nargis; Sarfraz, Muhammad; Tanoli, Saba Tahir; Akram, Muhammad Safwan; Sadiq, Abdul; Rashid, Umer; Tariq, Muhammad Ilyas

2017-06-01

Pursuing the strategy of developing potent AChE inhibitors, we attempted to carry out the N 1 -substitution of 2,3-dihydroquinazolin-4(1H)-one core. A set of 32 N-alkylated/benzylated quinazoline derivatives were synthesized, characterized and evaluated for their inhibition against cholinesterases. N-alkylation of the series of the compounds reported previously (N-unsubstituted) resulted in improved activity. All the compounds showed inhibition of both enzymes in the micromolar to submicromolar range. Structure activity relationship (SAR) of the 32 derivatives showed that N-benzylated compounds possess good activity than N-alkylated compounds. N-benzylated compounds 2ad and 2af were found very active with their IC 50 values toward AChE in submicromolar range (0.8µM and 0.6µM respectively). Binding modes of the synthesized compounds were explored by using GOLD (Genetic Optimization for Ligand Docking) suit v5.4.1. Computational predictions of ADMET studies reveal that all the compounds have good pharmacokinetic properties with no AMES toxicity and carcinogenicity. Moreover, all the compounds are predicted to be absorbed in human intestine and also have the ability to cross blood brain barrier. Overall, the synthesized compounds have established a structural foundation for the design of new inhibitors of cholinesterase. Copyright © 2017 Elsevier Inc. All rights reserved.

Ex vivo inhibition of Clostridium botulinum neurotoxin types B, C, E, and F by small molecular weight inhibitors.

PubMed

Montgomery, Vicki A; Ahmed, S Ashraf; Olson, Mark A; Mizanur, Rahman M; Stafford, Robert G; Roxas-Duncan, Virginia I; Smith, Leonard A

2015-05-01

Two small molecular weight inhibitors, compounds CB7969312 and CB7967495, that displayed inhibition of botulinum neurotoxin serotype A in a previous study, were evaluated for inhibition of botulinum neurotoxin serotypes B, C, E, and F. The small molecular weight inhibitors were assessed by molecular modeling, UPLC-based peptide cleavage assay; and an ex vivo assay, the mouse phrenic nerve - hemidiaphragm assay (MPNHDA). While both compounds were inhibitors of botulinum neurotoxin (BoNT) serotypes B, C, and F in the MPNHDA, compound CB7969312 was effective at lower molar concentrations than compound CB7967495. However, compound CB7967495 was significantly more effective at preventing BoNTE intoxication than compound CB7969312. In the UPLC-based peptide cleavage assay, CB7969312 was also more effective against LcC. Both compounds inhibited BoNTE, but not BoNTF, LcE, or LcF in the UPLC-based peptide cleavage assay. Molecular modeling studies predicted that both compounds would be effective inhibitors of BoNTs B, C, E, and F. But CB7967495 was predicted to be a more effective inhibitor of the four serotypes (B, C, E, and F) than CB7969312. This is the first report of a small molecular weight compound that inhibits serotypes B, C, E, and F in the ex vivo assay. Published by Elsevier Ltd.

Total Synthesis of Marine Cyclic Enol-Phosphotriester Salinipostin Compounds

NASA Astrophysics Data System (ADS)

Zhao, Mingliang; Wei, Xianfeng; Liu, Xuemeng; Dong, Xueyang; Yu, Rilei; Wan, Shengbiao; Jiang, Tao

2018-06-01

Due to their structural diversity and variety of biological activities, marine natural products have been the subject of extensive study. These compounds, especially phospholipid polycyclic aromatic hydrocarbons, have a wide range of pharmacological applications, including embedded DNA and central nervous system, anti-tumor, anti-virus, anti-parasite, anti-bacterial, and antithrombotic effects. Unfortunately, the insufficient drug sources have limited the development of these compounds. In this study, we isolated salinpostin compounds from a fermentation solution of marine-derived Salinospora sp., which has a common bicyclic enol-phosphotriester core framework, as well as potent and selective antimalarial activities against P. falciparum with EC50 = 50 nmol L-1. The chemical synthesis of these compounds in greater quantities is necessary for their use in bioactivity studies. Thus we explored a short route with high yields and mild reaction conditions, which can generate combinatorial libraries for drug discovery and lead optimization. We developed a new total synthesis method for six cyclic enol-phosphotriester salinipotin compounds and their diastereomers. For the total synthesis of cyclipostin P, we prepared cyclic enol-phosphotriester salinipostin compounds in 10 steps from a readily accessible starting material, 1,3-dihydroxyacetone, and obtained an overall yield of 1.29%. We fully characterized these compounds by proton nuclear magnetic resonance (1H-NMR), carbon-13 NMR (13C-NMR), and high-resolution mass spectrometry (HRMS) analyses, and found they coincide absolutely with the same compounds reported previously.

Optimization and application of atmospheric pressure chemical and photoionization hydrogen-deuterium exchange mass spectrometry for speciation of oxygen-containing compounds.

PubMed

Acter, Thamina; Kim, Donghwi; Ahmed, Arif; Jin, Jang Mi; Yim, Un Hyuk; Shim, Won Joon; Kim, Young Hwan; Kim, Sunghwan

2016-05-01

This paper presents a detailed investigation of the feasibility of optimized positive and negative atmospheric pressure chemical ionization (APCI) mass spectrometry (MS) and atmospheric pressure photoionization (APPI) MS coupled to hydrogen-deuterium exchange (HDX) for structural assignment of diverse oxygen-containing compounds. The important parameters for optimization of HDX MS were characterized. The optimized techniques employed in the positive and negative modes showed satisfactory HDX product ions for the model compounds when dichloromethane and toluene were employed as a co-solvent in APCI- and APPI-HDX, respectively. The evaluation of the mass spectra obtained from 38 oxygen-containing compounds demonstrated that the extent of the HDX of the ions was structure-dependent. The combination of information provided by different ionization techniques could be used for better speciation of oxygen-containing compounds. For example, (+) APPI-HDX is sensitive to compounds with alcohol, ketone, or aldehyde substituents, while (-) APPI-HDX is sensitive to compounds with carboxylic functional groups. In addition, the compounds with alcohol can be distinguished from other compounds by the presence of exchanged peaks. The combined information was applied to study chemical compositions of degraded oils. The HDX pattern, double bond equivalent (DBE) distribution, and previously reported oxidation products were combined to predict structures of the compounds produced from oxidation of oil. Overall, this study shows that APCI- and APPI-HDX MS are useful experimental techniques that can be applied for the structural analysis of oxygen-containing compounds.

Cytotoxic acyl amides from the soil fungus Gymnascella dankaliensis.

PubMed

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

2015-02-15

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

In vivo imaging of zebrafish digestive organ function using multiple quenched fluorescent reporters.

PubMed

Hama, Kotaro; Provost, Elayne; Baranowski, Timothy C; Rubinstein, Amy L; Anderson, Jennifer L; Leach, Steven D; Farber, Steven A

2009-02-01

Optical clarity of larvae makes the zebrafish ideal for real-time analyses of vertebrate organ function through the use of fluorescent reporters of enzymatic activities. A key function of digestive organs is to couple the generation of enzymes with mechanical processes that enable nutrient availability and absorption. However, it has been extremely difficult, and in many cases not possible, to directly observe digestive processes in a live vertebrate. Here we describe a new method to visualize intestinal protein and lipid processing simultaneously in live zebrafish larvae using a quenched fluorescent protein (EnzChek) and phospholipid (PED6). By employing these reagents, we found that wild-type larvae exhibit significant variation in intestinal phospholipase and protease activities within a group but display a strong correlation between the activities within individuals. Furthermore, we found that pancreas function is essential for larval digestive protease activity but not for larval intestinal phospholipase activity. Although fat-free (ffr) mutant larvae were previously described to exhibit impaired lipid processes, we found they also had significantly reduced protease activity. Finally, we selected and evaluated compounds that were previously suggested to have altered phospholipase activity and are known or suspected to have inflammatory effects in the intestinal tract including nonsteroidal anti-inflammatory drugs, and identified a compound that significantly increases intestinal phospholipid processing. Thus the multiple fluorescent reporter-based methodology facilitates the rapid analysis of digestive organ function in live zebrafish larvae.

Design and Synthesis of Novel Phenylpiperazine Derivatives as Potential Anticonvulsant Agents.

PubMed

Habib, Monica M W; Abdelfattah, Mohamed A O; Abadi, Ashraf H

2015-12-01

Eighteen new 5-benzylidene-3-(4-arylpiperazin-1-ylmethyl)-2-thioxo-imidazolidin-4-ones were designed as hybrid structures from previously reported anticonvulsant compounds, synthesized and tested for anticonvulsant activity. Initial anticonvulsant screening was performed using the strychnine (2 mg/kg IP) potent generalized-induced seizure and pentylenetetrazole (PTZ) (60 mg/kg IP) acute clonic-induced convulsion screens in mice. All the molecules were found to be effective in at least one seizure model, compounds 10, 13, 15, 17, and 18 were active against both types of seizures induced. Compound 13 turned out to be the most active candidate within the strychnine model, having an average survival time of 6 min close to that of the positive control phenytoin, while compound 8 showed 100% protection from the induced PTZ seizures, resembling the protection of the positive control phenobarbital. Initial SAR studies for anticonvulsant activity are discussed. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Design and Discovery of Functionally Selective Serotonin 2C (5-HT2C) Receptor Agonists.

PubMed

Cheng, Jianjun; McCorvy, John D; Giguere, Patrick M; Zhu, Hu; Kenakin, Terry; Roth, Bryan L; Kozikowski, Alan P

2016-11-10

On the basis of the structural similarity of our previous 5-HT 2C agonists with the melatonin receptor agonist tasimelteon and the putative biological cross-talk between serotonergic and melatonergic systems, a series of new (2,3-dihydro)benzofuran-based compounds were designed and synthesized. The compounds were evaluated for their selectivity toward 5-HT 2A , 5-HT 2B , and 5-HT 2C receptors in the calcium flux assay with the ultimate goal to generate selective 5-HT 2C agonists. Selected compounds were studied for their functional selectivity by comparing their transduction efficiency at the G protein signaling pathway versus β-arrestin recruitment. The most functionally selective compound (+)-7e produced weak β-arrestin recruitment and also demonstrated less receptor desensitization compared to serotonin in both calcium flux and phosphoinositide (PI) hydrolysis assays. We report for the first time that selective 5-HT 2C agonists possessing weak β-arrestin recruitment can produce distinct receptor desensitization properties.

Antituberculosis compounds from a deep-sea-derived fungus Aspergillus sp. SCSIO Ind09F01.

PubMed

Luo, Xiaowei; Zhou, Xuefeng; Lin, Xiuping; Qin, Xiaochu; Zhang, Tianyu; Wang, Junfeng; Tu, Zhengchao; Yang, Bin; Liao, Shengrong; Tian, Yongqi; Pang, Xiaoyan; Kaliyaperumal, Kumaravel; Li, Jian Lin; Tao, Huaming; Liu, Yonghong

2017-08-01

Eleven diketopiperazine and fumiquinazoline alkaloids (1-11) together with a tetracyclic triterpenoid helvolic acid (12) were obtained from the cultures of a deep-sea derived fungus Aspergillus sp. SCSIO Ind09F01. The structures of these compounds (1-12) were determined mainly by the extensive NMR, ESIMS spectra data and by comparison with previously described compounds. Besides, anti-tuberculosis, cytotoxic, antibacterial, COX-2 inhibitory and antiviral activities of these compounds were evaluated. Gliotoxin (3), 12,13-dihydroxy-fumitremorgin C (11) and helvolic acid (12) exhibited very strong anti-tuberculosis activity towards Mycobacterium tuberculosis with the prominent MIC 50 values of <0.03, 2.41 and 0.894 μM, respectively, which was here reported for the first time. Meanwhile gliotoxin also displayed significant selective cytotoxicities against K562, A549 and Huh-7 cell lines with the IC 50 values of 0.191, 0.015 and 95.4 μM, respectively.

Irradiated Benzene Ice Provides Clues to Meteoritic Organic Chemistry

NASA Technical Reports Server (NTRS)

Callahan, Michael Patrick; Gerakines, Perry Alexander; Martin, Mildred G.; Hudson, Reggie L.; Peeters, Zan

2013-01-01

Aromatic hydrocarbons account for a significant portion of the organic matter in carbonaceous chondrite meteorites, as a component of both the low molecular weight, solvent-extractable compounds and the insoluble organic macromolecular material. Previous work has suggested that the aromatic compounds in carbonaceous chondrites may have originated in the radiation-processed icy mantles of interstellar dust grains. Here we report new studies of the organic residue made from benzene irradiated at 19 K by 0.8 MeV protons. Polyphenyls with up to four rings were unambiguously identified in the residue by gas chromatography-mass spectrometry. Atmospheric pressure photoionization Fourier transform mass spectrometry was used to determine molecular composition, and accurate mass measurements suggested the presence of polyphenyls, partially hydrogenated polyphenyls, and other complex aromatic compounds. The profile of low molecular weight compounds in the residue compared well with extracts from the Murchison and Orgueil meteorites. These results are consistent with the possibility that solid phase radiation chemistry of benzene produced some of the complex aromatics found in meteorites.

Green coffee seed residue: A sustainable source of antioxidant compounds.

PubMed

Castro, A C C M; Oda, F B; Almeida-Cincotto, M G J; Davanço, M G; Chiari-Andréo, B G; Cicarelli, R M B; Peccinini, R G; Zocolo, G J; Ribeiro, P R V; Corrêa, M A; Isaac, V L B; Santos, A G

2018-04-25

Oil extraction from green coffee seeds generates residual mass that is discarded by agribusiness and has not been previously studied. Bioactive secondary metabolites in coffee include antioxidant phenolic compounds, such as chlorogenic acids. Coffee seeds also contain caffeine, a pharmaceutically important methylxanthine. Here, we report the chemical profile, antioxidant activity, and cytotoxicity of hydroethanolic extracts of green Coffea arabica L. seed residue. The extracts of the green seeds and the residue have similar chemical profiles, containing the phenolic compounds chlorogenic acid and caffeine. Five monoacyl and three diacyl esters of trans-cinnamic acids and quinic acid were identified by ultra-performance liquid chromatography/electrospray ionization-quadruple time of flight mass spectrometry. The residue extract showed antioxidant potential in DPPH, ABTS, and pyranine assays and low cytotoxicity. Thus, coffee oil residue has great potential for use as a raw material in dietary supplements, cosmetic and pharmaceutical products, or as a source of bioactive compounds. Copyright © 2017. Published by Elsevier Ltd.

Synthesis and improved photochromic properties of pyrazolones in the solid state by incorporation of halogen

NASA Astrophysics Data System (ADS)

Guo, Jixi; Yuan, Hui; Jia, Dianzeng; Guo, Mingxi; Li, Yinhua

2017-01-01

Four novel photochromic pyrazolones have been prepared by introducing halogen atoms as substituents on the benzene ring. All as-synthesized compounds exhibited excellent reversible photochromic performances in the solid state. Upon UV light irradiation, the as-synthesized compounds can change their structures from E-form to K-form with yellow coloration. Further processed by heating, they rapidly reverted to their initial states at 120 °С. Their photo-response and thermal bleaching kinetics were detailed investigated by UV absorption spectra. The results showed that the time constants were higher than that of our previously reported compounds at least one order of magnitude and the rate constants of the as-synthesized compounds were significantly influenced by the size and electronegativity of different halogen atoms. The fluorescence emission were modulated in a high degree via photoisomerization of pyrazolones, which might be due to the efficient energy transfer from E-form to K-form isomers for their partly overlaps between their E-form absorption spectra and K-form fluorescence spectra.

Phenolic content and antioxidant and antimutagenic activities in tomato peel, seeds, and byproducts.

PubMed

Valdez-Morales, Maribel; Espinosa-Alonso, Laura Gabriela; Espinoza-Torres, Libia Citlali; Delgado-Vargas, Francisco; Medina-Godoy, Sergio

2014-06-11

The phenolic content and antioxidant and antimutagenic activities from the peel and seeds of different tomato types (grape, cherry, bola and saladette type), and simulated tomato industrial byproducts, were studied. Methanolic extracts were used to quantify total phenolic content, groups of phenolic compounds, antioxidant activities, and the profile of phenolic compounds (by HPLC-DAD). Antimutagenic activity was determined by Salmonella typhimurium assay. The total phenolic content and antioxidant activity of tomato and tomato byproducts were comparable or superior to those previously reported for whole fruit and tomato pomace. Phenolic compounds with important biological activities, such as caffeic acid, ferulic acid, chlorogenic acids, quercetin-3-β-O-glycoside, and quercetin, were quantified. Differences in all phenolic determinations due to tomato type and part of the fruit analyzed were observed, peel from grape type showing the best results. Positive antimutagenic results were observed in all samples. All evaluated materials could be used as a source of potential nutraceutical compounds.

Profiling of alpha-dicarbonyl content of commercial honeys from different botanical origins: identification of 3,4-dideoxyglucoson-3-ene (3,4-DGE) and related compounds.

PubMed

Marceau, Eric; Yaylayan, Varoujan A

2009-11-25

The alpha-dicarbonyl contents of commercial honey samples from different botanical origins were analyzed as their quinoxaline derivatives using HPLC-DAD, HPLC-MS, HPLC-MS/MS, and HPLC-TOF-MS. A total of nine such compounds were detected, of which five were previously reported in honey (glucosone, 3-deoxyglucosone, glyoxal, methylglyoxal, and 2,3-butanedione) and three were reported only from sources other than honey [3-deoxypentulose, 1,4-dideoxyhexulose, and 3,4-dideoxyglucoson-3-ene (3,4-DGE)]. An unknown alpha-dicarbonyl compound was also tentatively identified as an oxidation product of 3,4-DGE and was termed 3,4-dideoxyglucosone-3,5-diene (3,4-DGD). Only glyoxal (0.3-1.3 mg/kg), methylglyoxal (0.8-33 mg/kg), and 2,3-butanedione (0-4.3 mg/kg) were quantified in all honey samples. Furthermore, analysis of the alpha-dicarbonyl profile of various honey samples indicated that certain alpha-dicarbonyl compounds are found in specific honey samples in much higher proportions relative to the average amounts. The free radical scavenging activity as measured by DPPH method has also indicated that the darker honey samples such as buckwheat, manuka, blueberry, and eucalyptus had higher antioxidant properties compared to lighter-colored samples.

Design and synthesis of L- and D-phenylalanine derived rhodanines with novel C5-arylidenes as inhibitors of HCV NS5B polymerase.

PubMed

Patel, Bhargav A; Krishnan, Ramalingam; Khadtare, Nikhil; Gurukumar, K R; Basu, Amartya; Arora, Payal; Bhatt, Aaditya; Patel, Maulik R; Dana, Dibyendu; Kumar, Sanjai; Kaushik-Basu, Neerja; Talele, Tanaji T

2013-06-01

Hepatitis C virus (HCV) NS5B polymerase is a key target for anti-HCV therapeutics development. Herein, we report the synthesis and in vitro evaluation of anti-NS5B polymerase activity of a molecular hybrid of our previously reported lead compounds 1 (IC50=7.7 μM) and 2 (IC50=10.6 μM) as represented by hybrid compound 27 (IC50=6.7 μM). We have explored the optimal substituents on the terminal phenyl ring of the 3-phenoxybenzylidene moiety in 27, by generating a set of six analogs. This resulted in the identification of compound 34 with an IC50 of 2.6 μM. To probe the role of stereochemistry towards the observed biological activity, we synthesized and evaluated the D-isomers 41 (IC50=19.3 μM) and 45 (IC50=5.4 μM) as enantiomers of the l-isomers 27 and 34, respectively. The binding site of compounds 32 and 34 was mapped to palm pocket-I (PP-I) of NS5B. The docking models of 34 and 45 within the PP-I of NS5B were investigated to envisage the molecular mechanism of inhibition. Copyright © 2013 Elsevier Ltd. All rights reserved.

Design and synthesis of L- and D-phenylalanine derived rhodanines with novel C5-arylidenes as inhibitors of HCV NS5B polymerase

PubMed Central

Patel, Bhargav; Krishnan, Ramalingam; Khadtare, Nikhil; Gurukumar, K. R.; Basu, Amartya; Arora, Payal; Bhatt, Aaditya; Patel, Maulik R.; Dana, Dibyendu; Kumar, Sanjai; Kaushik-Basu, Neerja; Talele, Tanaji T.

2013-01-01

Hepatitis C virus (HCV) NS5B polymerase is a key target for anti-HCV therapeutics development. Herein, we report the synthesis and in vitro evaluation of anti-NS5B polymerase activity of a molecular hybrid of our previously reported lead compounds 1 (IC50 = 7.7 µM) and 2 (IC50 = 10.6 µM) as represented by hybrid compound 27 (IC50 = 6.7 µM). We have explored the optimal substituents on the terminal phenyl ring of the 3-phenoxybenzylidene moiety in 27, by generating a set of six analogs. This resulted in the identification of compound 34 with an IC50 of 2.6 µM. To probe the role of stereochemistry towards the observed biological activity, we synthesized and evaluated the D-isomers 41 (IC50 = 19.3 µM) and 45 (IC50 = 5.4 µM) as enantiomers of the L-isomers 27 and 34, respectively. The binding site of compounds 32 and 34 was mapped to palm pocket-I (PP-I) of NS5B. The docking models of 34 and 45 within the PP-I of NS5B were investigated to envisage the molecular mechanism of inhibition. PMID:23598249

Solvent Extraction of Chemical Attribution Signature Compounds from Painted Wall Board: Final Report

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wahl, Jon H.; Colburn, Heather A.

2009-10-29

This report summarizes work that developed a robust solvent extraction procedure for recovery of chemical attribution signature (CAS) compound dimethyl methyl phosphonate (DMMP) (as well as diethyl methyl phosphonate (DEMP), diethyl methyl phosphonothioate (DEMPT), and diisopropyl methyl phosphonate (DIMP)) from painted wall board (PWB), which was selected previously as the exposed media by the chemical attribution scientific working group (CASWG). An accelerated solvent extraction approach was examined to determine the most effective method of extraction from PWB. Three different solvent systems were examined, which varied in solvent strength and polarity (i.e., 1:1 dichloromethane : acetone,100% methanol, and 1% isopropanol inmore » pentane) with a 1:1 methylene chloride : acetone mixture having the most robust and consistent extraction for four original target organophosphorus compounds. The optimum extraction solvent was determined based on the extraction efficiency of the target analytes from spiked painted wallboard as determined by gas chromatography x gas chromatography mass spectrometry (GCxGC-MS) analysis of the extract. An average extraction efficiency of approximately 60% was obtained for these four compounds. The extraction approach was further demonstrated by extracting and detecting the chemical impurities present in neat DMMP that was vapor-deposited onto painted wallboard tickets.« less

Dillapiole, isolated from Peperomia pellucida, shows gastroprotector activity against ethanol-induced gastric lesions in Wistar rats.

PubMed

Rojas-Martínez, Raúl; Arrieta, Jesús; Cruz-Antonio, Leticia; Arrieta-Baez, Daniel; Velázquez-Méndez, Antonio Magdiel; Sánchez-Mendoza, María Elena

2013-09-13

Peperomia pellucida is a plant used in traditional medicine to treat gastric ulcers. Although this gastroprotective activity was reported, the active compounds have not been identified. Therefore, the aim herein was to identify the most active compound in the gastroprotective activity of P. pellucida using an ethanol-induced gastric ulcer experimental rat model. A gastroprotective effect was observed when the hexane and dichloromethane extracts were tested, with the higher effect being obtained with the dichloromethane extract (82.3 ± 5.6%) at 100 mg/kg. Dillapiole was identified as the most active compound in this extract. Although there have been previous reports on dillapiole, this is the first on its gastroprotective activity. Rats treated with this compound at 3, 10, 30 and 100 mg/kg showed 23.1, 56.1, 73.2 and 85.5% gastroprotection, respectively. The effect elicited by dillapiole at 100 mg/kg was not attenuated by pretreatment with indomethacin (10 mg/kg, s.c.), a prostaglandin synthesis blocker, NG-nitro-l-arginine methyl ester (70 mg/kg, i.p.), a nitric oxide (NO) synthase inhibitor, or N-ethylmaleimide (10 mg/kg, s.c.), a blocker of sulfhydryl groups. This suggests that the gastroprotective mechanism of action of dillapiole does not involve prostaglandins, NO or sulfhydryl groups.

Methyl malondialdehyde is not suitable as an internal standard for malondialdehyde detection in urine after derivatisation with 2,4-dinitrophenylhydrazine.

PubMed

Korchazhkina, Olga; Yang, Ying

2004-07-05

A previously described method of measurement of malondialdehyde (MDA) in human urine after derivatisation with 2,4-dinitrophenylhydrazine (DNPH) was tested for a possibility of using methyl malondialdehyde (MeMDA) as an internal standard. Despite structural similarity, those compounds were found to produce different yields of derivatisation under the same conditions depending on urine matrix. We conclude, that MeMDA is not suitable as an internal standard for the measurement of MDA in urine under previously reported conditions when DNPH is used as a deriviatising agent.

Organic compounds in produced waters from coalbed natural gas wells in the Powder River Basin, Wyoming, USA

USGS Publications Warehouse

Orem, W.H.; Tatu, C.A.; Lerch, H.E.; Rice, C.A.; Bartos, T.T.; Bates, A.L.; Tewalt, S.; Corum, M.D.

2007-01-01

The organic composition of produced water samples from coalbed natural gas (CBNG) wells in the Powder River Basin, WY, sampled in 2001 and 2002 are reported as part of a larger study of the potential health and environmental effects of organic compounds derived from coal. The quality of CBNG produced waters is a potential environmental concern and disposal problem for CBNG producers, and no previous studies of organic compounds in CBNG produced water have been published. Organic compounds identified in the produced water samples included: phenols, biphenyls, N-, O-, and S-containing heterocyclic compounds, polycyclic aromatic hydrocarbons (PAHs), aromatic amines, various non-aromatic compounds, and phthalates. Many of the identified organic compounds (phenols, heterocyclic compounds, PAHs) are probably coal-derived. PAHs represented the group of organic compounds most commonly observed. Concentrations of total PAHs ranged up to 23 ??g/L. Concentrations of individual compounds ranged from about 18 to <0.01 ??g/L. Temporal variability of organic compound concentrations was documented, as two wells with relatively high organic compound contents in produced water in 2001 had much lower concentrations in 2002. In many areas, including the PRB, coal strata provide aquifers for drinking water wells. Organic compounds observed in produced water are also likely present in drinking water supplied from wells in the coal. Some of the organic compounds identified in the produced water samples are potentially toxic, but at the levels measured in these samples are unlikely to have acute health effects. The human health effects of low-level, chronic exposure to coal-derived organic compounds in drinking water are currently unknown. Continuing studies will evaluate possible toxic effects from low level, chronic exposure to coal-derived organic compounds in drinking water supplies.

New cytotoxic constituents from the Red Sea soft coral Nephthea sp.

PubMed

Hegazy, Mohamed-Elamir F; Gamal-Eldeen, Amira M; Mohamed, Tarik A; Alhammady, Montaser A; Hassanien, Abuzeid A; Shreadah, Mohamed A; Abdelgawad, Ibrahim I; Elkady, Eman M; Paré, Paul W

2016-06-01

Nephthea are soft coral species rich in sesquiterpenoids and steroids. An organic extract of Nephthea sp. resulted in the isolation of a new steroid (1), as well as several previously reported metabolites (2-9). Structures were elucidated by employing NMR and HR-EI-MS analyses. The total extract, fractions and purified compounds exhibited differential cytotoxicity against the breast cancer MCF-7 cell line.

Cyclometalated Iminophosphorane Gold(III) and Platinum(II) Complexes. A Highly Permeable Cationic Platinum(II) Compound with Promising Anticancer Properties

PubMed Central

2015-01-01

New organometallic gold(III) and platinum(II) complexes containing iminophosphorane ligands are described. Most of them are more cytotoxic to a number of human cancer cell lines than cisplatin. Cationic Pt(II) derivatives 4 and 5, which differ only in the anion, Hg2Cl62– or PF6– respectively, display almost identical IC50 values in the sub-micromolar range (25–335-fold more active than cisplatin on these cell lines). The gold compounds induced mainly caspase-independent cell death, as previously reported for related cycloaurated compounds containing IM ligands. Cycloplatinated compounds 3, 4, and 5 can also activate alternative caspase-independent mechanisms of death. However, at short incubation times cell death seems to be mainly caspase dependent, suggesting that the main mechanism of cell death for these compounds is apoptosis. Mercury-free compound 5 does not interact with plasmid (pBR322) DNA or with calf thymus DNA. Permeability studies of 5 by two different assays, in vitro Caco-2 monolayers and a rat perfusion model, have revealed a high permeability profile for this compound (comparable to that of metoprolol or caffeine) and an estimated oral fraction absorbed of 100%, which potentially makes it a good candidate for oral administration. PMID:26147404

Synthesis and Neuroprotective Action of Xyloketal Derivatives in Parkinson’s Disease Models

PubMed Central

Li, Shichang; Shen, Cunzhou; Guo, Wenyuan; Zhang, Xuefei; Liu, Shixin; Liang, Fengyin; Xu, Zhongliang; Pei, Zhong; Song, Huacan; Qiu, Liqin; Lin, Yongcheng; Pang, Jiyan

2013-01-01

Parkinson’s disease (PD) is the second most common neurodegenerative disease affecting people over age 55. Oxidative stress actively participates in the dopaminergic (DA) neuron degeneration of PD. Xyloketals are a series of natural compounds from marine mangrove fungus strain No. 2508 that have been reported to protect against neurotoxicity through their antioxidant properties. However, their protection versus 1-methyl-4-phenylpyridinium (MPP+)-induced neurotoxicity is only modest, and appropriate structural modifications are necessary to discover better candidates for treating PD. In this work, we designed and synthesized 39 novel xyloketal derivatives (1–39) in addition to the previously reported compound, xyloketal B. The neuroprotective activities of all 40 compounds were evaluated in vivo via respiratory burst assays and longevity-extending assays. During the zebrafish respiratory burst assay, compounds 1, 9, 23, 24, 36 and 39 strongly attenuated reactive oxygen species (ROS) generation at 50 μM. In the Caenorhabditis elegans longevity-extending assay, compounds 1, 8, 15, 16 and 36 significantly extended the survival rates (p < 0.005 vs. dimethyl sulfoxide (DMSO)). A total of 15 compounds were tested for the treatment of Parkinson’s disease using the MPP+-induced C. elegans model, and compounds 1 and 8 exhibited the highest activities (p < 0.005 vs. MPP+). In the MPP+-induced C57BL/6 mouse PD model, 40 mg/kg of 1 and 8 protected against MPP+-induced dopaminergic neurodegeneration and increased the number of DA neurons from 53% for the MPP+ group to 78% and 74%, respectively (p < 0.001 vs. MPP+ group). Thus, these derivatives are novel candidates for the treatment of PD. PMID:24351912

Design and Growth of Novel Compounds for Radiation Sensors: Multinary Chalcogenides

NASA Technical Reports Server (NTRS)

Singh, N. B.; Su, Ching-Hua; Nagaradona, Teja; Arnold, Brad; Choa, Fow-Sen

2016-01-01

Increasing threats of radiological weapons have revitalized the researches for low cost large volume ?-ray and neutron ray sensors In the past few years we have designed and grown ternary and quaternary lead and thallium chalcogenides and lead selenoiodides for detectors to meet these challenges. These materials are congruent, can be tailored to enhance the parameters required for radiation sensors. In addition, this class of compounds can be grown by Bridgman method which promises for large volume productions. We have single crystals of several compounds from the melt including Tl3AsSe3, Tl3AsSe3-xSx, TlGaSe2, AgGaGe3Se8, AgxLi1-xAgGaGe3Se8 and PbTlI5-x Sex compounds. Experimental studies indicate that these have very low absorption coefficient, low defect density and can be fabricated in any shape and sizes. These crystals do not require post growth annealing and do not show any second phase precipitates when processed for electrode bonding and other fabrication steps. In this paper we report purification, growth and fabrication of large Tl3AsSe3 (TAS) crystals. We observed that TAS crystals grown by using further purification of as supplied high purity source materials followed by directionally solidified charge showed higher resistivity than previously reported values. TAS also showed constant value as the function of voltage. A low thermal gradient and high purity source material were used to reduce thermal stresses in large crystals. By improving the purification of the as supplied source materials very high quality thallium, selenium and arsenic was achieved for preparing stoichiometric Tl3AsSe3 compound. Low gradient (<20K/cm) and slow growth rate (1-2 cm/day) produced crystals with reduced stress. Crystals did not show any micro cracking during fabrication of crystals grown with high purity and at low thermal gradient. Since thallium is a major component and very sensitive to surface oxidation, removal of surface and bulk oxides is very important. Intentional increase in the growth rate from 1cm/day to higher speed (>5cm/day) showed very different morphologies on the surface of the crystals. Electrical resistivity was one order of magnitude higher than previously reported value and it was observed to be constant as the function of frequency.

Nano-sized Mn3O4 and β-MnOOH from the decomposition of β-cyclodextrin-Mn: 2. The water-oxidizing activities.

PubMed

Najafpour, Mohammad Mahdi; Mostafalu, Ramin; Hołyńska, Małgorzata; Ebrahimi, Foad; Kaboudin, Babak

2015-11-01

Nano-sized Mn oxides contain Mn3O4, β-MnOOH and Mn2O3 have been prepared by a previously reported method using thermal decomposition of β-cyclodextrin-Mn complexes. In the next step, the water-oxidizing activities of these Mn oxides using cerium(IV) ammonium nitrate as a chemical oxidant are studied. The turnover frequencies for β-MnO(OH) and Mn3O4 are 0.24 and 0.01-0.17 (mmol O2/mol Mns), respectively. Subsequently, water-oxidizing activities of these compounds are compared to the other previously reported Mn oxides. Important factors affecting water oxidation by these Mn oxides are also discussed. Copyright © 2015 Elsevier B.V. All rights reserved.

Prediction of Multi-Target Networks of Neuroprotective Compounds with Entropy Indices and Synthesis, Assay, and Theoretical Study of New Asymmetric 1,2-Rasagiline Carbamates

PubMed Central

Romero Durán, Francisco J.; Alonso, Nerea; Caamaño, Olga; García-Mera, Xerardo; Yañez, Matilde; Prado-Prado, Francisco J.; González-Díaz, Humberto

2014-01-01

In a multi-target complex network, the links (Lij) represent the interactions between the drug (di) and the target (tj), characterized by different experimental measures (Ki, Km, IC50, etc.) obtained in pharmacological assays under diverse boundary conditions (cj). In this work, we handle Shannon entropy measures for developing a model encompassing a multi-target network of neuroprotective/neurotoxic compounds reported in the CHEMBL database. The model predicts correctly >8300 experimental outcomes with Accuracy, Specificity, and Sensitivity above 80%–90% on training and external validation series. Indeed, the model can calculate different outcomes for >30 experimental measures in >400 different experimental protocolsin relation with >150 molecular and cellular targets on 11 different organisms (including human). Hereafter, we reported by the first time the synthesis, characterization, and experimental assays of a new series of chiral 1,2-rasagiline carbamate derivatives not reported in previous works. The experimental tests included: (1) assay in absence of neurotoxic agents; (2) in the presence of glutamate; and (3) in the presence of H2O2. Lastly, we used the new Assessing Links with Moving Averages (ALMA)-entropy model to predict possible outcomes for the new compounds in a high number of pharmacological tests not carried out experimentally. PMID:25255029

A cytotoxic hydroperoxy sterol from the brown alga, Nizamuddinia zanardinii

PubMed Central

2013-01-01

Background The marine environment is a unique source of bioactive natural products, of which Nizamuddinia zanardinii is an important brown algae distributed in Oman Sea. Literature revealed that there is no report on phytochemistry and pharmacology of this valuable algae. Methods Bioguided fractionation of the methanolic extract of Nizamuddinia zanardinii, collected from Oman Sea, led to the isolation of a hydroperoxy sterol. Its structure was determined by analysis of the spectroscopic data as 24-hydroperoxy-24-vinyl cholesterol (HVC). In vitro cytotoxic activity of this compound was evaluated against HT29, MCF7, A549, HepG2 and MDBK cell lines. Results Although 24(R)-hydroproxy-24-vinylcholesterol has been previously reported from Sargassum and Padina species, it is the first report on the presence of this compound from N. zanardinii. This compound exhibited cytotoxicity in all cell lines (IC50, 3.62, 9.09, 17.96, 32.31 and 37.31 μg/mL respectively). HVC was also evaluated for apoptotic activity and demonstrated positive results in terminal deoxynucleotidyl transferase dUTP Nick End labeling (TUNEL) assay suggesting it a candidate for further apoptotic studies. Conclusions Nizamuddinia zanardinii, a remarkable brown algae of Oman Sea, is a good source of hydroproxy sterols with promising cytotoxic on various cell lines particularly human colon adenocarcinoma. PMID:23497504

Synthesis and evaluation of 1-amino-6-halo-β-carbolines as antimalarial and antiprion agents.

PubMed

Thompson, Mark J; Louth, Jennifer C; Little, Susan M; Jackson, Matthew P; Boursereau, Yohan; Chen, Beining; Coldham, Iain

2012-04-01

Malaria is one of the world's most devastating parasitic diseases, causing almost one million deaths each year. Growing resistance to classical antimalarial drugs, such as chloroquine, necessitates the discovery of new therapeutic agents for successful control of this global disease. Here, we report the synthesis of some 6-halo-β-carbolines as analogues of the potent antimalarial natural product, manzamine A, retaining its heteroaromatic core whilst providing compounds with much improved synthetic accessibility. Two compounds displayed superior activity to chloroquine itself against a resistant Plasmodium falciparum strain, identifying them as promising leads for future development. Furthermore, in line with previous reports of similarities in antimalarial and antiprion effects of aminoaryl-based antimalarial agents, the 1-amino-β-carboline libraries were also found to possess significant bioactivity against a prion-infected cell line. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Electronic and total energy properties of ternary and quaternary semiconductor compounds, alloys and superlattices

NASA Technical Reports Server (NTRS)

Lambrecht, Walter R. L.

1992-01-01

This proposal was mainly concerned with the theoretical study of semiconductor compounds, alloys, and superlattices of interest for photovoltaic applications. In the last year (1991) a study was devoted to metal/graphite bonding in relation to use of graphite fiber reinforcement of Cu for high thermal conductivity applications. The main research topics addressed during the full period of the grant are briefly described: studies of the In-Ga-As ternary system; band-offsets at common anion and InAs/GaSb/AlSb heterojunctions; alloy theory (cluster variation method); and Cu/graphite bonding. Most of the work was described more extensively in previous yearly reports and renewal applications and in publications. The last topic is described more fully in a separate report attached. A list of publications resulting directly from this grant or from other grants but related to this work and of conference presentations is given at the end.

Two-Dimensional Superconductivity Emerged at Monatomic Bi(2-) Square Net in Layered Y2O2Bi via Oxygen Incorporation.

PubMed

Sei, Ryosuke; Kitani, Suguru; Fukumura, Tomoteru; Kawaji, Hitoshi; Hasegawa, Tetsuya

2016-09-07

Discovery of layered superconductors such as cuprates and iron-based compounds has unveiled new science and compounds. In these superconductors, quasi-two-dimensional layers including transition metal cations play principal role in the superconductivity via carrier doping by means of aliovalent-ion substitution. Here, we report on a two-dimensional superconductivity at 2 K in ThCr2Si2-type layered oxide Y2O2Bi possessing conducting monatomic Bi(2-) square net, possibly associated with an exotic superconductivity. The superconductivity emerges only in excessively oxygen-incorporated Y2O2Bi with expanded inter-net distance, in stark contrast to nonsuperconducting pristine Y2O2Bi reported previously. This result suggests that the element incorporation into hidden interstitial site could be an alternative approach to conventional substitution and intercalation methods for search of novel superconductors.

Computational analysis of calculated physicochemical and ADMET properties of protein-protein interaction inhibitors

NASA Astrophysics Data System (ADS)

Lagorce, David; Douguet, Dominique; Miteva, Maria A.; Villoutreix, Bruno O.

2017-04-01

The modulation of PPIs by low molecular weight chemical compounds, particularly by orally bioavailable molecules, would be very valuable in numerous disease indications. However, it is known that PPI inhibitors (iPPIs) tend to have properties that are linked to poor Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET) and in some cases to poor clinical outcomes. Previously reported in silico analyses of iPPIs have essentially focused on physicochemical properties but several other ADMET parameters would be important to assess. In order to gain new insights into the ADMET properties of iPPIs, computations were carried out on eight datasets collected from several databases. These datasets involve compounds targeting enzymes, GPCRs, ion channels, nuclear receptors, allosteric modulators, oral marketed drugs, oral natural product-derived marketed drugs and iPPIs. Several trends are reported that should assist the design and optimization of future PPI inhibitors, either for drug discovery endeavors or for chemical biology projects.

Electronic and total energy properties of ternary and quaternary semiconductor compounds, alloys and superlattices

NASA Astrophysics Data System (ADS)

Lambrecht, Walter R. L.

1992-08-01

This proposal was mainly concerned with the theoretical study of semiconductor compounds, alloys, and superlattices of interest for photovoltaic applications. In the last year (1991) a study was devoted to metal/graphite bonding in relation to use of graphite fiber reinforcement of Cu for high thermal conductivity applications. The main research topics addressed during the full period of the grant are briefly described: studies of the In-Ga-As ternary system; band-offsets at common anion and InAs/GaSb/AlSb heterojunctions; alloy theory (cluster variation method); and Cu/graphite bonding. Most of the work was described more extensively in previous yearly reports and renewal applications and in publications. The last topic is described more fully in a separate report attached. A list of publications resulting directly from this grant or from other grants but related to this work and of conference presentations is given at the end.

Tamarixetin 3-O-β-d-Glucopyranoside from Azadirachta indica Leaves: Gastroprotective Role through Inhibition of Matrix Metalloproteinase-9 Activity in Mice.

PubMed

Yadav, Dharmendra K; Bharitkar, Yogesh P; Hazra, Abhijit; Pal, Uttam; Verma, Sugreev; Jana, Sayantan; Singh, Umesh P; Maiti, Nakul C; Mondal, Nirup B; Swarnakar, Snehasikta

2017-05-26

Neem (Azadirachta indica) is a well-known medicinal and insecticidal plant. Although previous studies have reported the antiulcer activity of neem leaf extract, the lead compound is still unidentified. The present study reports tamarixetin 3-O-β-d-glucopyranoside (1) from a methanol extract of neem leaves and its gastroprotective activity in an animal model. Compound 1 showed significant protection against indomethacin-induced gastric ulceration in mice in a dose-dependent manner. Moreover, ex vivo and circular dichroism studies confirmed that 1 inhibited the enzyme matrix metalloproteinase-9 (MMP-9) activity with an IC 50 value of ca. 50 μM. Molecular docking and dynamics showed the binding of 1 into the pocket of the active site of MMP-9, forming a coordination complex with the catalytic zinc, thus leading to inhibition of MMP-9 activity.

IR spectra and properties of solid acetone, an interstellar and cometary molecule

NASA Astrophysics Data System (ADS)

Hudson, Reggie L.; Gerakines, Perry A.; Ferrante, Robert F.

2018-03-01

Mid-infrared spectra of amorphous and crystalline acetone are presented along with measurements of the refractive index and density for both forms of the compound. Infrared band strengths are reported for the first time for amorphous and crystalline acetone, along with IR optical constants. Vapor pressures and a sublimation enthalpy for crystalline acetone also are reported. Positions of 13C-labeled acetone are measured. Band strengths are compared to gas-phase values and to the results of a density-functional calculation. A 73% error in previous work is identified and corrected.

Mini-Review: Antifouling Natural Products from Marine Microorganisms and Their Synthetic Analogs

PubMed Central

Wu, Ze-Hong; Wang, Yu; Wang, Chang-Yun; Xu, Ying

2017-01-01

Biofouling causes huge economic loss and generates serious ecological issues worldwide. Marine coatings incorporated with antifouling (AF) compounds are the most common practices to prevent biofouling. With a ban of organotins and an increase in the restrictions regarding the use of other AF alternatives, exploring effective and environmentally friendly AF compounds has become an urgent demand for marine coating industries. Marine microorganisms, which have the largest biodiversity, represent a rich and important source of bioactive compounds and have many medical and industrial applications. This review summarizes 89 natural products from marine microorganisms and 13 of their synthetic analogs with AF EC50 values ≤ 25 μg/mL from 1995 (the first report about marine microorganism-derived AF compounds) to April 2017. Some compounds with the EC50 values < 5 μg/mL and LC50/EC50 ratios > 50 are highlighted as potential AF compounds, and the preliminary analysis of structure-relationship (SAR) of these compounds is also discussed briefly. In the last part, current challenges and future research perspectives are proposed based on opinions from many previous reviews. To provide clear guidance for the readers, the AF compounds from microorganisms and their synthetic analogs in this review are categorized into ten types, including fatty acids, lactones, terpenes, steroids, benzenoids, phenyl ethers, polyketides, alkaloids, nucleosides and peptides. In addition to the major AF compounds which targets macro-foulers, this review also includes compounds with antibiofilm activity since micro-foulers also contribute significantly to the biofouling communities. PMID:28846626

Mini-Review: Antifouling Natural Products from Marine Microorganisms and Their Synthetic Analogs.

PubMed

Wang, Kai-Ling; Wu, Ze-Hong; Wang, Yu; Wang, Chang-Yun; Xu, Ying

2017-08-28

Biofouling causes huge economic loss and generates serious ecological issues worldwide. Marine coatings incorporated with antifouling (AF) compounds are the most common practices to prevent biofouling. With a ban of organotins and an increase in the restrictions regarding the use of other AF alternatives, exploring effective and environmentally friendly AF compounds has become an urgent demand for marine coating industries. Marine microorganisms, which have the largest biodiversity, represent a rich and important source of bioactive compounds and have many medical and industrial applications. This review summarizes 89 natural products from marine microorganisms and 13 of their synthetic analogs with AF EC 50 values ≤ 25 μg/mL from 1995 (the first report about marine microorganism-derived AF compounds) to April 2017. Some compounds with the EC 50 values < 5 μg/mL and LC 50 /EC 50 ratios > 50 are highlighted as potential AF compounds, and the preliminary analysis of structure-relationship (SAR) of these compounds is also discussed briefly. In the last part, current challenges and future research perspectives are proposed based on opinions from many previous reviews. To provide clear guidance for the readers, the AF compounds from microorganisms and their synthetic analogs in this review are categorized into ten types, including fatty acids, lactones, terpenes, steroids, benzenoids, phenyl ethers, polyketides, alkaloids, nucleosides and peptides. In addition to the major AF compounds which targets macro-foulers, this review also includes compounds with antibiofilm activity since micro-foulers also contribute significantly to the biofouling communities.

New Hydroxyproline Radiocarbon Dates from Sungir, Russia, Confirm Early Mid Upper Palaeolithic Burials in Eurasia

PubMed Central

Nalawade-Chavan, Shweta; McCullagh, James; Hedges, Robert

2014-01-01

Sungir (Russia) is a key Mid-Upper Palaeolithic site in Eurasia, containing several spectacular burials that disclose early evidence for complex burial rites in the form of a range of grave goods deposited along with the dead. Dating has been particularly challenging, with multiple radiocarbon dates ranging from 19,160±270 to 28,800±240 BP for burials that are believed to be closely similar in age. There are disparities in the radiocarbon dates of human bones, faunal remains and charcoal found on the floor of burials [1], [2], [3]. Our approach has been to develop compound-specific methods using High Performance Liquid Chromatography (HPLC) to separate single amino acids, such as hydroxyproline, and thereby avoid the known human contamination on the bones themselves. Previously, we applied this technique to obtain radiocarbon dates of ∼30,000 BP for Sungir 2, Sungir 3 and a mammoth bone from the occupation levels of the site [4]. The single amino acid radiocarbon dates were in good agreement with each other compared to all the dates previously reported, supporting their reliability. Here we report new hydroxyproline dates for two more human burials from the same site, Sungir 1 and Sungir 4. All five hydroxyproline dates reported are statistically indistinguishable and support an identical age for the group. The results suggest that compound-specific radiocarbon analysis should be considered seriously as the method of choice when precious archaeological remains are to be dated because they give a demonstrably contaminant-free radiocarbon age. The new ages are, together with the previously dated ‘Red Lady of Paviland’ human in the British Isles, the earliest for Mid Upper Palaeolithic burial behaviour in Eurasia, and point to the precocious appearance of this form of rite in Europe Russia. PMID:24416120

New hydroxyproline radiocarbon dates from Sungir, Russia, confirm early Mid Upper Palaeolithic burials in Eurasia.

PubMed

Nalawade-Chavan, Shweta; McCullagh, James; Hedges, Robert

2014-01-01

Sungir (Russia) is a key Mid-Upper Palaeolithic site in Eurasia, containing several spectacular burials that disclose early evidence for complex burial rites in the form of a range of grave goods deposited along with the dead. Dating has been particularly challenging, with multiple radiocarbon dates ranging from 19,160±270 to 28,800±240 BP for burials that are believed to be closely similar in age. There are disparities in the radiocarbon dates of human bones, faunal remains and charcoal found on the floor of burials. Our approach has been to develop compound-specific methods using High Performance Liquid Chromatography (HPLC) to separate single amino acids, such as hydroxyproline, and thereby avoid the known human contamination on the bones themselves. Previously, we applied this technique to obtain radiocarbon dates of ∼30,000 BP for Sungir 2, Sungir 3 and a mammoth bone from the occupation levels of the site. The single amino acid radiocarbon dates were in good agreement with each other compared to all the dates previously reported, supporting their reliability. Here we report new hydroxyproline dates for two more human burials from the same site, Sungir 1 and Sungir 4. All five hydroxyproline dates reported are statistically indistinguishable and support an identical age for the group. The results suggest that compound-specific radiocarbon analysis should be considered seriously as the method of choice when precious archaeological remains are to be dated because they give a demonstrably contaminant-free radiocarbon age. The new ages are, together with the previously dated 'Red Lady of Paviland' human in the British Isles, the earliest for Mid Upper Palaeolithic burial behaviour in Eurasia, and point to the precocious appearance of this form of rite in Europe Russia.

Mixing of sulfur between pyritic and organic phases during coal conversion processes: Annual final report, March 1, 1986-February 28, 1987

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dunkerton, L.V.; Nigam, A.; Mitra, S.

1987-05-01

In preparation for using /sup 33/S NMR for characterization of organic sulfur types in coal, previously prepared substituted dibenzothiophene model compounds were converted to their corresponding sulfones and their sulfur-33 nmr recorded. The sulfur-33 NMR spectra of dibenzothiophene-5,5-dioxide (2), 2-(p-methylphenylsulfonyl) dibenzothiophene-5,5-dioxide (4), and 2-(methylsulfonyl) dibenzothiophene-5,5-dioxide (6) are reported. The chemical shifts were in the +2 to -21 ppM range. The line widths ranged 70 to 200 Hz. The changes in /sup 13/C chemical shift experienced by aromatic carbons upon oxidizing the sulfide to its sulfone were also studied and the data used to identify which sulfone was formed in multiplemore » thioether-containing aromatics after partial oxidation. Continuing results on the use of the substituted dibenzothiophenes to monitor mixing of sulfur between pyritic and organic phases are also reported. Non-isothermal hydrodesulfurization of model organic sulfur compounds was carried out in a cola-like environment. The model sulfur compounds represented different types of carbon-sulfur bonds commonly encountered in coal. Similar experiments were carried out in the presence of troilite (iron sulfide) to investigate the possibility of sulfur migration from the organic compound to the iron sulfide. Next, iron pyrite was hydrodesulfurized in the presence of some organic molecules to see if sulfur could be incorporated into the organic molecules during the process. Results show that sulfur from organic compounds can be absorbed by troilite, and, similarly, sulfur from pyrite can form new carbon-sulfur bonds during hydrodesulfurization. Based on these observations, it is suggested that during coal conversion reactions it is possible to have intermigration of sulfur between the organic and the inorganic phases.« less

Design, Synthesis, and Evaluation of Dihydrobenzo[cd]indole-6-sulfonamide as TNF-α Inhibitors.

PubMed

Deng, Xiaobing; Zhang, Xiaoling; Tang, Bo; Liu, Hongbo; Shen, Qi; Liu, Ying; Lai, Luhua

2018-01-01

Tumor necrosis factor-α (TNF-α) plays a pivotal role in inflammatory response. Dysregulation of TNF can lead to a variety of disastrous pathological effects, including auto-inflammatory diseases. Antibodies that directly targeting TNF-α have been proven effective in suppressing symptoms of these disorders. Compared to protein drugs, small molecule drugs are normally orally available and less expensive. Till now, peptide and small molecule TNF-α inhibitors are still in the early stage of development, and much more efforts should be made. In a previously study, we reported a TNF-α inhibitor, EJMC-1 with modest activity. Here, we optimized this compound by shape screen and rational design. In the first round, we screened commercial compound library for EJMC-1 analogs based on shape similarity. Out of the 68 compounds tested, 20 compounds showed better binding affinity than EJMC-1 in the SPR competitive binding assay. These 20 compounds were tested in cell assay and the most potent compound was 2-oxo-N-phenyl-1,2-dihydrobenzo[ cd ]indole-6-sulfonamide ( S10 ) with an IC 50 of 14 μM, which was 2.2-fold stronger than EJMC-1 . Based on the docking analysis of S10 and EJMC-1 binding with TNF-α, in the second round, we designed S10 analogs, purchased seven of them, and synthesized seven new compounds. The best compound, 4e showed an IC 50 -value of 3 μM in cell assay, which was 14-fold stronger than EJMC-1 . 4e was among the most potent TNF-α organic compound inhibitors reported so far. Our study demonstrated that 2-oxo-N-phenyl-1,2-dihydrobenzo[ cd ]indole-6-sulfonamide analogs could be developed as potent TNF-α inhibitors. 4e can be further optimized for its activity and properties. Our study provides insights into designing small molecule inhibitors directly targeting TNF-α and for protein-protein interaction inhibitor design.

Design, Synthesis, and Evaluation of Dihydrobenzo[cd]indole-6-sulfonamide as TNF-alpha Inhibitors

NASA Astrophysics Data System (ADS)

Deng, Xiaobing; Zhang, Xiaoling; Tang, Bo; Liu, Hongbo; Shen, Qi; Liu, Ying; Lai, Luhua

2018-04-01

Tumor necrosis factor-α (TNF-α) plays a pivotal role in inflammatory response. Dysregulation of TNF can lead to a variety of disastrous pathological effects, including auto-inflammatory diseases. Antibodies that directly targeting TNF-α have been proven effective in suppressing symptoms of these disorders. Compared to protein drugs, small molecule drugs are normally orally available and less expensive. Till now, peptide and small molecule TNF-α inhibitors are still in the early stage of development, and much more efforts should be made. In a previously study, we reported a TNF-α inhibitor, EJMC-1 with modest activity. Here, we optimized this compound by shape screen and rational design. In the first round, we screened commercial compound library for EJMC-1 analogs based on shape similarity. Out of the 68 compounds tested, 20 compounds showed better binding affinity than EJMC-1 in the SPR competitive binding assay. These 20 compounds were tested in cell assay and the most potent compound was 2-oxo-N-phenyl-1,2-dihydrobenzo[cd]indole-6-sulfonamide (S10) with an IC50 of 14 M, which was 2.2-fold stronger than EJMC-1. Based on the docking analysis of S10 and EJMC-1 binding with TNF-α, in the second round, we designed S10 analogues, purchased 7 of them and synthesized 7 new compounds. The best compound, 4e showed an IC50 value of 3 M in cell assay, which was 14-fold stronger than EJMC-1. 4e was among the most potent TNF-α organic compound inhibitors reported so far. Our study demonstrated that 2-oxo-N-phenyl-1,2-dihydrobenzo[cd]indole-6-sulfonamide analogues could be developed as potent TNF-α inhibitors. 4e can be further optimized for its activity and properties. Our study provides insights into designing small molecule inhibitors directly targeting TNF-α and for protein-protein interaction inhibitor design.

Biosynthesis of polybrominated aromatic organic compounds by marine bacteria

PubMed Central

Agarwal, Vinayak; El Gamal, Abrahim A.; Yamanaka, Kazuya; Poth, Dennis; Kersten, Roland D.; Schorn, Michelle; Allen, Eric E.; Moore, Bradley S.

2014-01-01

Polybrominated diphenyl ethers (PBDEs) and polybrominated bipyrroles are natural products that bioaccumulate in the marine food chain. PBDEs have attracted widespread attention due to their persistence in the environment and potential toxicity to humans. However, the natural origins of PBDE biosynthesis are not known. Here we report marine bacteria as producers of PBDEs and establish a genetic and molecular foundation for their production that unifies paradigms for the elaboration of bromophenols and bromopyrroles abundant in marine biota. We provide biochemical evidence of marine brominase enzymes revealing decarboxylative-halogenation enzymology previously unknown among halogenating enzymes. Biosynthetic motifs discovered in our study were used to mine sequence databases to discover unrealized marine bacterial producers of organobromine compounds. PMID:24974229

Synthesis of a mixed-valent tin nitride and considerations of its possible crystal structures

DOE PAGES

Caskey, Christopher M.; Holder, Aaron; Shulda, Sarah; ...

2016-04-12

Recent advances in theoretical structure prediction methods and high-throughput computational techniques are revolutionizing experimental discovery of the thermodynamically stable inorganic materials. Metastable materials represent a new frontier for these studies, since even simple binary non-ground state compounds of common elements may be awaiting discovery. However, there are significant research challenges related to non-equilibrium thin film synthesis and crystal structure predictions, such as small strained crystals in the experimental samples and energy minimization based theoretical algorithms. Here, we report on experimental synthesis and characterization, as well as theoretical first-principles calculations of a previously unreported mixed-valent binary tin nitride. Thin film experimentsmore » indicate that this novel material is N-deficient SnN with tin in the mixed ii/iv valence state and a small low-symmetry unit cell. Theoretical calculations suggest that the most likely crystal structure has the space group 2 (SG2) related to the distorted delafossite (SG166), which is nearly 0.1 eV/atom above the ground state SnN polymorph. Furthermore, this observation is rationalized by the structural similarity of the SnN distorted delafossite to the chemically related Sn 3N 4 spinel compound, which provides a fresh scientific insight into the reasons for growth of polymorphs of metastable materials. In addition to reporting on the discovery of the simple binary SnN compound, this paper illustrates a possible way of combining a wide range of advanced characterization techniques with the first-principle property calculation methods, to elucidate the most likely crystal structure of the previously unreported metastable materials.« less

Synthesis of a mixed-valent tin nitride and considerations of its possible crystal structures

NASA Astrophysics Data System (ADS)

Caskey, Christopher M.; Holder, Aaron; Shulda, Sarah; Christensen, Steven T.; Diercks, David; Schwartz, Craig P.; Biagioni, David; Nordlund, Dennis; Kukliansky, Alon; Natan, Amir; Prendergast, David; Orvananos, Bernardo; Sun, Wenhao; Zhang, Xiuwen; Ceder, Gerbrand; Ginley, David S.; Tumas, William; Perkins, John D.; Stevanovic, Vladan; Pylypenko, Svitlana; Lany, Stephan; Richards, Ryan M.; Zakutayev, Andriy

2016-04-01

Recent advances in theoretical structure prediction methods and high-throughput computational techniques are revolutionizing experimental discovery of the thermodynamically stable inorganic materials. Metastable materials represent a new frontier for these studies, since even simple binary non-ground state compounds of common elements may be awaiting discovery. However, there are significant research challenges related to non-equilibrium thin film synthesis and crystal structure predictions, such as small strained crystals in the experimental samples and energy minimization based theoretical algorithms. Here, we report on experimental synthesis and characterization, as well as theoretical first-principles calculations of a previously unreported mixed-valent binary tin nitride. Thin film experiments indicate that this novel material is N-deficient SnN with tin in the mixed ii/iv valence state and a small low-symmetry unit cell. Theoretical calculations suggest that the most likely crystal structure has the space group 2 (SG2) related to the distorted delafossite (SG166), which is nearly 0.1 eV/atom above the ground state SnN polymorph. This observation is rationalized by the structural similarity of the SnN distorted delafossite to the chemically related Sn3N4 spinel compound, which provides a fresh scientific insight into the reasons for growth of polymorphs of metastable materials. In addition to reporting on the discovery of the simple binary SnN compound, this paper illustrates a possible way of combining a wide range of advanced characterization techniques with the first-principle property calculation methods, to elucidate the most likely crystal structure of the previously unreported metastable materials.

Synthesis of a mixed-valent tin nitride and considerations of its possible crystal structures.

PubMed

Caskey, Christopher M; Holder, Aaron; Shulda, Sarah; Christensen, Steven T; Diercks, David; Schwartz, Craig P; Biagioni, David; Nordlund, Dennis; Kukliansky, Alon; Natan, Amir; Prendergast, David; Orvananos, Bernardo; Sun, Wenhao; Zhang, Xiuwen; Ceder, Gerbrand; Ginley, David S; Tumas, William; Perkins, John D; Stevanovic, Vladan; Pylypenko, Svitlana; Lany, Stephan; Richards, Ryan M; Zakutayev, Andriy

2016-04-14

Recent advances in theoretical structure prediction methods and high-throughput computational techniques are revolutionizing experimental discovery of the thermodynamically stable inorganic materials. Metastable materials represent a new frontier for these studies, since even simple binary non-ground state compounds of common elements may be awaiting discovery. However, there are significant research challenges related to non-equilibrium thin film synthesis and crystal structure predictions, such as small strained crystals in the experimental samples and energy minimization based theoretical algorithms. Here, we report on experimental synthesis and characterization, as well as theoretical first-principles calculations of a previously unreported mixed-valent binary tin nitride. Thin film experiments indicate that this novel material is N-deficient SnN with tin in the mixed ii/iv valence state and a small low-symmetry unit cell. Theoretical calculations suggest that the most likely crystal structure has the space group 2 (SG2) related to the distorted delafossite (SG166), which is nearly 0.1 eV/atom above the ground state SnN polymorph. This observation is rationalized by the structural similarity of the SnN distorted delafossite to the chemically related Sn3N4 spinel compound, which provides a fresh scientific insight into the reasons for growth of polymorphs of metastable materials. In addition to reporting on the discovery of the simple binary SnN compound, this paper illustrates a possible way of combining a wide range of advanced characterization techniques with the first-principle property calculation methods, to elucidate the most likely crystal structure of the previously unreported metastable materials.

The relationship between reinforcing effects and in vitro effects of D1 agonists in monkeys.

PubMed

Weed, M R; Paul, I A; Dwoskin, L P; Moore, S E; Woolverton, W L

1997-10-01

The reinforcing effects of many psychomotor stimulants have been related to increased dopaminergic neurotransmission and stimulation of central nervous system (CNS) dopamine (DA) receptors. Consistent with this notion, some drugs that directly stimulate DA receptors have been found to function as positive reinforcers. The present experiments were designed to examine why some, but not all, D1 receptor agonists can function as reinforcers in rhesus monkeys by comparing behavioral and CNS in vitro measures of potency and efficacy. Seven rhesus monkeys were allowed to self-administer cocaine under a progressive-ratio (PR) schedule until stable responding was established. Various doses of D1 agonists, previously reported to function as positive reinforcers, were then made available for self-administration. Stimulation of cAMP production in rhesus and rat striatal tissue was studied for these compounds and for D1 agonists previously reported not to function as positive reinforcers in monkeys (SKF 38393, SKF 77434 and S(-)-6-BrAPB). Blockade of DA uptake in rat striata was also examined for all compounds. SKF 81297, SKF 82958 and R(+)-6-BrAPB maintained responding under the PR schedule and did not differ significantly in efficacy as positive reinforcers; SKF 81297 was less potent than the other two agonists. SKF 81297, SKF 82958 and R(+)-6-BrAPB stimulated higher levels of cAMP production in rhesus striata than did SKF 38393, SKF 77434 and S(-)-6-BrAPB. In contrast, all compounds blocked DA uptake. Thus, reinforcing efficacy among D1 agonists increases with efficacy in stimulating D1 receptors.

Synthesis of a mixed-valent tin nitride and considerations of its possible crystal structures

DOE Office of Scientific and Technical Information (OSTI.GOV)

Caskey, Christopher M.; Colorado School of Mines, Golden, Colorado 80401; Larix Chemical Science, Golden, Colorado 80401

2016-04-14

Recent advances in theoretical structure prediction methods and high-throughput computational techniques are revolutionizing experimental discovery of the thermodynamically stable inorganic materials. Metastable materials represent a new frontier for these studies, since even simple binary non-ground state compounds of common elements may be awaiting discovery. However, there are significant research challenges related to non-equilibrium thin film synthesis and crystal structure predictions, such as small strained crystals in the experimental samples and energy minimization based theoretical algorithms. Here, we report on experimental synthesis and characterization, as well as theoretical first-principles calculations of a previously unreported mixed-valent binary tin nitride. Thin film experimentsmore » indicate that this novel material is N-deficient SnN with tin in the mixed II/IV valence state and a small low-symmetry unit cell. Theoretical calculations suggest that the most likely crystal structure has the space group 2 (SG2) related to the distorted delafossite (SG166), which is nearly 0.1 eV/atom above the ground state SnN polymorph. This observation is rationalized by the structural similarity of the SnN distorted delafossite to the chemically related Sn{sub 3}N{sub 4} spinel compound, which provides a fresh scientific insight into the reasons for growth of polymorphs of metastable materials. In addition to reporting on the discovery of the simple binary SnN compound, this paper illustrates a possible way of combining a wide range of advanced characterization techniques with the first-principle property calculation methods, to elucidate the most likely crystal structure of the previously unreported metastable materials.« less

Cyanobacteria as a Source for Novel Anti-Leukemic Compounds.

PubMed

Humisto, Anu; Herfindal, Lars; Jokela, Jouni; Karkman, Antti; Bjørnstad, Ronja; Choudhury, Romi R; Sivonen, Kaarina

2016-01-01

Cyanobacteria are an inspiring source of bioactive secondary metabolites. These bioactive agents are a diverse group of compounds which are varying in their bioactive targets, the mechanisms of action, and chemical structures. Cyanobacteria from various environments, especially marine benthic cyanobacteria, are found to be rich sources for the search for novel bioactive compounds. Several compounds with anticancer activities have been discovered from cyanobacteria and some of these have succeeded to enter the clinical trials. Varying anticancer agents are needed to overcome increasing challenges in cancer treatments. Different search methods are used to reveal anticancer compounds from natural products, but cell based methods are the most common. Cyanobacterial bioactive compounds as agents against acute myeloid leukemia are not well studied. Here we examined our new results combined with previous studies of anti-leukemic compounds from cyanobacteria with emphasis to reveal common features in strains producing such activity. We report that cyanobacteria harbor specific anti-leukemic compounds since several studied strains induced apoptosis against AML cells but were inactive against non-malignant cells like hepatocytes. We noted that particularly benthic strains from the Baltic Sea, such as Anabaena sp., were especially potential AML apoptosis inducers. Taken together, this review and re-analysis of data demonstrates the power of maintaining large culture collections for the search for novel bioactivities, and also how anti-AML activity in cyanobacteria can be revealed by relatively simple and low-cost assays.

Synthesis and Evaluation of the Tumor Cell Growth Inhibitory Potential of New Putative HSP90 Inhibitors.

PubMed

Bizarro, Ana; Sousa, Diana; Lima, Raquel T; Musso, Loana; Cincinelli, Raffaella; Zuco, Vantina; De Cesare, Michelandrea; Dallavalle, Sabrina; Vasconcelos, M Helena

2018-02-13

Heat shock protein 90 (HSP90) is a well-known target for cancer therapy. In a previous work, some of us have reported a series of 3-aryl-naphtho[2,3- d ]isoxazole-4,9-diones as inhibitors of HSP90. In the present work, various compounds with new chromenopyridinone and thiochromenopyridinone scaffolds were synthesized as potential HSP90 inhibitors. Their binding affinity to HSP90 was studied in vitro. Selected compounds ( 5 and 8 ) were further studied in various tumor cell lines regarding their potential to cause cell growth inhibition, alter the cell cycle profile, inhibit proliferation, and induce apoptosis. Their effect on HSP90 client protein levels was also confirmed in two cell lines. Finally, the antitumor activity of compound 8 was studied in A431 squamous cell carcinoma xenografts in nude mice. Our results indicated that treatment with compounds 5 and 8 decreased the proliferation of tumor cell lines and compound 8 induced apoptosis. In addition, these two compounds were able to downregulate selected proteins known as "clients" of HSP90. Finally, treatment of xenografted mice with compound 5 resulted in a considerable dose-dependent inhibition of tumor growth. Our results show that two new compounds with a chromenopyridinone and thiochromenopyridinone scaffold are promising putative HSP90 inhibitors causing tumor cell growth inhibition.

Fast detection and characterization of organic and inorganic gunshot residues on the hands of suspects by CMV-GC-MS and LIBS.

PubMed

Tarifa, Anamary; Almirall, José R

2015-05-01

A rapid method for the characterization of both organic and inorganic components of gunshot residues (GSR) is proposed as an alternative tool to facilitate the identification of a suspected shooter. In this study, two fast screening methods were developed and optimized for the detection of organic compounds and inorganic components indicative of GSR presence on the hands of shooters and non-shooters. The proposed methods consist of headspace extraction of volatile organic compounds using a capillary microextraction of volatiles (CMV) device previously reported as a high-efficiency sampler followed by detection by GC-MS. This novel sampling technique has the potential to yield fast results (<2min sampling) and high sensitivity capable of detecting 3ng of diphenylamine (DPA) and 8ng of nitroglycerine (NG). Direct analysis of the headspace of over 50 swabs collected from the hands of suspected shooters (and non-shooters) provides information regarding VOCs present on their hands. In addition, a fast laser induced breakdown spectroscopy (LIBS) screening method for the detection of the inorganic components indicative of the presence of GSR (Sb, Pb and Ba) is described. The sampling method for the inorganics consists of liquid extraction of the target elements from the same cotton swabs (previously analyzed for VOCs) and an additional 30 swab samples followed by spiking 1μL of the extract solution onto a Teflon disk and then analyzed by LIBS. Advantages of LIBS include fast analysis (~12s per sample) and high selectivity and sensitivity, with expected LODs 0.1-18ng for each of the target elements after sampling. The analytical performance of the LIBS method is also compared to previously reported methods (inductively coupled plasma-optical emission spectroscopy). The combination of fast CMV sampling, unambiguous organic compound identification with GC-MS and fast LIBS analysis provides the basis for a new comprehensive screening method for GSR. Copyright © 2015 Forensic Science Society. Published by Elsevier Ireland Ltd. All rights reserved.

Inability to induce tympanic squamous metaplasia using organochlorine compounds in vitamin A-deficient red-eared sliders (Trachemys scripta elegans).

PubMed

Kroenlein, Karl R; Sleeman, Jonathan M; Holladay, Steven D; Joyner, Priscilla H; Brown, Justin D; Griffin, Mark; Saunders, Geoffrey; Smith, Stephen A

2008-07-01

Previously, we reported that wild eastern box turtles (Terrapene carolina carolina) with aural abscesses contained higher body burdens of organochlorine (OC) compounds than those without the lesion. This lesion in captive chelonians is associated with turtles that are fed diets deficient in vitamin A. To examine the pathophysiology of this lesion and evaluate the relationship between OC burdens and vitamin A metabolism, we maintained red-eared sliders (Trachemys scripta elegans) under different conditions of OC exposure and dietary vitamin A concentrations from August 2005 to February 2006. Dietary vitamin A concentration (0 or 5 international units/g in the diet) and OC exposure (no OC compound or the mixture of 2 mg/kg chlordane, 0.25 mg/kg aroclor, and 1 mg/kg lindane) did not affect histologic score based on degree of squamous metaplasia of the tympanic epithelium or levels of plasma or liver vitamin A among the study groups. The results of this study suggest that 6 mo of exposure to the selected OC compounds, or similar duration of reduced dietary vitamin A concentrations do not influence the formation of squamous metaplasia and aural abscesses in red-eared sliders. Further studies are required to determine whether the duration of the experiment was insufficient, the OC compounds selected were inappropriate, the dosing was incorrect, and whether there are other unknown mechanisms causing the reported association between OC exposure and aural abscesses seen in eastern box turtles.

Optimization of Aryl Amides that Extend Survival in Prion-Infected Mice.

PubMed

Giles, Kurt; Berry, David B; Condello, Carlo; Dugger, Brittany N; Li, Zhe; Oehler, Abby; Bhardwaj, Sumita; Elepano, Manuel; Guan, Shenheng; Silber, B Michael; Olson, Steven H; Prusiner, Stanley B

2016-09-01

Developing therapeutics for neurodegenerative diseases (NDs) prevalent in the aging population remains a daunting challenge. With the growing understanding that many NDs progress by conformational self-templating of specific proteins, the prototypical prion diseases offer a platform for ND drug discovery. We evaluated high-throughput screening hits with the aryl amide scaffold and explored the structure-activity relationships around three series differing in their N-aryl core: benzoxazole, benzothiazole, and cyano. Potent anti-prion compounds were advanced to pharmacokinetic studies, and the resulting brain-penetrant leads from each series, together with a related N-aryl piperazine lead, were escalated to long-term dosing and efficacy studies. Compounds from each of the four series doubled the survival of mice infected with a mouse-passaged prion strain. Treatment with aryl amides altered prion strain properties, as evidenced by the distinct patterns of neuropathological deposition of prion protein and associated astrocytic gliosis in the brain; however, none of the aryl amide compounds resulted in drug-resistant prion strains, in contrast to previous studies on compounds with the 2-aminothiazole (2-AMT) scaffold. As seen with 2-AMTs and other effective anti-prion compounds reported to date, the novel aryl amides reported here were ineffective in prolonging the survival of transgenic mice infected with human prions. Most encouraging is our discovery that aryl amides show that the development of drug resistance is not an inevitable consequence of efficacious anti-prion therapeutics. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

Optimization of Aryl Amides that Extend Survival in Prion-Infected Mice

PubMed Central

Giles, Kurt; Berry, David B.; Condello, Carlo; Dugger, Brittany N.; Li, Zhe; Oehler, Abby; Bhardwaj, Sumita; Elepano, Manuel; Guan, Shenheng; Silber, B. Michael; Olson, Steven H.

2016-01-01

Developing therapeutics for neurodegenerative diseases (NDs) prevalent in the aging population remains a daunting challenge. With the growing understanding that many NDs progress by conformational self-templating of specific proteins, the prototypical prion diseases offer a platform for ND drug discovery. We evaluated high-throughput screening hits with the aryl amide scaffold and explored the structure–activity relationships around three series differing in their N-aryl core: benzoxazole, benzothiazole, and cyano. Potent anti-prion compounds were advanced to pharmacokinetic studies, and the resulting brain-penetrant leads from each series, together with a related N-aryl piperazine lead, were escalated to long-term dosing and efficacy studies. Compounds from each of the four series doubled the survival of mice infected with a mouse-passaged prion strain. Treatment with aryl amides altered prion strain properties, as evidenced by the distinct patterns of neuropathological deposition of prion protein and associated astrocytic gliosis in the brain; however, none of the aryl amide compounds resulted in drug-resistant prion strains, in contrast to previous studies on compounds with the 2-aminothiazole (2-AMT) scaffold. As seen with 2-AMTs and other effective anti-prion compounds reported to date, the novel aryl amides reported here were ineffective in prolonging the survival of transgenic mice infected with human prions. Most encouraging is our discovery that aryl amides show that the development of drug resistance is not an inevitable consequence of efficacious anti-prion therapeutics. PMID:27317802

Studies of long chain lipids in insects by high temperature gas chromatography and high temperature gas chromatography-mass spectrometry.

PubMed

Sutton, Paul A; Wilde, Michael J; Martin, Stephen J; Cvačka, Josef; Vrkoslav, Vladimír; Rowland, Steven J

2013-07-05

The organic compounds occurring naturally on the cuticles (surfaces) of insects are important for insect communication, help to act as protective water barriers and are useful in chemical taxonomy. Typically the cuticular lipids are only studied by gas chromatography-mass spectrometry (GC-MS) of hexane or pentane extracts, so the normal limitations of GC-MS makes it perhaps unsurprising that compounds with more than about 35 carbon atoms have only rarely been reported. Here we show by high temperature (HT) GC and HTGC-MS of extracts of eleven species of insects from nine genera, that longer chain compounds are actually common. Wax esters and triacylglycerides are virtually ubiquitous in such extracts, but long chain (>C35) hydrocarbons also sometimes occur. Whilst the latter have occasionally been reported previously from mass spectrometry studies, the use of the HTGC combination with MS allowed even some isobaric isomers to be separated and thus more complete lipid distributions to be monitored. Since the physical properties of cuticular compounds depend on this composition of the mixtures, such differences may influence the water loss rates of the insects, amongst other effects. In addition, the high molecular weight compound profiles may allow species to be more easily differentiated, one from another. It would be interesting to apply these methods to examination of the cuticular lipids of insects on a more routine basis, ideally in combination with MALDI-TOF-MS and imaging methods. Copyright © 2013 Elsevier B.V. All rights reserved.

Chemical composition and antioxidant capacity of açaí (Euterpe oleracea) genotypes and commercial pulps.

PubMed

Carvalho, Ana Vânia; Ferreira Ferreira da Silveira, Tayse; Mattietto, Rafaella de Andrade; Padilha de Oliveira, Maria do Socorro; Godoy, Helena Teixeira

2017-03-01

Açaí has been reported to contain many bioactive compounds, including phenolic compounds such as anthocyanins. This study aimed to determine the chemical composition and antioxidant potential of pulps of three different açaí genotypes from the Active Germplasm Bank of Embrapa Eastern Amazon and three commercial açaí pulps from Belém, state of Pará, Brazil. Anthocyanin 3-rutinoside was the major anthocyanin present in freeze-dried açaí pulp samples. The commercial sample C showed the greatest amounts of cyanidin 3-glucoside and cyanidin 3-rutinoside (18 942 and 34 397 µg g -1 respectively). The content of phenolic compounds varied significantly among the commercial and genotype samples, and vanillic acid was found in the highest concentration in the samples studied. All açaí samples showed high DPPH, ORAC and TEAC values, confirming the exceptionally high radical-scavenging capacity of açaí pulp previously reported by other researchers. The commercial samples showed higher antioxidant capacity and higher levels of anthocyanins and non-anthocyanic compounds than those of the genotype samples. Among the genotypes studied, L4P16 stood out for its higher contents of fibre and bioactive compounds and higher antioxidant capacity, indicating that this genotype has great potential for use in plant breeding programs that should be further explored. © 2016 Society of Chemical Industry. © 2016 Society of Chemical Industry.

Matrix Optical Absorption in UV-MALDI MS

NASA Astrophysics Data System (ADS)

Robinson, Kenneth N.; Steven, Rory T.; Bunch, Josephine

2018-03-01

In ultraviolet matrix-assisted laser desorption/ionization mass spectrometry (UV-MALDI MS) matrix compound optical absorption governs the uptake of laser energy, which in turn has a strong influence on experimental results. Despite this, quantitative absorption measurements are lacking for most matrix compounds. Furthermore, despite the use of UV-MALDI MS to detect a vast range of compounds, investigations into the effects of laser energy have been primarily restricted to single classes of analytes. We report the absolute solid state absorption spectra of the matrix compounds α-cyano-4-hydroxycinnamic acid (CHCA), para-nitroaniline (PNA), 2-mercaptobenzothiazole (MBT), 2,5-dihydroxybenzoic acid (2,5-DHB), and 2,4,6-trihydroxyacetophenone (THAP). The desorption/ionization characteristics of these matrix compounds with respect to laser fluence was investigated using mixed systems of matrix with either angiotensin II, PC(34:1) lipid standard, or haloperidol, acting as representatives for typical classes of analyte encountered in UV-MALDI MS. The first absolute solid phase spectra for PNA, MBT, and THAP are reported; additionally, inconsistencies between previously published spectra for CHCA are resolved. In light of these findings, suggestions are made for experimental optimization with regards to matrix and laser wavelength selection. The relationship between matrix optical cross-section and wavelength-dependant threshold fluence, fluence of maximum ion yield, and R, a new descriptor for the change in ion intensity with fluence, are described. A matrix cross-section of 1.3 × 10-17 cm-2 was identified as a potential minimum for desorption/ionization of analytes.

Matrix Optical Absorption in UV-MALDI MS.

PubMed

Robinson, Kenneth N; Steven, Rory T; Bunch, Josephine

2018-03-01

In ultraviolet matrix-assisted laser desorption/ionization mass spectrometry (UV-MALDI MS) matrix compound optical absorption governs the uptake of laser energy, which in turn has a strong influence on experimental results. Despite this, quantitative absorption measurements are lacking for most matrix compounds. Furthermore, despite the use of UV-MALDI MS to detect a vast range of compounds, investigations into the effects of laser energy have been primarily restricted to single classes of analytes. We report the absolute solid state absorption spectra of the matrix compounds α-cyano-4-hydroxycinnamic acid (CHCA), para-nitroaniline (PNA), 2-mercaptobenzothiazole (MBT), 2,5-dihydroxybenzoic acid (2,5-DHB), and 2,4,6-trihydroxyacetophenone (THAP). The desorption/ionization characteristics of these matrix compounds with respect to laser fluence was investigated using mixed systems of matrix with either angiotensin II, PC(34:1) lipid standard, or haloperidol, acting as representatives for typical classes of analyte encountered in UV-MALDI MS. The first absolute solid phase spectra for PNA, MBT, and THAP are reported; additionally, inconsistencies between previously published spectra for CHCA are resolved. In light of these findings, suggestions are made for experimental optimization with regards to matrix and laser wavelength selection. The relationship between matrix optical cross-section and wavelength-dependant threshold fluence, fluence of maximum ion yield, and R, a new descriptor for the change in ion intensity with fluence, are described. A matrix cross-section of 1.3 × 10 -17 cm -2 was identified as a potential minimum for desorption/ionization of analytes. Graphical Abstract ᅟ.

Evaluation of the Effects of Lime-bassanite-charcoal Amendment on the Immobilization of Cadmium in Contaminated Soil.

PubMed

Huang, Shunhong; Yang, Yi; Li, Qian; Su, Zhen; Yuan, Cuiyu; Ouyang, Kun

2017-03-01

The effects of amendments, such as lime, bassanite, sodium phosphate, steel slag and charcoal, and their compounds on the immobilization of cadmium (Cd) are investigated. The lime-bassanite-charcoal compound shows the best remediation performance compared to other agents in conducted experiments. The optimum condition for lime-bassanite-charcoal application in contaminated soil is lime-bassanite-charcoal with a mass ratio of 1:1/3:2/3, a dose of 2% of the soil weight, and a liquid-to-solid ratio of 35%-40%; additionally, the agents should be added before water addition. The highest Cd removal rate was 58.94% (±1.19%) with a ∆pH of 0.23, which is much higher than the rates reported in previous studies. The compound amendment was used in a field experiment, demonstrating a Cd removal efficiency of 48.78% (±4.23), further confirming its effectiveness.

Synthesis and structure-activity relationship studies of novel [6,6,5] tricyclic oxazolidinone derivatives as potential antibacterial agents.

PubMed

Xue, Tao; Ding, Shi; Guo, Bin; Chu, Wenjing; Wang, Hui; Yang, Yushe

2015-01-01

In our previous Letter, we reported the discovery of a novel benzoxazinyl-oxazolidinone antibacterial candidate 2. In order to identify a potential backup compound, extensive modifications on the B/C ring and C3 side chain were undertaken. A series of novel [6,6,5] tricyclic analogues were synthesized and their in vitro antibacterial activities were tested against a panel of susceptible and resistant Gram-positive pathogens. Among of them, benzothiazinyl-oxazolidinones with acetamide or thioamide as C3 side chains exhibited moderate to good antibacterial activity, such as compounds 54, 58, 59 and 63. In vitro liver microsomal stability was further evaluated and the results manifested that compounds 54 and 58 were both metabolically stable in rat and human liver microsomes. Additionally, insights gained from this investigation should provide directions for the further research of new oxazolidinone antibiotics. Copyright © 2015 Elsevier Ltd. All rights reserved.

Scent gland constituents of the Middle American burrowing python, Loxocemus bicolor (Serpentes: Loxocemidae).

PubMed

Schulze, Thies; Weldon, Paul J; Schulz, Stefan

2017-07-14

Analysis by gas chromatography/mass spectrometry of the scent gland secretions of male and female Middle American burrowing pythons (Loxocemus bicolor) revealed the presence of over 300 components including cholesterol, fatty acids, glyceryl monoalkyl ethers, and alcohols. The fatty acids, over 100 of which were identified, constitute most of the compounds in the secretions and show the greatest structural diversity. They include saturated and unsaturated, unbranched and mono-, di-, and trimethyl-branched compounds ranging in carbon-chain length from 13 to 24. The glyceryl monoethers possess saturated or unsaturated, straight or methyl-branched alkyl chains ranging in carbon-chain length from 13 to 24. Alcohols, which have not previously been reported from the scent glands, possess straight, chiefly saturated carbon chains ranging in length from 13 to 24. Sex or individual differences in secretion composition were not observed. Compounds in the scent gland secretions of L. bicolor may deter offending arthropods, such as ants.

In situ imaging and proteome profiling indicate andrographolide is a highly promiscuous compound

NASA Astrophysics Data System (ADS)

Li, Lin; Wijaya, Hadhi; Samanta, Sanjay; Lam, Yulin; Yao, Shao Q.

2015-06-01

Natural products represent an enormous source of pharmacologically useful compounds, and are often used as the starting point in modern drug discovery. Many biologically interesting natural products are however not being pursued as potential drug candidates, partly due to a lack of well-defined mechanism-of-action. Traditional in vitro methods for target identification of natural products based on affinity protein enrichment from crude cellular lysates cannot faithfully recapitulate protein-drug interactions in living cells. Reported herein are dual-purpose probes inspired by the natural product andrographolide, capable of both reaction-based, real-time bioimaging and in situ proteome profiling/target identification in live mammalian cells. Our results confirm that andrographolide is a highly promiscuous compound and engaged in covalent interactions with numerous previously unknown cellular targets in cell type-specific manner. We caution its potential therapeutic effects should be further investigated in detail.

Volatile composition of coffee berries at different stages of ripeness and their possible attraction to the coffee berry borer Hypothenemus hampei (Coleoptera: Curculionidae).

PubMed

Ortiz, Américo; Ortiz, Aristófeles; Vega, Fernando E; Posada, Francisco

2004-09-22

The analysis of volatile emissions of coffee berries in different physiological states of ripeness was performed using dynamic headspace and gas chromatography/mass spectrometry analysis for Coffea arabica, var. Colombia. The composition of the volatiles emitted by coffee berries is dominated by very high levels of alcohols, mainly ethanol, in all stages of ripeness in comparison with other compounds. Overripe coffee berries have high volatile emissions and show a composition dominated mainly by esters followed by alcohols, ketones, and aldehydes. The lowest level compounds were monoterpenes. 2-Methyl furan was detected in various ripening stages; this compound has not been previously reported as a coffee berry volatile. The presence of ethanol and other alcohols in the volatile composition might explain the effectiveness of using traps with mixed alcohols for detection and capture of coffee berry borers.

Distributed Drug Discovery, Part 3: Using D3 Methodology to Synthesize Analogs of an Anti-Melanoma Compound

PubMed Central

2008-01-01

For the successful implementation of Distributed Drug Discovery (D3) (outlined in the accompanying Perspective), students, in the course of their educational laboratories, must be able to reproducibly make new, high quality, molecules with potential for biological activity. This article reports the successful achievement of this goal. Using previously rehearsed alkylating agents, students in a second semester organic chemistry laboratory performed a solid-phase combinatorial chemistry experiment in which they made 38 new analogs of the most potent member of a class of antimelanoma compounds. All compounds were made in duplicate, purified by silica gel chromatography, and characterized by NMR and LC/MS. As a continuing part of the Distributed Drug Discovery program, a virtual D3 catalog based on this work was then enumerated and is made freely available to the global scientific community. PMID:19105723

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

PubMed

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

2014-12-04

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

Microbial use of gas phase organic compounds in the surface ocean

NASA Astrophysics Data System (ADS)

Arrieta, Jesus M.; Duarte, Carlos M.; Monserrat Sala, M.; Dachs, Jordi

2016-04-01

Large diffusive air-sea fluxes of gas-phase organic carbon (GOC) have been identified, indicating that the ocean may be a major sink for these compounds. However, little is known about the fate of these GOC compounds entering the surface ocean. We report efficient use of atmospheric GOC by marine prokaryotes at different locations in the NE Subtropical Atlantic Ocean, the Arctic Ocean and the Mediterranean Sea. Our results indicate that between 2 to 27% of the prokaryotic carbon demand was supported by GOC. Between 1 and 94% of the GOC entering the ocean was consumed by prokaryotes depending on locations, thus sustaining a disequilibrium, which drives the transfer of GOC from the atmosphere into the ocean. The magnitude of this, previously unnoticed, microbial GOC utilization stresses the need for incorporating the oceanic uptake of gaseous organic carbon into the global carbon budget.

Sterols from Sargassum oligocystum, a brown algae from the Persian Gulf, and their bioactivity.

PubMed

Permeh, Parisa; Saeidnia, Soodabeh; Mashinchian-Moradi, Ali; Gohari, Ahmad R

2012-01-01

Sargassum oligocystum (Heterokontophyta) is one of the most abundant algae distributed in the Persian Gulf. In this study, the cytotoxic effects of this algae on brine shrimp larvae were evaluated and the main sterols of the algae identified. Separation and purification of the compounds was carried out using silica gel column chromatography and HPLC to obtain eight pure compounds, 1-8. Structural elucidation of the constituents was based on the data obtained from (1)H-NMR, (13)C-NMR, HSQC, HMBC, DEPT and EI-MS. The compounds separated from S. oligocystum were identified as 22-dehydrocholesterol (1), cholesterol (2), fucosterol (3), 29-hydroperoxystigmasta-5,24(28)-dien-3β-ol (4), 24-hydroperoxy-24-vinylcholesterol (5), a mixture of 24(S)-hydroxy-24-vinylcholesterol (6) and 24(R)-hydroxy-24-vinylcholesterol (7), and ostreasterol (8) based on their spectral data and from comparison with those previously reported in the literature.

Effect of selenium deficiency on the thermoelectric properties of n -type In 4 Se 3 - x compounds

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhu, G. H.; Lan, Y. C.; Wang, H.

2011-03-01

Thermoelectric properties of dense bulk polycrystalline In 4 Se 3 - x ( x = 0, 0.25, 0.5, 0.65, and 0.8) compounds are investigated. A peak dimensionless thermoelectric figure of merit ( ZT ) of about 1 is achieved for x = 0.65 and 0.8. The peak ZT is about 50% higher than the previously reported highest value for polycrystalline In 4 Se 3 - x compounds. Our In 4 Se 3 - x samples were prepared by ball milling and hot pressing. We show that it is possible to effectively control the electrical conductivity and thermal conductivity by controllingmore » selenium (Se) deficiency x . The ZT enhancement is mainly attributed to the thermal conductivity reduction due to the increased phonon scattering by Se deficiency, defects, and nanoscale inclusions in the ball-milled and hot-pressed dense bulk In 4 Se 3 - x samples.« less

Effect of selenium deficiency on the thermoelectric properties of n-type In 4Se 3-x compounds

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhu, G H; Lan, Y C; Wang, H

2011-03-04

Thermoelectric properties of dense bulk polycrystalline In 4Se 3-x (x = 0, 0.25, 0.5, 0.65, and 0.8) compounds are investigated. A peak dimensionless thermoelectric figure of merit (ZT) of about 1 is achieved for x = 0.65 and 0.8. The peak ZT is about 50% higher than the previously reported highest value for polycrystalline In 4Se 3-x} compounds. Our In 4Se 3-x samples were prepared by ball milling and hot pressing. We show that it is possible to effectively control the electrical conductivity and thermal conductivity by controlling selenium (Se) deficiency x. The ZT enhancement is mainly attributed to themore » thermal conductivity reduction due to the increased phonon scattering by Se deficiency, defects, and nanoscale inclusions in the ball-milled and hot-pressed dense bulk In 4Se 3-x samples.« less

Hydrophobization potential of organic compounds deriving from olive oil production waste water

NASA Astrophysics Data System (ADS)

Egerer, Sina E.; Bandow, Nicole; Marschner, Bernd; Schaumann, Gabriele E.

2010-05-01

Olive oil production waste water (OPWW) is rich in dissolved organic carbon and nutrients (e.g. potassium). In order to use it as organic fertilizer, small-scale and family run olive oil production farms in Israel and Palestine often discharge it directly onto agricultural land without any previous treatment. One unwanted side effect that can be observed is the development of soil water repellency (SWR) which is probably induced by amphiphilic substances. Previous studies on the composition of OPWW have shown that it contains oil components such as phenols, fats and large-molecular organic compounds (e.g. Gonzalezvila et al., 1995), some of which have been reported to induce water repellency on soil mineral surfaces (e.g. Ma'shum et al., 1988; Leelamanie and Karube, 2007). For prioritization of compounds the individual hydrophobization potential of 16 common OPWW components was systematically evaluated using the sessile drop and the Wilhelmy plate method. Acid-washed sand was taken as model soil mineral material. In a batch experiment OPWW samples from Israel and Palestine were applied to sand and two different soils in order to investigate their hydrophobization potential under different temperature and humidity conditions. To facilitate the identification of the chemicals responsible for inducing SWR, a fractionation procedure was applied to fraction the OPWW samples using solvents of different polarity. The prioritized compounds were analyzed by GC-MS. First results of this identification will be presented as well.

Report for Full-Scale Mulch Wall Treatment of Chlorinated Hydrocarbon-Impacted Groundwater

DTIC Science & Technology

2004-04-13

7.1 Direction of Groundwater Flow Through the Test Area Static water level measurements were taken every quarter after the installation of the...volatile organic compounds, alternate electron acceptors/byproducts and water quality parameters. Potentiometric surface maps showed the groundwater ... groundwater and surface water restrictions 10 Established clear zone (3000 ft by 3000 ft) Building 301 CEA Previously installed soil boring MW-19I 19

Effect of lipophilicity modulation on inhibition of human rhinovirus capsid binders.

PubMed

Morley, Andrew; Tomkinson, Nicholas; Cook, Andrew; MacDonald, Catherine; Weaver, Richard; King, Sarah; Jenkinson, Lesley; Unitt, John; McCrae, Christopher; Phillips, Tim

2011-10-15

To try and generate broad spectrum human rhinovirus VP1 inhibitors with more attractive physicochemical, DMPK and safety profiles, we explored the current SAR of known VP1 compounds. This lead to the identification of specific structural regions where reduction in polarity can be achieved, so guiding chemistry to analogues with significantly superior profiles to previously reported inhibitors. Copyright © 2011 Elsevier Ltd. All rights reserved.

Electrostatic Safety with Explosion Suppressant Foams.

DTIC Science & Technology

1983-03-01

the foam, and (2) sorption of alkylphenol type substances, present as oxidation inhibitors in the fuel, by the foam. It had been previously reported... alkylphenol type substances. The use of antistatic ingredients in the reticulated polyurethane foam was suggested as a means of minimizing static...foam with JP-4 are: o Removal of diethylhexyl phthalate from the foam. o Sorption of alkylphenol type compounds by the foam. Tne latter of these two

Development and application of a sensitive, phenotypic, high-throughput image-based assay to identify compound activity against Trypanosoma cruzi amastigotes

PubMed Central

Sykes, Melissa L.; Avery, Vicky M.

2015-01-01

We have developed a high content 384-well, image-based assay to estimate the effect of compound treatment on Trypanosoma cruzi amastigotes in 3T3 fibroblasts. In the same well, the effect of compound activity on host cells can also be determined, as an initial indicator of cytotoxicity. This assay has been used to identify active compounds from an in-house library of compounds with either known biological activity or that are FDA approved, and separately, from the Medicines for Malaria Venture Malaria Box collection. Active compounds were screened against T. cruzi trypomastigotes, utilising an assay developed with the viability dye resazurin. Twelve compounds with reconfirmed solid sample activity, with IC50 values of less than 10 μM and selectivity indices to T. cruzi amastigotes over 3T3 host cells of between >22 and 319 times were identified from these libraries. As 3T3 cells are contact inhibited, with limited proliferation in the assay, selective compounds of interest were profiled in a separate assay to estimate the viability of compound treated, replicating HEK293 cells. Selective compounds that were not previously reported in the literature were further profiled by extending the incubation time against amastigote infected 3T3 cells to determine if there were residual amastigotes post-treatment, important for the consideration of the exposure time required for further biological characterisation. The assay development process and the suitability of identified compounds as hit molecules for Chagas disease research are discussed. PMID:27120069

Development and application of a sensitive, phenotypic, high-throughput image-based assay to identify compound activity against Trypanosoma cruzi amastigotes.

PubMed

Sykes, Melissa L; Avery, Vicky M

2015-12-01

We have developed a high content 384-well, image-based assay to estimate the effect of compound treatment on Trypanosoma cruzi amastigotes in 3T3 fibroblasts. In the same well, the effect of compound activity on host cells can also be determined, as an initial indicator of cytotoxicity. This assay has been used to identify active compounds from an in-house library of compounds with either known biological activity or that are FDA approved, and separately, from the Medicines for Malaria Venture Malaria Box collection. Active compounds were screened against T. cruzi trypomastigotes, utilising an assay developed with the viability dye resazurin. Twelve compounds with reconfirmed solid sample activity, with IC50 values of less than 10 μM and selectivity indices to T. cruzi amastigotes over 3T3 host cells of between >22 and 319 times were identified from these libraries. As 3T3 cells are contact inhibited, with limited proliferation in the assay, selective compounds of interest were profiled in a separate assay to estimate the viability of compound treated, replicating HEK293 cells. Selective compounds that were not previously reported in the literature were further profiled by extending the incubation time against amastigote infected 3T3 cells to determine if there were residual amastigotes post-treatment, important for the consideration of the exposure time required for further biological characterisation. The assay development process and the suitability of identified compounds as hit molecules for Chagas disease research are discussed. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

Pityriazepin and other potent AhR ligands isolated from Malassezia furfur yeast

PubMed Central

Mexia, Nikitia; Gaitanis, George; Velegraki, Aristea; Soshilov, Anatoly; Denison, Michael S.; Magiatis, Prokopios

2015-01-01

Malassezia furfur yeast strains isolated from diseased human skin preferentially biosynthesize indole alkaloids which can be detected in human skin and are highly potent activators of the aryl hydrocarbon receptor (AhR) and AhR-dependent gene expression. Chemical analysis of an EtOAc extract of a M. furfur strain obtained from diseased human skin and grown on L-tryptophan agar revealed several known AhR active tryptophan metabolites along with a previously unidentified compound, pityriazepin. While its structure resembled that of the known alkaloid pityriacitrin, the comprised pyridine ring had been transformed into an azepinone. The indoloazepinone scaffold of pityriazepin is extremely rare in nature and has only been reported once previously. Pityriazepin, like the other isolated compounds, was found to be a potent activator of the AhR-dependent reporter gene assays in recombinant cell lines derived from four different species, although significant species differences in relative potency was observed. The ability of pityriazepin to competitively bind to the AhR and directly stimulate AhR DNA binding classified it as a new naturally-occurring potent AhR agonist. Malassezia furfur produces an expanded collection of extremely potent naturally occurring AhR agonists, which produce their biological effects in a species-specific manner.1 PMID:25721496

In vivo occupancy of dopamine D2 receptors by antipsychotic drugs and novel compounds in the mouse striatum and olfactory tubercles.

PubMed

Assié, Marie-Bernadette; Dominguez, Hélène; Consul-Denjean, Nathalie; Newman-Tancredi, Adrian

2006-09-01

Interaction with dopamine D2-like receptors plays a major role in the therapeutic effects of antipsychotic drugs. We examined in vivo dopamine D2 receptor occupancy of various established and potential antipsychotics in mouse striatum and olfactory tubercles 1 h after administration of the compound, using [3H]nemonapride as a ligand. All the compounds reduced in vivo binding of [3H]nemonapride in the striatum. When administered systemically, conventional antipsychotics, D2 antagonists, nemonapride (ID50: 0.034 mg/kg), eticlopride (0.047), haloperidol (0.11) and raclopride (0.11) potently inhibited [3H]nemonapride binding. The 'atypical' antipsychotics, risperidone (0.18), ziprasidone (0.38), aripiprazole (1.6), olanzapine (0.99), and clozapine (11.1) were less potent for occupying D2-like receptors. New compounds, displaying marked agonism at 5-HT1A receptors in addition to D2 receptor affinity, exhibited varying D2 receptor occupancy: bifeprunox (0.25), SLV313 (0.78), SSR181507 (1.6) and sarizotan (6.7). ID50 values for inhibition of [3H]nemonapride binding in the striatum correlated with those in the olfactory tubercles (r=0.95, P<0.0001). These values also correlated with previously-reported in vitro affinity of the compounds at rat D2 receptors (r=0.85, P=0.0001) and with inhibition of apomorphine-induced climbing in mice (r=0.79 P=0.0005). In contrast, there was no significant correlation between ID50 values herein and previously-reported ED50 values for catalepsy in mice. These data indicate that: (1) there is no difference in D2 receptor occupancy in limbic versus striatal regions between most classical and atypical or potential antipsychotics; and (2) high occupancy of D2 receptors can be dissociated from catalepsy, if the drugs also activate 5-HT1A receptors. Taken together, these data support the strategy of simultaneously targeting D2 receptor blockade and 5-HT1A receptor activation for new antipsychotics.

Building blocks for automated elucidation of metabolites: natural product-likeness for candidate ranking.

PubMed

Jayaseelan, Kalai Vanii; Steinbeck, Christoph

2014-07-05

In metabolomics experiments, spectral fingerprints of metabolites with no known structural identity are detected routinely. Computer-assisted structure elucidation (CASE) has been used to determine the structural identities of unknown compounds. It is generally accepted that a single 1D NMR spectrum or mass spectrum is usually not sufficient to establish the identity of a hitherto unknown compound. When a suite of spectra from 1D and 2D NMR experiments supplemented with a molecular formula are available, the successful elucidation of the chemical structure for candidates with up to 30 heavy atoms has been reported previously by one of the authors. In high-throughput metabolomics, usually 1D NMR or mass spectrometry experiments alone are conducted for rapid analysis of samples. This method subsequently requires that the spectral patterns are analyzed automatically to quickly identify known and unknown structures. In this study, we investigated whether additional existing knowledge, such as the fact that the unknown compound is a natural product, can be used to improve the ranking of the correct structure in the result list after the structure elucidation process. To identify unknowns using as little spectroscopic information as possible, we implemented an evolutionary algorithm-based CASE mechanism to elucidate candidates in a fully automated fashion, with input of the molecular formula and 13C NMR spectrum of the isolated compound. We also tested how filters like natural product-likeness, a measure that calculates the similarity of the compounds to known natural product space, might enhance the performance and quality of the structure elucidation. The evolutionary algorithm is implemented within the SENECA package for CASE reported previously, and is available for free download under artistic license at http://sourceforge.net/projects/seneca/. The natural product-likeness calculator is incorporated as a plugin within SENECA and is available as a GUI client and command-line executable. Significant improvements in candidate ranking were demonstrated for 41 small test molecules when the CASE system was supplemented by a natural product-likeness filter. In spectroscopically underdetermined structure elucidation problems, natural product-likeness can contribute to a better ranking of the correct structure in the results list.

Rotational Spectroscopy of Two Tellurol Compounds : Ethyl and Vinyl-Tellurol

NASA Astrophysics Data System (ADS)

Motiyenko, R.; Margulès, L.; Goubet, M.; Møllendal, H.; Guillemin, J. C.

2009-06-01

Among the compounds containing a chalcogen, the tellurols (R-TeH) have been poorly investigated previously. Only H_2Te was studied in rotational spectroscopy. This fact can be explained by high toxicity and high chemical reactivity of these compounds. However quite recently, a new method allowing easily obtention of pure samples has been reported. Thanks to this approach, very high acidity of these tellurols in gas phase has been measured and photoelectron spectra have been recorded. It should be noted that, even if simple derivatives are known since a long time, no microwave spectrum of these compounds has been recorded previously. The determination of their rotational constants is however a determining step to have a quite complete knowledge of such systems and to be able to perform comparisons of their physicochemical properties with those of the corresponding thiols and selenols which have been more extensively studied. The rotational spectra of vinyl and ethyl-tellurol have been recorded in the frequency range up to 210 GHz. For both compounds gauche forms have been assigned due to rather distinguishable patterns of a-type transitions. The assignments were confirmed by comparison with the results of ab initio calculations. For ethyl-tellurol the rotational transitions were observed as doublets. The splittings are probably caused by tunneling effect between two equivalent configurations (gauche^+, gauche^-). The assignment and analysis of the rotational spectra of both molecules is in progress. The latest results will be reported. I. N. Kozin, P. Jensen, O. Polanz, S. Klee, L. Poteau, and J. Demaison, J. Mol. Spectrosc., 180 402-413 (1996) J. C. Guillemin, A. Bouayard, D. Vijaykumar, D. Chem. Commun., 1163-1164 (2000) J. C. Guillemin, El. H. Riague, J. F. Gal, P. C. Marris, O. Mo., M. Yanez, Chem. Eur. J. 11, 2145-2153 (2005) B. Khater, J. C. Guillemin, G. Bajor, T. Veszprémi, P. C. Marris, O. Mo., M. Yanez, Inorg. Chem. 112, 3053-3060 (2008) A. Baroni, Atti Accad. Naz. Lincei, Cl. Sci. Fis., Mat. Nat., Rend. 27, 238-242 (1938)

Novel biological properties of Oenothera paradoxa defatted seed extracts: effects on metallopeptidase activity.

PubMed

Kiss, Anna K; Derwińska, Małgorzata; Dawidowska, Anna; Naruszewicz, Marek

2008-09-10

In this study, for the first time, we used the in vitro metallopeptidase model for the identification of a potential novel activity of defatted evening primrose seed extracts. Prepared extracts of different polarity (aqueous, 60% ethanolic, isopropanolic, and 30% isopropanolic) at concentrations of 1.5-100 microg/mL exhibited a significant and dose dependent inhibition of three tested enzymes. The 50% inhibition of enzymes activity showed that aminopeptidase N (APN) was the enzyme affected to the greatest extent with IC50 at the level of 2.8 microg/mL and 2.9 microg/mL for aqueous and 30% isopropanolic extracts, respectively. The activity of neutral endopeptidase (NEP) was quite strongly inhibited by the extracts as well. The HPLC-DAD analysis and bioguided fractionation led to the identification of four active compounds: (-)-epicatechin gallate, proanthocyanidin B3, oenothein B, and penta-O-galloyl-beta-D-glucose (PGG). Oenothein B has been shown previously to inhibit metallopeptidases. The three other compounds are known to inhibit angiotensin-converting enzyme (ACE), but they have not been previously reported to inhibit the NEP and APN activity. PGG and procyanidins with different degrees of polymerization, as the dominating compounds in O. paradoxa seeds, seemed to play a role in the crude extract activity.

Testosterone metabolism revisited: discovery of new metabolites.

PubMed

Pozo, Oscar J; Marcos, Josep; Ventura, Rosa; Fabregat, Andreu; Segura, Jordi

2010-10-01

The metabolism of testosterone is revisited. Four previously unreported metabolites were detected in urine after hydrolysis with KOH using a liquid chromatography-tandem mass spectrometry method and precursor ion scan mode. The metabolites were characterized by a product ion scan obtained with accurate mass measurements. Androsta-4,6-dien-3,17-dione, androsta-1,4-dien-3,17-dione, 17-hydroxy-androsta-4,6-dien-3-one and 15-androsten-3,17-dione were proposed as feasible structures for these metabolites on the basis of the mass spectrometry data. The proposed structures were confirmed by analysis of synthetic reference compounds. Only 15-androsten-3,17-dione could not be confirmed, owing to the lack of a commercially available standard. That all four compounds are testosterone metabolites was confirmed by the qualitative analysis of several urine samples collected before and after administration of testosterone undecanoate. The metabolite androsta-1,4-dien-3,17-dione has a structure analogous to that of the exogenous anabolic steroid boldenone. Specific transitions for boldenone and its metabolite 17β-hydroxy-5β-androst-1-en-3-one were also monitored. Both compounds were also detected after KOH treatment, suggesting that this metabolic pathway is involved in the endogenous detection of boldenone previously reported by several authors.

Differentiation between decomposed remains of human origin and bigger mammals.

PubMed

Rosier, E; Loix, S; Develter, W; Van de Voorde, W; Cuypers, E; Tytgat, J

2017-08-01

This study is a follow-up study in the search for a human specific marker in the decomposition where the VOC-profile of decomposing human, pig, lamb and roe remains were analyzed using a thermal desorber combined with a gas chromatograph coupled to a mass spectrometer in a laboratory environment during 6 months. The combination of 8 previously identified human and pig specific compounds (ethyl propionate, propyl propionate, propyl butyrate, ethyl pentanoate, 3-methylthio-1-propanol, methyl(methylthio)ethyl disulfide, diethyl disulfide and pyridine) was also seen in these analyzed mammals. However, combined with 5 additional compounds (hexane, heptane, octane, N-(3-methylbutyl)- and N-(2-methylpropyl)acetamide) human remains could be separated from pig, lamb and roe remains. Based on a higher number of remains analyzed, as compared with the pilot study, it was no longer possible to rely on the 5 previously proposed esters to separate pig from human remains. From this follow-up study reported, it was found that pyridine is an interesting compound specific to human remains. Such a human specific marker can help in the training of cadaver dogs or in the development of devices to search for human remains. However, further investigations have to verify these results. Copyright © 2017 Elsevier Ltd and Faculty of Forensic and Legal Medicine. All rights reserved.

Groundwater geochemical and selected volatile organic compound data, Operable Unit 1, Naval Undersea Warfare Center, Division Keyport, Washington, June and October 2012

USGS Publications Warehouse

Huffman, R.L.

2013-01-01

Previous investigations indicate that concentrations of chlorinated volatile organic compounds are substantial in groundwater beneath the 9-acre former landfill at Operable Unit 1, Naval Undersea Warfare Center, Division Keyport, Washington. The U.S. Geological Survey has continued to monitor groundwater geochemistry to ensure that conditions remain favorable for contaminant biodegradation as specified in the Record of Decision for the site. This report presents groundwater geochemical and selected chlorinated volatile organic compound data collected at Operable Unit 1 by the U.S. Geological Survey during June and October 2012, in support of long-term monitoring for natural attenuation. Groundwater samples were collected from 13 wells and 9 piezometers, as well as from 10 shallow groundwater passive-diffusion sampling sites in the nearby marsh. Samples from all wells and piezometers were analyzed for oxidation-reduction (redox) sensitive constituents and dissolved gases. Samples from all piezometers also were analyzed for chlorinated volatile organic compounds, as were all samples from the passive-diffusion sampling sites. In 2012, concentrations of redox-sensitive constituents measured at all wells and piezometers were consistent with those measured in previous years, with dissolved oxygen concentrations all at 0.4 milligram per liter or less; little to no detectable nitrate; abundant dissolved manganese, iron, and methane; and commonly detected sulfide. In the upper aquifer of the northern plantation in 2012, chlorinated volatile organic compound (CVOC) concentrations at all piezometers were similar to those measured in previous years, and concentrations of the reductive dechlorination byproducts ethane and ethene were slightly higher or the same as concentrations measured in 2011. In the upper aquifer of the southern plantation, CVOC concentrations measured in piezometers during 2012 continued to be extremely variable as in previous years, and often very high, and reductive dechlorination byproducts were detected in two of the four wells and in all piezometers. Beneath the marsh adjacent to the southern plantation, chloroethene concentrations measured in 2012 continued to vary spatially and temporarily, and also were very high. Additionally, CVOC concentrations measured in samplers deployed in access tubes were about two to four times less than those measured in the two samplers buried nearby, beneath the marsh stream. Total CVOC concentration, at what has been historically the most contaminated passive-diffusion sampler site (S-4), continued an increasing trend. For the intermediate aquifer in 2012, concentrations of reductive dechlorination byproducts ethane and ethene were consistent with those measured in previous years.

A method for screening active components from Chinese herbs by cell membrane chromatography-offline-high performance liquid chromatography/mass spectrometry and an online statistical tool for data processing.

PubMed

Cao, Yan; Wang, Shaozhan; Li, Yinghua; Chen, Xiaofei; Chen, Langdong; Wang, Dongyao; Zhu, Zhenyu; Yuan, Yongfang; Lv, Diya

2018-03-09

Cell membrane chromatography (CMC) has been successfully applied to screen bioactive compounds from Chinese herbs for many years, and some offline and online two-dimensional (2D) CMC-high performance liquid chromatography (HPLC) hyphenated systems have been established to perform screening assays. However, the requirement of sample preparation steps for the second-dimensional analysis in offline systems and the need for an interface device and technical expertise in the online system limit their extensive use. In the present study, an offline 2D CMC-HPLC analysis combined with the XCMS (various forms of chromatography coupled to mass spectrometry) Online statistical tool for data processing was established. First, our previously reported online 2D screening system was used to analyze three Chinese herbs that were reported to have potential anti-inflammatory effects, and two binding components were identified. By contrast, the proposed offline 2D screening method with XCMS Online analysis was applied, and three more ingredients were discovered in addition to the two compounds revealed by the online system. Then, cross-validation of the three compounds was performed, and they were confirmed to be included in the online data as well, but were not identified there because of their low concentrations and lack of credible statistical approaches. Last, pharmacological experiments showed that these five ingredients could inhibit IL-6 release and IL-6 gene expression on LPS-induced RAW cells in a dose-dependent manner. Compared with previous 2D CMC screening systems, this newly developed offline 2D method needs no sample preparation steps for the second-dimensional analysis, and it is sensitive, efficient, and convenient. It will be applicable in identifying active components from Chinese herbs and practical in discovery of lead compounds derived from herbs. Copyright © 2018 Elsevier B.V. All rights reserved.

Compendium of Experimental Cetane Numbers

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yanowitz, Janet; Ratcliff, Matthew A.; McCormick, Robert L.

This report is an updated version of the 2014 Compendium of Experimental Cetane Number Data and presents a compilation of measured cetane numbers for pure chemical compounds. It includes all available single-compound cetane number data found in the scientific literature up until December 2016 as well as a number of previously unpublished values, most measured over the past decade at the National Renewable Energy Laboratory. This version of the compendium contains cetane values for 496 pure compounds, including 204 hydrocarbons and 292 oxygenates. 176 individual measurements are new to this version of the compendium, all of them collected using ASTMmore » Method D6890, which utilizes an Ignition Quality Tester (IQT) a type of constant-volume combustion chamber. For many compounds, numerous measurements are included, often collected by different researchers using different methods. The text of this document is unchanged from the 2014 version, except for the numbers of compounds in Section 3.1, the Appendices, Table 1. Primary Cetane Number Data Sources and Table 2. Number of Measurements Included in Compendium. Cetane number is a relative ranking of a fuel's autoignition characteristics for use in compression ignition engines. It is based on the amount of time between fuel injection and ignition, also known as ignition delay. The cetane number is typically measured either in a single-cylinder engine or a constant-volume combustion chamber. Values in the previous compendium derived from octane numbers have been removed and replaced with a brief analysis of the correlation between cetane numbers and octane numbers. The discussion on the accuracy and precision of the most commonly used methods for measuring cetane number has been expanded, and the data have been annotated extensively to provide additional information that will help the reader judge the relative reliability of individual results.« less

Concentrations of organochlorine pesticides, polybrominated diphenyl ethers and perfluorinated compounds in the atmosphere of North Greenland.

PubMed

Bossi, Rossana; Vorkamp, Katrin; Skov, Henrik

2016-10-01

Atmospheric concentrations of organochlorine pesticides (OCPs), polybrominated diphenyl ethers (PBDEs) and neutral per- and polyfluoroalkyl substances (PFAS) have been measured at Villum Research Station, Station Nord (North Greenland) in the period 2008-2013. Atmospheric concentrations of OCPs at the same site have been previously reported for the years 2008-2010. The detection frequency and the average concentrations of OCPs have not significantly changed since the previous study. PBDE congeners (∑13PBDEs) were measured for the first time in North Greenland at concentrations similar to those observed for other remote sites, confirming that these compounds are ubiquitous in the Northern Hemisphere. The ∑13PBDEs concentration ranged from not detected (n.d.) to 6.26 pg m(-3). The BDE congeners found in more than 30% of the samples were BDE-17, BDE-28, BDE-47, BDE-71, BDE-99 and BDE-100. Also for neutral PFAS we present for the first time a multiyear series of measurements for North Greenland. The average sum of the seven measured neutral PFAS (∑7PFAS) ranged from 1.82 to 32.1 pg m(-3). The most abundant compound was 8:2 FTOH (44% of ∑7PFAS), followed by 6:2 FTOH and 10:2 FTOH. Perfluoroalkyl sulfonamides (FOSA) and perfluoroalkyl sulfonamidoethanols (FOSE) were also detected but at much lower concentrations than FTOHs. Temporal trends were investigated for all measured compounds but no significant trend in concentration was observed. Monthly average concentrations for the six years were calculated for each compound and the seasonal variation was investigated. Some OCPs and FTOHs showed seasonal variations, and in most cases a maximum was found during summer. Copyright © 2016 Elsevier Ltd. All rights reserved.

N-Alkyl Urea Hydroxamic Acids as a New Class of Peptide Deformylase Inhibitors with Antibacterial Activity

PubMed Central

Hackbarth, Corinne J.; Chen, Dawn Z.; Lewis, Jason G.; Clark, Kirk; Mangold, James B.; Cramer, Jeffrey A.; Margolis, Peter S.; Wang, Wen; Koehn, Jim; Wu, Charlotte; Lopez, S.; Withers III, George; Gu, Helen; Dunn, Elina; Kulathila, R.; Pan, Shi-Hao; Porter, Wilma L.; Jacobs, Jeff; Trias, Joaquim; Patel, Dinesh V.; Weidmann, Beat; White, Richard J.; Yuan, Zhengyu

2002-01-01

Peptide deformylase (PDF) is a prokaryotic metalloenzyme that is essential for bacterial growth and is a new target for the development of antibacterial agents. All previously reported PDF inhibitors with sufficient antibacterial activity share the structural feature of a 2-substituted alkanoyl at the P1′ site. Using a combination of iterative parallel synthesis and traditional medicinal chemistry, we have identified a new class of PDF inhibitors with N-alkyl urea at the P1′ site. Compounds with MICs of ≤4 μg/ml against gram-positive and gram-negative pathogens, including Staphylococcus aureus, Streptococcus pneumoniae, and Haemophilus influenzae, have been identified. The concentrations needed to inhibit 50% of enzyme activity (IC50s) for Escherichia coli Ni-PDF were ≤0.1 μM, demonstrating the specificity of the inhibitors. In addition, these compounds were very selective for PDF, with IC50s of consistently >200 μM for matrilysin and other mammalian metalloproteases. Structure-activity relationship analysis identified preferred substitutions resulting in improved potency and decreased cytotoxity. One of the compounds (VRC4307) was cocrystallized with PDF, and the enzyme-inhibitor structure was determined at a resolution of 1.7 Å. This structural information indicated that the urea compounds adopt a binding position similar to that previously determined for succinate hydroxamates. Two compounds, VRC4232 and VRC4307, displayed in vivo efficacy in a mouse protection assay, with 50% protective doses of 30.8 and 17.9 mg/kg of body weight, respectively. These N-alkyl urea hydroxamic acids provide a starting point for identifying new PDF inhibitors that can serve as antimicrobial agents. PMID:12183225

Development of an ex vivo lymph node explant model for identification of novel molecules active against Leishmania major.

PubMed

Peniche, Alex G; Osorio, Yaneth; Renslo, Adam R; Frantz, Doug E; Melby, Peter C; Travi, Bruno L

2014-01-01

Leishmaniasis is a vector-borne zoonotic infection affecting people in tropical and subtropical regions of the world. Current treatments for cutaneous leishmaniasis are difficult to administer, toxic, expensive, and limited in effectiveness and availability. Here we describe the development and application of a medium-throughput screening approach to identify new drug candidates for cutaneous leishmaniasis using an ex vivo lymph node explant culture (ELEC) derived from the draining lymph nodes of Leishmania major-infected mice. The ELEC supported intracellular amastigote proliferation and contained lymph node cell populations (and their secreted products) that enabled the testing of compounds within a system that mimicked the immunopathological environment of the infected host, which is known to profoundly influence parasite replication, killing, and drug efficacy. The activity of known antileishmanial drugs in the ELEC system was similar to the activity measured in peritoneal macrophages infected in vitro with L. major. Using the ELEC system, we screened a collection of 334 compounds, some of which we had demonstrated previously to be active against L. donovani, and identified 119 hits, 85% of which were confirmed to be active by determination of the 50% effective concentration (EC50). We found 24 compounds (7%) that had an in vitro therapeutic index (IVTI; 50% cytotoxic/effective concentration [CC50]/EC50) > 100; 19 of the compounds had an EC50 below 1 μM. According to PubChem searchs, 17 of those compounds had not previously been reported to be active against Leishmania. We expect that this novel method will help to accelerate discovery of new drug candidates for treatment of cutaneous leishmaniasis.

Development of an Ex Vivo Lymph Node Explant Model for Identification of Novel Molecules Active against Leishmania major

PubMed Central

Peniche, Alex G.; Osorio, Yaneth; Renslo, Adam R.; Frantz, Doug E.; Melby, Peter C.

2014-01-01

Leishmaniasis is a vector-borne zoonotic infection affecting people in tropical and subtropical regions of the world. Current treatments for cutaneous leishmaniasis are difficult to administer, toxic, expensive, and limited in effectiveness and availability. Here we describe the development and application of a medium-throughput screening approach to identify new drug candidates for cutaneous leishmaniasis using an ex vivo lymph node explant culture (ELEC) derived from the draining lymph nodes of Leishmania major-infected mice. The ELEC supported intracellular amastigote proliferation and contained lymph node cell populations (and their secreted products) that enabled the testing of compounds within a system that mimicked the immunopathological environment of the infected host, which is known to profoundly influence parasite replication, killing, and drug efficacy. The activity of known antileishmanial drugs in the ELEC system was similar to the activity measured in peritoneal macrophages infected in vitro with L. major. Using the ELEC system, we screened a collection of 334 compounds, some of which we had demonstrated previously to be active against L. donovani, and identified 119 hits, 85% of which were confirmed to be active by determination of the 50% effective concentration (EC50). We found 24 compounds (7%) that had an in vitro therapeutic index (IVTI; 50% cytotoxic/effective concentration [CC50]/EC50) > 100; 19 of the compounds had an EC50 below 1 μM. According to PubChem searchs, 17 of those compounds had not previously been reported to be active against Leishmania. We expect that this novel method will help to accelerate discovery of new drug candidates for treatment of cutaneous leishmaniasis. PMID:24126577

From Chemistry to Behavior. Molecular Structure and Bioactivity of Repellents against Ixodes ricinus Ticks

PubMed Central

Fabbro, Simone Del; Nazzi, Francesco

2013-01-01

Tick-borne zoonoses are considered as emerging diseases. Tick repellents represent an effective tool for reducing the risk of tick bite and pathogens transmission. Previous work demonstrated the repellent activity of the phenylpropanoid eugenol against Ixodes ricinus; here we investigate the relationship between molecular structure and repellency in a group of substances related to that compound. We report the biological activity of 18 compounds varying for the presence/number of several moieties, including hydroxyl and methoxy groups and carbon side-chain. Each compound was tested at different doses with a bioassay designed to measure repellency against individual tick nymphs. Both vapor pressure and chemical features of the tested compounds appeared to be related to repellency. In particular, the hydroxyl and methoxy groups as well as the side-chain on the benzene ring seem to play a role. These results are discussed in light of available data on chemical perception in ticks. In the course of the study new repellent compounds were identified; the biological activity of some of them (at least as effective as the “gold standard” repellent DEET) appears to be very promising from a practical point of view. PMID:23805329

Phytotoxic and Antifungal Metabolites from Curvularia crepinii QTYC-1 Isolated from the Gut of Pantala flavescens.

PubMed

Yin, Caiping; Jin, Liping; Sun, Feifei; Xu, Xiao; Shao, Mingwei; Zhang, Yinglao

2018-04-19

Four metabolites ( 1 ⁻ 4 ), including a new macrolide, O -demethylated-zeaenol ( 2 ), and three known compounds, zeaenol ( 1 ), adenosine ( 3 ), and ergosta-5,7,22-trien-3b-ol ( 4 ) were isolated and purified from Curvularia crepinii QTYC-1, a fungus residing in the gut of Pantala flavescens . The structures of isolated compounds were identified on the basis of extensive spectroscopic analysis and by comparison of the corresponding data with those reported in the literature previously. The new compound 2 showed good phytotoxic activity against Echinochloa crusgalli with an IC 50 value of less than 5 µg/mL, which was comparable to that of positive 2,4-dichlorophenoxyacetic acid (2,4-D). Compound 1 exhibited moderate herbicidal activity against E. crusgalli with an IC 50 value of 28.8 μg/mL. Furthermore, the new metabolite 2 was found to possess moderate antifungal activity against Valsa mali at the concentration of 100 µg/mL, with the inhibition rate of 50%. These results suggest that the new macrolide 2 and the known compound 1 have potential to be used as biocontrol agents in agriculture.

High field ESR study of the pi-d interaction effect in beta-(BDA-TTP)2MCl4 (M=Fe, Ga)

NASA Astrophysics Data System (ADS)

Tokumoto, Takahisa; Vantol, J.; Brunel, L.-C.; Choi, E. S.; Brooks, J. S.; Kaihatsu, T.; Akutsu, H.; Yamada, J.

2007-03-01

Novel magnetic organic conductors with pi-d interaction have commanded attention since the discovery of field induced superconductivity. One of them, beta-(BDA-TTP)2FeCl4, has alternating donor molecules and quasi 2D electrical properties. Previous studies of electrical and magnetic properties show an M-I transition at 120K and an AF transition at TN=8.5K, suggesting an exchange interaction between the conduction electrons and the Fe^3+ d-electrons. The properties of beta-(BDA-TTP)2GaCl4 are similar with exception of the absence of the AF transition, which is apparently due to the absence of pi-d exchange interaction. We report angular/temperature dependent 240GHz quasi optical ESR measurements on both compounds to probe the magnetic properties. The Ga compound signals follow the donor molecule structure, and show no magnetic order at any temperature. The Fe compound signals are quite different from the Ga compound, and exhibit AF behavior below TN. The difference of Fe and Ga compounds will be discussed in terms of the interaction between localized and itinerant magnetic moments.

Synthesis and evaluation of 5-(arylthio)-9H-pyrimido[4,5-b]indole-2,4-diamines as receptor tyrosine kinase and thymidylate synthase inhibitors and as antitumor agents.

PubMed

Zaware, Nilesh; Kisliuk, Roy; Bastian, Anja; Ihnat, Michael A; Gangjee, Aleem

2017-04-01

In an effort to optimize the structural requirements for combined cytostatic and cytotoxic effects in single agents, a series of 5-(arylthio)-9H-pyrimido[4,5-b]indole-2,4-diamines 3-7 were synthesized and evaluated as inhibitors of receptor tyrosine kinases (RTKs) as well as thymidylate synthase (TS). The synthesis of these compounds involved the nucleophilic displacement of the common intermediate 5-bromo/5-chloro-9H-pyrimido[4,5-b]indole-2,4-diamine with appropriate aryl thiols. A novel four step synthetic scheme to the common intermediate was developed which is more efficient relative to the previously reported six-step sequence. Biological evaluation of these compounds indicated dual activity in RTKs and human TS (hTS). In the VEGFR-2 assay, compound 5 was equipotent to the standard compound semaxanib and was better than standard TS inhibitor pemetrexed, in the hTS assay. Compounds 3, 6 and 7 were nanomolar inhibitors of hTS and were several fold better than pemetrexed. Copyright © 2017 Elsevier Ltd. All rights reserved.

Design, synthesis and evaluation of novel 7-aminoalkyl-substituted flavonoid derivatives with improved cholinesterase inhibitory activities.

PubMed

Luo, Wen; Chen, Ying; Wang, Ting; Hong, Chen; Chang, Li-Ping; Chang, Cong-Cong; Yang, Ya-Cheng; Xie, Song-Qiang; Wang, Chao-Jie

2016-02-15

A novel series of 7-aminoalkyl-substituted flavonoid derivatives 5a-5r were designed, synthesized and evaluated as potential cholinesterase inhibitors. The results showed that most of the synthesized compounds exhibited potent acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities at the micromolar range. Compound 2-(naphthalen-1-yl)-7-(8-(pyrrolidin-1-yl)octyloxy)-4H-chromen-4-one (5q) showed the best inhibitory activity (IC50, 0.64μM for AChE and 0.42μM for BChE) which were better than our previously reported compounds and the commercially available cholinergic agent Rivastigmine. The results from a Lineweaver-Burk plot indicated a mixed-type inhibition for compound 5q with AChE and BChE. Furthermore, molecular modeling study showed that 5q targeted both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. Besides, these compounds (5a-5r) did not affect PC12 and HepG2 cell viability at the concentration of 10μM. Consequently, these flavonoid derivatives should be further investigated as multipotent agents for the treatment of Alzheimer's disease. Copyright © 2015 Elsevier Ltd. All rights reserved.

Inhibitory Activities of Phenolic Compounds Isolated from Adina rubella Leaves Against 5α-Reductase Associated with Benign Prostatic Hypertrophy.

PubMed

Yin, Jun; Heo, Jun Hyeok; Hwang, Yoon Jeong; Le, Thi Tam; Lee, Min Won

2016-07-07

Adina rubella Hance (AR), a plant native to Korea, has been used as traditional medicine for dysentery, eczema, intoxication, and external hemorrhages. Previous phytochemical studies of AR have reported several components, including terpenoids, phenolics, and alkaloids. The current study evaluated the anti-oxidative and anti-inflammatory activities and 5α-reductase inhibition of isolated compounds of AR leaves to find a potential therapeutic agent for benign prostatic hypertrophy (BPH). Repeated chromatographic isolation of an 80% acetone extract of AR leaves yielded seven phenolic compounds: caffeic acid (1), chlorogenic acid (2), methyl chlorogenate (3), quercetin-3-rutinoside (4), kaempferol-3-O-α-l-rhamnopyranosyl-(1→6)-β-d-glucopyranoside (5), hyperoside (6), and grandifloroside (7). Compound 7 is a novel compound in AR. Caffeoyl derivatives 1-3 and 7 showed good anti-oxidative activities. In particular, caffeic acid (1) and grandifloroside (7) showed potent anti-inflammatory activities, and 7 also exhibited potent inhibitory activity against TNF-α and 5α-reductase. Our results show that the extract and grandifloroside (7) from leaves of AR might be developed as a source of potent anti-oxidative and anti-inflammatory agents and therapeutic agent for BPH.

New hydrogen-rich ammonium metal borohydrides, NH4[M(BH4)4], M = Y, Sc, Al, as potential H2 sources.

PubMed

Starobrat, A; Jaroń, T; Grochala, W

2018-03-26

Three metal-ammonium borohydrides, NH4[M(BH4)4] M = Y, Sc, Al, denoted 1, 2, 3, respectively, were prepared via a low temperature mechanochemical synthesis and characterized using PXRD, FTIR and TGA/DSC/MS. The compounds 1 and 2 adopt the P21/c space group while the compound 3 crystallizes in an orthorhombic unit cell (Fddd). The first decomposition step of all three derivatives of ammonium borohydride has the maximum rate at 48 °C, 53 °C and 35 °C for 1, 2 and 3, respectively, which are comparable to that for NH4BH4 (53 °C). The thermal decomposition of these metal-ammonium borohydrides is a multistep process, with predominantly exothermic low-temperature stages. The compound 1 decomposes via known Y(BH4)3, however, some of the solid decomposition products of the other two compounds have not been fully identified. In the system containing compound 2, a new, more dense polymorph of the previously reported LiSc(BH4)4 has been detected as the intermediate of slow decomposition at room temperature.

Prevention of poxvirus infection by tetrapyrroles

PubMed Central

Chen-Collins, Avril RM; Dixon, Dabney W; Vzorov, Andrei N; Marzilli, Luigi G; Compans, Richard W

2003-01-01

Background Prevention of poxvirus infection is a topic of great current interest. We report inhibition of vaccinia virus in cell culture by porphyrins and phthalocyanines. Most previous work on the inhibition of viruses with tetrapyrroles has involved photodynamic mechanisms. The current study, however, investigates light-independent inhibition activity. Methods The Western Reserve (WR) and International Health Department-J (IHD-J) strains of vaccinia virus were used. Virucidal and antiviral activities as well as the cytotoxicity of test compounds were determined. Results Examples of active compounds include zinc protoporphyrin, copper hematoporphyrin, meso(2,6-dihydroxyphenyl)porphyrin, the sulfonated tetra-1-naphthyl and tetra-1-anthracenylporphyrins, selected sulfonated derivatives of halogenated tetraphenyl porphyrins and the copper chelate of tetrasulfonated phthalocyanine. EC50 values for the most active compounds are as low as 0.05 µg/mL (40 nM). One of the most active compounds was the neutral meso(2,6-dihydroxyphenyl)porphyrin, indicating that the compounds do not have to be negatively charged to be active. Conclusions Porphyrins and phthalocyanines have been found to be potent inhibitors of infection by vaccinia virus in cell culture. These tetrapyrroles were found to be active against two different virus strains, and against both enveloped and non-enveloped forms of the virus, indicating that these compounds may be broadly effective in their ability to inhibit poxvirus infection. PMID:12773208

Isoquinoline Alkaloids from Erythrinapoeppigiana (Leguminosae) and Cytotoxic Activity Against Breast Cancer Cells Line MCF-7 In Silico

NASA Astrophysics Data System (ADS)

Herlina, T.; Mardianingrum, R.; Gaffar, S.; Supratman, U.

2017-02-01

Erythrinapoeppigiana(Leguminosae) is a higher plant that has been used as a folk for the treatment of infection, fever, and inflammation. In the course of our continuing search for novel cytotoxic compounds from genus Erythrina, the methanol extract of E. poeppigiana showed a significant cytotoxic activity against breast cancer cells line MCF-7 in silico. The compounds in methanol extract of the E. poeppigiana was separated using a bioassay-guided fractionation. By using a cytotoxic activity to follow separation, the methylene chloride was separated by several column chromatography techniques on silica gel and ODS to yield three active compounds (1-3). The chemical structures of active compounds were determined on the basis of spectroscopic evidence and comparison with those identical compounds that previously reported and identified as a 10,11-dihydroxyerysodine (1) 6,7-dihydro-17-hydroxyerysotrine (2) 6,7-dihydro-11-methoxyerysotrine (3). Compounds (1-3) showed cytotoxic activity inhibits EGFR 2 against breast cancer cell line MCF-7 in silico molecular docking method with bond Gibbs free energy (ΔG) (kcal/mol) and inhibition constants (Ki) (nM) of value (-8.61121, 4.84×10-7) (-8.1145, 1.12×10-6) and (-7.3394, 4.14×10-6), respectively.

Anti-tumor and anti-angiogenic ergosterols from Ganoderma lucidum

NASA Astrophysics Data System (ADS)

Chen, Shaodan; Yong, Tianqiao; Zhang, Yifang; Su, Jiyan; Jiao, Chunwei; Xie, Yizhen

2017-10-01

This study was carried out to isolate chemical constituents from the lipid enriched fraction of Ganoderma lucidum extract and to evaluate their anti-proliferative effect on cancer cell lines and human umbilical vein endothelial cells. Ergosterol derivatives (1-14) were isolated from the lipid enriched fraction of G. lucidum. Their structures were established on the basis of spectroscopic analyses or by comparison of mass and NMR spectral data with those reported previously. Amongst, compound 1 was isolated and identified as a new compound. All the compounds were evaluated for their inhibitory effect on tumor cells and human umbilical vein endothelial cells in vitro. Compounds 9-13 displayed inhibitory activity against two tumor cell lines and human umbilical vein endothelial cells, which indicated that these four compounds had both anti-tumor and anti-angiogenesis activities. Compound 2 had significant selective inhibition against two tumor cell lines, while 3 exhibited selective inhibition against human umbilical vein endothelial cells. The structure–activity relationships for inhibiting human HepG2 cells were revealed by 3D-QASR. Ergosterol content in different parts of the raw material and products of G. lucidum was quantified. This study provides a basis for further development and utilization of ergosterol derivatives as natural nutraceuticals and functional food ingredients, or as source of new potential antitumor or anti-angiogenesis chemotherapy agent.

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

Structure determination and sensory analysis of bitter-tasting 4-vinylcatechol oligomers and their identification in roasted coffee by means of LC-MS/MS.

PubMed

Frank, Oliver; Blumberg, Simone; Kunert, Christof; Zehentbauer, Gerhard; Hofmann, Thomas

2007-03-07

Aimed at elucidating intense bitter-tasting molecules in coffee, various bean ingredients were thermally treated in model experiments and evaluated for their potential to produce bitter compounds. As caffeic acid was found to generate intense bitterness reminiscent of the bitter taste of a strongly roasted espresso-type coffee, the reaction products formed were screened for bitter compounds by means of taste dilution analysis, and the most bitter tastants were isolated and purified. LC-MS/MS as well as 1-D/2-D NMR experiments enabled the identification of 10 bitter compounds with rather low recognition threshold concentrations ranging between 23 and 178 micromol/L. These bitter compounds are the previously unreported 1,3-bis(3',4'-dihydroxyphenyl) butane, trans-1,3-bis(3',4'-dihydroxyphenyl)-1-butene, and eight multiply hydroxylated phenylindanes, among which five derivatives are reported for the first time. In addition, the occurrence of each of these bitter compounds in a coffee brew was verified by means of LC-MS/MS (ESI-) operating in the multiple reaction monitoring (MRM) mode. The structures of these bitter compounds show strong evidence that they are generated by oligomerization of 4-vinylcatechol released from caffeic acid moieties upon roasting.

Development of an orally-administrative MELK-targeting inhibitor that suppresses the growth of various types of human cancer.

PubMed

Chung, Suyoun; Suzuki, Hanae; Miyamoto, Takashi; Takamatsu, Naofumi; Tatsuguchi, Ayako; Ueda, Koji; Kijima, Kyoko; Nakamura, Yusuke; Matsuo, Yo

2012-12-01

We previously reported MELK (maternal embryonic leucine zipper kinase) as a novel therapeutic target for breast cancer. MELK was also reported to be highly upregulated in multiple types of human cancer. It was implied to play indispensable roles in cancer cell survival and indicated its involvement in the maintenance of tumor-initiating cells. We conducted a high-throughput screening of a compound library followed by structure-activity relationship studies, and successfully obtained a highly potent MELK inhibitor OTSSP167 with IC₅₀ of 0.41 nM. OTSSP167 inhibited the phosphorylation of PSMA1 (proteasome subunit alpha type 1) and DBNL (drebrin-like), which we identified as novel MELK substrates and are important for stem-cell characteristics and invasiveness. The compound suppressed mammosphere formation of breast cancer cells and exhibited significant tumor growth suppression in xenograft studies using breast, lung, prostate, and pancreas cancer cell lines in mice by both intravenous and oral administration. This MELK inhibitor should be a promising compound possibly to suppress the growth of tumor-initiating cells and be applied for treatment of a wide range of human cancer.

Cyclopentenone derivatives and polyhydroxylated steroids from the soft coral Sinularia acuta.

PubMed

Zhang, Nai-Xia; Tang, Xu-Li; van Ofwegen, Leen; Xue, Lei; Song, Wen-Juan; Li, Ping-Lin; Li, Guo-Qiang

2015-02-01

Four new polyhydroxylated steroids, 1-4, and the racemic form of cyclopentenone 9, together with four known steroids, 5-8, one known cyclopentenone derivative, 10, and one known butenolide derivative, 11, were isolated from the soft coral Sinularia acuta collected from Weizhou Island of Guangxi Province, P. R. China. Their structures were elucidated on the basis of spectroscopic analyses and by comparison of the corresponding data with those previously reported. The cytotoxicities of the isolates 1-11 in vitro against the selected tumor cell lines HL-60, HeLa, and K562 were evaluated. Compounds 2 and 5 showed potent cytotoxicities against HL-60 cell lines with IC50 values of 7.3 and 9.9 μM, respectively. Compounds 5 and 6 showed moderate activities against K562 cell lines with IC50 values of 10.9 and 11.7 μM, respectively, while compounds 1, 2, and 6 showed weak activities against HeLa cell lines with respective IC50 values of 44.8, 27.1, and 18.2 μM. This is the first report on chemical and bioactivity research of S. acuta. Copyright © 2015 Verlag Helvetica Chimica Acta AG, Zürich.

Novel Compound Heterozygous Mutations Expand the Recognized Phenotypes of FARS2-Linked Disease.

PubMed

Walker, Melissa A; Mohler, Kyle P; Hopkins, Kyle W; Oakley, Derek H; Sweetser, David A; Ibba, Michael; Frosch, Matthew P; Thibert, Ronald L

2016-08-01

Mutations in mitochondrial aminoacyl-tRNA synthetases are an increasingly recognized cause of human diseases, often arising in individuals with compound heterozygous mutations and presenting with system-specific phenotypes, frequently neurologic. FARS2 encodes mitochondrial phenylalanyl transfer ribonucleic acid (RNA) synthetase (mtPheRS), perturbations of which have been reported in 6 cases of an infantile, lethal disease with refractory epilepsy and progressive myoclonus. Here the authors report the case of juvenile onset refractory epilepsy and progressive myoclonus with compound heterozygous FARS2 mutations. The authors describe the clinical course over 6 years of care at their institution and diagnostic studies including electroencephalogram (EEG), brain magnetic resonance imaging (MRI), serum and cerebrospinal fluid analyses, skeletal muscle biopsy histology, and autopsy gross and histologic findings, which include features shared with Alpers-Huttenlocher syndrome, Leigh syndrome, and a previously published case of FARS2 mutation associated infantile onset disease. The authors also present structure-guided analysis of the relevant mutations based on published mitochondrial phenylalanyl transfer RNA synthetase and related protein crystal structures as well as biochemical analysis of the corresponding recombinant mutant proteins. © The Author(s) 2016.

1E7-03, a low MW compound targeting host protein phosphatase-1, inhibits HIV-1 transcription

PubMed Central

Ammosova, Tatyana; Platonov, Maxim; Ivanov, Andrei; Kont, Yasemin Saygideğer; Kumari, Namita; Kehn-Hall, Kylene; Jerebtsova, Marina; Kulkarni, Amol A; Üren, Aykut; Kovalskyy, Dmytro; Nekhai, Sergei

2014-01-01

Background and Purpose HIV-1 transcription is activated by the Tat protein which recruits the cyclin-dependent kinase CDK9/cyclin T1 to TAR RNA. Tat binds to protein phosphatase-1 (PP1) through the Q35VCF38 sequence and translocates PP1 to the nucleus. PP1 dephosphorylates CDK9 and activates HIV-1 transcription. We have synthesized a low MW compound 1H4, that targets PP1 and prevents HIV-1 Tat interaction with PP1 and inhibits HIV-1 gene transcription. Here, we report our further work with the 1H4-derived compounds and analysis of their mechanism of action. Experimental Approach Using the 1H4-PP1 complex as a model, we iteratively designed and synthesized follow-up libraries that were analysed for the inhibition of HIV-1 transcription and toxicity. We also confirmed the mechanism of action of the PP1-targeting molecules by determining the affinity of binding of these molecules to PP1, by analysing their effects on PP1 activity, disruption of PP1 binding to Tat and shuttling of PP1 to the nucleus. Key Results We identified a tetrahydroquinoline derivative, compound 7, which disrupted the interaction of Tat with PP1. We further optimized compound 7 and obtained compound 7c, renamed 1E7-03, which inhibited HIV-1 with low IC50 (fivefold lower than the previously reported compound, 1H4), showed no cytotoxicity and displayed a plasma half-life greater than 8 h in mice. 1E7-03 bound to PP1 in vitro and prevented shuttling of PP1 into the nucleus. Conclusions and Implications Our study shows that low MW compounds that functionally mimic the PP1-binding RVxF peptide can inhibit HIV-1 transcription by deregulating PP1. PMID:25073485

Photo-affinity labelling and biochemical analyses identify the target of trypanocidal simplified natural product analogues

PubMed Central

Tulloch, Lindsay B.; Menzies, Stefanie K.; Fraser, Andrew L.; Gould, Eoin R.; King, Elizabeth F.; Zacharova, Marija K.; Florence, Gordon J.

2017-01-01

Current drugs to treat African sleeping sickness are inadequate and new therapies are urgently required. As part of a medicinal chemistry programme based upon the simplification of acetogenin-type ether scaffolds, we previously reported the promising trypanocidal activity of compound 1, a bis-tetrahydropyran 1,4-triazole (B-THP-T) inhibitor. This study aims to identify the protein target(s) of this class of compound in Trypanosoma brucei to understand its mode of action and aid further structural optimisation. We used compound 3, a diazirine- and alkyne-containing bi-functional photo-affinity probe analogue of our lead B-THP-T, compound 1, to identify potential targets of our lead compound in the procyclic form T. brucei. Bi-functional compound 3 was UV cross-linked to its target(s) in vivo and biotin affinity or Cy5.5 reporter tags were subsequently appended by Cu(II)-catalysed azide-alkyne cycloaddition. The biotinylated protein adducts were isolated with streptavidin affinity beads and subsequent LC-MSMS identified the FoF1-ATP synthase (mitochondrial complex V) as a potential target. This target identification was confirmed using various different approaches. We show that (i) compound 1 decreases cellular ATP levels (ii) by inhibiting oxidative phosphorylation (iii) at the FoF1-ATP synthase. Furthermore, the use of GFP-PTP-tagged subunits of the FoF1-ATP synthase, shows that our compounds bind specifically to both the α- and β-subunits of the ATP synthase. The FoF1-ATP synthase is a target of our simplified acetogenin-type analogues. This mitochondrial complex is essential in both procyclic and bloodstream forms of T. brucei and its identification as our target will enable further inhibitor optimisation towards future drug discovery. Furthermore, the photo-affinity labeling technique described here can be readily applied to other drugs of unknown targets to identify their modes of action and facilitate more broadly therapeutic drug design in any pathogen or disease model. PMID:28873407

Deoxycholate-Based Glycosides (DCGs) for Membrane Protein Stabilisation.

PubMed

Bae, Hyoung Eun; Gotfryd, Kamil; Thomas, Jennifer; Hussain, Hazrat; Ehsan, Muhammad; Go, Juyeon; Loland, Claus J; Byrne, Bernadette; Chae, Pil Seok

2015-07-06

Detergents are an absolute requirement for studying the structure of membrane proteins. However, many conventional detergents fail to stabilise denaturation-sensitive membrane proteins, such as eukaryotic proteins and membrane protein complexes. New amphipathic agents with enhanced efficacy in stabilising membrane proteins will be helpful in overcoming the barriers to studying membrane protein structures. We have prepared a number of deoxycholate-based amphiphiles with carbohydrate head groups, designated deoxycholate-based glycosides (DCGs). These DCGs are the hydrophilic variants of previously reported deoxycholate-based N-oxides (DCAOs). Membrane proteins in these agents, particularly the branched diglucoside-bearing amphiphiles DCG-1 and DCG-2, displayed favourable behaviour compared to previously reported parent compounds (DCAOs) and conventional detergents (LDAO and DDM). Given their excellent properties, these agents should have significant potential for membrane protein studies. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

In vivo imaging of zebrafish digestive organ function using multiple quenched fluorescent reporters

PubMed Central

Hama, Kotaro; Provost, Elayne; Baranowski, Timothy C.; Rubinstein, Amy L.; Anderson, Jennifer L.; Leach, Steven D.; Farber, Steven A.

2009-01-01

Optical clarity of larvae makes the zebrafish ideal for real-time analyses of vertebrate organ function through the use of fluorescent reporters of enzymatic activities. A key function of digestive organs is to couple the generation of enzymes with mechanical processes that enable nutrient availability and absorption. However, it has been extremely difficult, and in many cases not possible, to directly observe digestive processes in a live vertebrate. Here we describe a new method to visualize intestinal protein and lipid processing simultaneously in live zebrafish larvae using a quenched fluorescent protein (EnzChek) and phospholipid (PED6). By employing these reagents, we found that wild-type larvae exhibit significant variation in intestinal phospholipase and protease activities within a group but display a strong correlation between the activities within individuals. Furthermore, we found that pancreas function is essential for larval digestive protease activity but not for larval intestinal phospholipase activity. Although fat-free (ffr) mutant larvae were previously described to exhibit impaired lipid processes, we found they also had significantly reduced protease activity. Finally, we selected and evaluated compounds that were previously suggested to have altered phospholipase activity and are known or suspected to have inflammatory effects in the intestinal tract including nonsteroidal anti-inflammatory drugs, and identified a compound that significantly increases intestinal phospholipid processing. Thus the multiple fluorescent reporter-based methodology facilitates the rapid analysis of digestive organ function in live zebrafish larvae. PMID:19056761

Rodent repellents: Preparation and properties of thiouronium compounds and cyclic imides

USGS Publications Warehouse

Bellack, E.; DeWitt, J.B.

1954-01-01

Syntheses and bioassays of cyclic imides and thiouronium compounds were carried out as part of a search for materials capable of preventing rodent damage to packaged commodities. Previous studies had shown that repellent activity was associated with functional groups containing nitrogen and sulfur, and was enhanced by the presence of ionic linkages. Twenty-seven thiouronium compounds and 40 imides, including 1 0 compounds not described previously, were prepared for these tests. Ten imides and 26 thiouronium compounds were repellent under the conditions of test. Information obtained in these studies will be utilized in the development and selection of more effective materials for prevention of rodent damage to foods and other commodities.

Design and growth of novel compounds for radiation sensors: multinary chalcogenides

NASA Astrophysics Data System (ADS)

Singh, N. B.; Su, Ching-Hua; Nagaradona, Teja; Arnold, Brad; Choa, Fow-Sen

2016-05-01

Increasing threats of radiological weapons have revitalized the researches for low cost large volume γ-ray and neutron ray sensors In the past few years we have designed and grown ternary and quaternary lead and thallium chalcogenides and lead selenoiodides for detectors to meet these challenges. These materials are congruent, can be tailored to enhance the parameters required for radiation sensors. In addition, this class of compounds can be grown by Bridgman method which promises for large volume productions. We have single crystals of several compounds from the melt including Tl3AsSe3, Tl3AsSe3-xSx, TlGaSe2, AgGaGe3Se8, AgxLi1-xAgGaGe3Se8 and PbTlI5-x Sex compounds. Experimental studies indicate that these have very low absorption coefficient, low defect density and can be fabricated in any shape and sizes. These crystals do not require post growth annealing and do not show any second phase precipitates when processed for electrode bonding and other fabrication steps. In this paper we report purification, growth and fabrication of large Tl3AsSe3 (TAS) crystals. We observed that TAS crystals grown by using further purification of as supplied high purity source materials followed by directionally solidified charge showed higher resistivity than previously reported values. TAS also showed constant value as the function of voltage.

Development of potent ALK inhibitor and its molecular inhibitory mechanism against NSCLC harboring EML4-ALK proteins.

PubMed

Kang, Chung Hyo; Yun, Jeong In; Lee, Kwangho; Lee, Chong Ock; Lee, Heung Kyoung; Yun, Chang-Soo; Hwang, Jong Yeon; Cho, Sung Yun; Jung, Heejung; Kim, Pilho; Ha, Jae Du; Jeon, Jeong Hee; Choi, Sang Un; Jeong, Hye Gwang; Kim, Hyoung Rae; Park, Chi Hoon

2015-08-28

Here, we show the newly synthesized and potent ALK inhibitor having similar scaffold to KRCA-0008, which was reported previously, and its molecular mechanism against cancer cells harboring EML4-ALK fusion protein. Through ALK wild type enzyme assay, we selected two compounds, KRCA-0080 and KRCA-0087, which have trifluoromethyl instead of chloride in R2 position. We characterized these newly synthesized compounds by in vitro and in vivo assays. Enzyme assay shows that KRCA-0080 is more potent against various ALK mutants, including L1196M, G1202R, T1151_L1152insT, and C1156Y, which are seen in crizotinib-resistant patients, than KRCA-0008 is. Cell based assays demonstrate our compounds downregulate the cellular signaling, such as Akt and Erk, by suppressing ALK activity to inhibit the proliferation of the cells harboring EML4-ALK. Interestingly, our compounds induced strong G1/S arrest in H3122 cells leading to the apoptosis, which is proved by PARP-1 cleavage. In vivo H3122 xenograft assay, we found that KRCA-0080 shows significant reduction in tumor size compared to crizotinib and KRCA-0008 by 15-20%. Conclusively, we report a potent ALK inhibitor which shows significant in vivo efficacy as well as excellent inhibitory activity against various ALK mutants. Copyright © 2015 Elsevier Inc. All rights reserved.

Insights into structure and activity of natural compound inhibitors of pneumolysin

PubMed Central

Li, Hongen; Zhao, Xiaoran; Deng, Xuming; Wang, Jianfeng; Song, Meng; Niu, Xiaodi; Peng, Liping

2017-01-01

Pneumolysin is the one of the major virulence factor of the bacterium Streptococcus pneumoniae. In previous report, it is shown that β-sitosterol, a natural compound without antimicrobial activity, is a potent antagonist of pneumolysin. Here, two new pneumolysin natural compound inhibitors, with differential activity, were discovered via haemolysis assay. To explore the key factor of the conformation for the inhibition activity, the interactions between five natural compound inhibitors with differential activity and pneumolysin were reported using molecular modelling, the potential of mean force profiles. Interestingly, it is found that incorporation of the single bond (C22-C23-C24-C25) to replace the double bond (hydrocarbon sidechain) improved the anti-haemolytic activity. In view of the molecular modelling, binding of the five inhibitors to the conserved loop region (Val372, Leu460, and Tyr461) of the cholesterol binding sites led to stable complex systems, which was consistent with the result of β-sitosterol. Owing to the single bond (C22-C23-C24-C25), campesterol and brassicasterol could form strong interactions with Val372 and show higher anti-haemolytic activity, which indicated that the single bond (C22-C23-C24-C25) in inhibitors was required for the anti-haemolytic activity. Overall, the current molecular modelling work provides a starting point for the development of rational design and higher activity pneumolysin inhibitors. PMID:28165051

Clinical breath analysis: Discriminating between human endogenous compounds and exogenous (environmental) chemical confounders

EPA Science Inventory

Volatile organic compounds (VOCs) in exhaled breath originate from current or previous environmental exposures (exogenous compounds) and internal metabolic anabolic and catabolic) production (endogenous compounds). The origins of certain VOCs in breath presumed to be endogenous ...

Measurement and Modeling of Setschenow Constants for Selected Hydrophilic Compounds in NaCl and CaCl2 Simulated Carbon Storage Brines.

PubMed

Burant, Aniela; Lowry, Gregory V; Karamalidis, Athanasios K

2017-06-20

Carbon capture, utilization, and storage (CCUS), a climate change mitigation strategy, along with unconventional oil and gas extraction, generates enormous volumes of produced water containing high salt concentrations and a litany of organic compounds. Understanding the aqueous solubility of organic compounds related to these operations is important for water treatment and reuse alternatives, as well as risk assessment purposes. The well-established Setschenow equation can be used to determine the effect of salts on aqueous solubility. However, there is a lack of reported Setschenow constants, especially for polar organic compounds. In this study, the Setschenow constants for selected hydrophilic organic compounds were experimentally determined, and linear free energy models for predicting the Setschenow constant of organic chemicals in concentrated brines were developed. Solid phase microextraction was employed to measure the salting-out behavior of six selected hydrophilic compounds up to 5 M NaCl and 2 M CaCl 2 and in Na-Ca-Cl brines. All compounds, which include phenol, p-cresol, hydroquinone, pyrrole, hexanoic acid, and 9-hydroxyfluorene, exhibited log-linear behavior up to these concentrations, meaning Setschenow constants previously measured at low salt concentrations can be extrapolated up to high salt concentrations for hydrophilic compounds. Setschenow constants measured in NaCl and CaCl 2 brines are additive for the compounds measured here; meaning Setschenow constants measured in single salt solutions can be used in multiple salt solutions. The hydrophilic compounds in this study were selected to elucidate differences in salting-out behavior based on their chemical structure. Using data from this study, as well as literature data, linear free energy relationships (LFERs) for prediction of NaCl, CaCl 2 , LiCl, and NaBr Setschenow constants were developed and validated. Two LFERs were improved. One LFER uses the Abraham solvation parameters, which include the index of refraction of the organic compound, organic compound's polarizability, hydrogen bonding acidity and basicity of the organic compound, and the molar volume of the compound. The other uses an octanol-water partitioning coefficient to predict NaCl Setschenow constants. Improved models from this study now include organic compounds that are structurally and chemically more diverse than the previous models. The CaCl 2 , LiCl, and NaBr single parameter LFERs use concepts from the Hofmeister series to predict new, respective Setschenow constants from NaCl Setschenow constants. The Setschenow constants determined here, as well as the LFERs developed, can be incorporated into CCUS reactive transport models to predict aqueous solubility and partitioning coefficients of organic compounds. This work also has implications for beneficial reuse of water from CCUS; this can aide in determining treatment technologies for produced waters.

Structural relationship of curcumin derivatives binding to the BRCT domain of human DNA polymerase lambda.

PubMed

Takeuchi, Toshifumi; Ishidoh, Tomomi; Iijima, Hiroshi; Kuriyama, Isoko; Shimazaki, Noriko; Koiwai, Osamu; Kuramochi, Kouji; Kobayashi, Susumu; Sugawara, Fumio; Sakaguchi, Kengo; Yoshida, Hiromi; Mizushina, Yoshiyuki

2006-03-01

We previously reported that phenolic compounds, petasiphenol and curcumin (diferuloylmethane), were a selective inhibitor of DNA polymerase lambda (pol lambda) in vitro. The purpose of this study was to investigate the molecular structural relationship of curcumin and 13 chemically synthesized derivatives of curcumin. The inhibitory effect on pol lambda (full-length, i.e. intact pol lambda including the BRCA1 C- terminal [BRCT] domain) by some derivatives was stronger than that by curcumin, and monoacetylcurcumin (compound 13) was the strongest pol lambda inhibitor of all the compounds tested, achieving 50% inhibition at a concentration of 3.9 microm. The compound did not influence the activities of replicative pols such as alpha, delta, and epsilon. It had no effect on pol beta activity either, although the three-dimensional structure of pol beta is thought to be highly similar to that of pol lambda. Compound 13 did not inhibit the activity of the C-terminal catalytic domain of pol lambda including the pol beta-like core, in which the BRCT motif was deleted from its N-terminal region. MALDI-TOF MS analysis demonstrated that compound 13 bound selectively to the N-terminal domain of pol lambda, but did not bind to the C-terminal region. Based on these results, the pol lambda-inhibitory mechanism of compound 13 is discussed.

Identification of Drugs Inducing Phospholipidosis by Novel in vitro Data

PubMed Central

Muehlbacher, Markus; Tripal, Philipp; Roas, Florian; Kornhuber, Johannes

2012-01-01

Drug-induced phospholipidosis (PLD) is a lysosomal storage disorder characterized by the accumulation of phospholipids within the lysosome. This adverse drug effect can occur in various tissues and is suspected to impact cellular viability. Therefore, it is important to test chemical compounds for their potential to induce PLD during the drug design process. PLD has been reported to be a side effect of many commonly used drugs, especially those with cationic amphiphilic properties. To predict drug-induced PLD in silico, we established a high-throughput cell-culture-based method to quantitatively determine the induction of PLD by chemical compounds. Using this assay, we tested 297 drug-like compounds at two different concentrations (2.5 μm and 5.0 μm). We were able to identify 28 previously unknown PLD-inducing agents. Furthermore, our experimental results enabled the development of a binary classification model to predict PLD-inducing agents based on their molecular properties. This random forest prediction system yields a bootstrapped validated accuracy of 86 %. PLD-inducing agents overlap with those that target similar biological processes; a high degree of concordance with PLD-inducing agents was identified for cationic amphiphilic compounds, small molecules that inhibit acid sphingomyelinase, compounds that cross the blood–brain barrier, and compounds that violate Lipinski’s rule of five. Furthermore, we were able to show that PLD-inducing compounds applied in combination additively induce PLD. PMID:22945602

Regulation of Compound Leaf Development in Medicago truncatula by Fused Compound Leaf1, a Class M KNOX Gene[C][W

PubMed Central

Peng, Jianling; Yu, Jianbin; Wang, Hongliang; Guo, Yingqing; Li, Guangming; Bai, Guihua; Chen, Rujin

2011-01-01

Medicago truncatula is a legume species belonging to the inverted repeat lacking clade (IRLC) with trifoliolate compound leaves. However, the regulatory mechanisms underlying development of trifoliolate leaves in legumes remain largely unknown. Here, we report isolation and characterization of fused compound leaf1 (fcl1) mutants of M. truncatula. Phenotypic analysis suggests that FCL1 plays a positive role in boundary separation and proximal-distal axis development of compound leaves. Map-based cloning indicates that FCL1 encodes a class M KNOX protein that harbors the MEINOX domain but lacks the homeodomain. Yeast two-hybrid assays show that FCL1 interacts with a subset of Arabidopsis thaliana BEL1-like proteins with slightly different substrate specificities from the Arabidopsis homolog KNATM-B. Double mutant analyses with M. truncatula single leaflet1 (sgl1) and palmate-like pentafoliata1 (palm1) leaf mutants show that fcl1 is epistatic to palm1 and sgl1 is epistatic to fcl1 in terms of leaf complexity and that SGL1 and FCL1 act additively and are required for petiole development. Previous studies have shown that the canonical KNOX proteins are not involved in compound leaf development in IRLC legumes. The identification of FCL1 supports the role of a truncated KNOX protein in compound leaf development in M. truncatula. PMID:22080596

Effect of plant diversity on the diversity of soil organic compounds.

PubMed

El Moujahid, Lamiae; Le Roux, Xavier; Michalet, Serge; Bellvert, Florian; Weigelt, Alexandra; Poly, Franck

2017-01-01

The effect of plant diversity on aboveground organisms and processes was largely studied but there is still a lack of knowledge regarding the link between plant diversity and soil characteristics. Here, we analyzed the effect of plant identity and diversity on the diversity of extractible soil organic compounds (ESOC) using 87 experimental grassland plots with different levels of plant diversity and based on a pool of over 50 plant species. Two pools of low molecular weight organic compounds, LMW1 and LMW2, were characterized by GC-MS and HPLC-DAD, respectively. These pools include specific organic acids, fatty acids and phenolics, with more organic acids in LMW1 and more phenolics in LMW2. Plant effect on the diversity of LMW1 and LMW2 compounds was strong and weak, respectively. LMW1 richness observed for bare soil was lower than that observed for all planted soils; and the richness of these soil compounds increased twofold when dominant plant species richness increased from 1 to 6. Comparing the richness of LMW1 compounds observed for a range of plant mixtures and for plant monocultures of species present in these mixtures, we showed that plant species richness increases the richness of these ESOC mainly through complementarity effects among plant species associated with contrasted spectra of soil compounds. This could explain previously reported effects of plant diversity on the diversity of soil heterotrophic microorganisms.

Effect of plant diversity on the diversity of soil organic compounds

PubMed Central

El Moujahid, Lamiae; Michalet, Serge; Bellvert, Florian; Weigelt, Alexandra; Poly, Franck

2017-01-01

The effect of plant diversity on aboveground organisms and processes was largely studied but there is still a lack of knowledge regarding the link between plant diversity and soil characteristics. Here, we analyzed the effect of plant identity and diversity on the diversity of extractible soil organic compounds (ESOC) using 87 experimental grassland plots with different levels of plant diversity and based on a pool of over 50 plant species. Two pools of low molecular weight organic compounds, LMW1 and LMW2, were characterized by GC-MS and HPLC-DAD, respectively. These pools include specific organic acids, fatty acids and phenolics, with more organic acids in LMW1 and more phenolics in LMW2. Plant effect on the diversity of LMW1 and LMW2 compounds was strong and weak, respectively. LMW1 richness observed for bare soil was lower than that observed for all planted soils; and the richness of these soil compounds increased twofold when dominant plant species richness increased from 1 to 6. Comparing the richness of LMW1 compounds observed for a range of plant mixtures and for plant monocultures of species present in these mixtures, we showed that plant species richness increases the richness of these ESOC mainly through complementarity effects among plant species associated with contrasted spectra of soil compounds. This could explain previously reported effects of plant diversity on the diversity of soil heterotrophic microorganisms. PMID:28166250

Network dimensionality and ligand flexibility in lanthanide terephthalate hydrates

NASA Astrophysics Data System (ADS)

Zehnder, Ralph A.; Renn, Robert A.; Pippin, Ethan; Zeller, Matthias; Wheeler, Kraig A.; Carr, Jason A.; Fontaine, Nick; McMullen, Nathan C.

2011-01-01

Various lanthanide open framework materials incorporating the terephthalate (TP) entity were prepared using hydrothermal synthesis methods at a moderate temperature of 170 °C. The compounds Nd 2(TP) 3(H 2O) 4( 1), Er 2(TP) 3(H 2O) 4( 2), Yb 2(TP) 3(H 2O) 2( 3), Yb 2(TP) 3(H 2O) 6( 4), and Yb 2(TP) 3(H 2O) 8·2H 2O ( 5), were characterized by single crystal structural analysis and FT-IR spectroscopy. While compounds 1 and 2 have been reported before on the basis of powder X-ray diffraction, the structural characterization of any ytterbium terephthalate species is unprecedented. Compounds 1- 5 crystallize in triclinic settings with space group P-1. The compounds are compared with their previously reported Er and Tb-counterparts and the reduction of the dimensionality of the resulting networks from 3D over 2D to 1D with increasing level of hydration is discussed. Compounds 1, 2, and 3 with the lowest water content assemble in three-dimensional network lattices. Compounds 4 and 5, however, form 2D layered systems and 1D rod like chains, respectively, which are held together by hydrogen bonds originating from coordinating H 2O. The crystal lattices of the 3D networks experience higher levels of tension as can be seen by increasing out-of-plane torsion with regard to the terephthalate carboxylate groups. Moreover, there seems to be a correlation between the level of strain on the aromatic ligands and the reduction of the number of carboxylate oxygen atoms that are part of the coordination polyhedra.

Potential artifacts associated with historical preparation of joint compound samples and reported airborne asbestos concentrations.

PubMed

Brorby, G P; Sheehan, P J; Berman, D W; Bogen, K T; Holm, S E

2011-05-01

Airborne samples collected in the 1970s for drywall workers using asbestos-containing joint compounds were likely prepared and analyzed according to National Institute of Occupational Safety and Health Method P&CAM 239, the historical precursor to current Method 7400. Experimentation with a re-created, chrysotile-containing, carbonate-based joint compound suggested that analysis following sample preparation by the historical vs. current method produces different fiber counts, likely because of an interaction between the different clearing and mounting chemicals used and the carbonate-based joint compound matrix. Differences were also observed during analysis using Method 7402, depending on whether acetic acid/dimethylformamide or acetone was used during preparation to collapse the filter. Specifically, air samples of sanded chrysotile-containing joint compound prepared by the historical method yielded fiber counts significantly greater (average of 1.7-fold, 95% confidence interval: 1.5- to 2.0-fold) than those obtained by the current method. In addition, air samples prepared by Method 7402 using acetic acid/dimethylformamide yielded fiber counts that were greater (2.8-fold, 95% confidence interval: 2.5- to 3.2-fold) than those prepared by this method using acetone. These results indicated (1) there is an interaction between Method P&CAM 239 preparation chemicals and the carbonate-based joint compound matrix that reveals fibers that were previously bound in the matrix, and (2) the same appeared to be true for Method 7402 preparation chemicals acetic acid/dimethylformamide. This difference in fiber counts is the opposite of what has been reported historically for samples of relatively pure chrysotile dusts prepared using the same chemicals. This preparation artifact should be considered when interpreting historical air samples for drywall workers prepared by Method P&CAM 239. Copyright © 2011 JOEH, LLC

Knock-Limited Power Outputs from a CFR Engine Using Internal Coolants. 3; Four Alkyl Amines, Three Alkanolamines, Six Amides, and Eight Heterocyclic Compounds

NASA Technical Reports Server (NTRS)

Imming, Harry S.; Bellman, Donald R.

1947-01-01

An investigation of the antiknock effectiveness of various additive-water solutions when used as internal coolants has been conducted at the NACA Cleveland laboratory. Nine compounds have been previously run in a CFR engine and the results are presented. In an effort to find a good anti-knock-coolant additive with more desirable physical properties than those of the nine compounds previously investigated, water solutions of four alkyl amines, three alkanolamines, six amides, and eight heterocyclic compounds were investigated and the results are presented.

Serendipitous discovery of light-induced (In Situ) formation of an Azo-bridged dimeric sulfonated naphthol as a potent PTP1B inhibitor.

PubMed

Bongard, Robert D; Lepley, Michael; Thakur, Khushabu; Talipov, Marat R; Nayak, Jaladhi; Lipinski, Rachel A Jones; Bohl, Chris; Sweeney, Noreena; Ramchandran, Ramani; Rathore, Rajendra; Sem, Daniel S

2017-05-31

Protein tyrosine phosphatases (PTPs) like dual specificity phosphatase 5 (DUSP5) and protein tyrosine phosphatase 1B (PTP1B) are drug targets for diseases that include cancer, diabetes, and vascular disorders such as hemangiomas. The PTPs are also known to be notoriously difficult targets for designing inihibitors that become viable drug leads. Therefore, the pipeline for approved drugs in this class is minimal. Furthermore, drug screening for targets like PTPs often produce false positive and false negative results. Studies presented herein provide important insights into: (a) how to detect such artifacts, (b) the importance of compound re-synthesis and verification, and (c) how in situ chemical reactivity of compounds, when diagnosed and characterized, can actually lead to serendipitous discovery of valuable new lead molecules. Initial docking of compounds from the National Cancer Institute (NCI), followed by experimental testing in enzyme inhibition assays, identified an inhibitor of DUSP5. Subsequent control experiments revealed that this compound demonstrated time-dependent inhibition, and also a time-dependent change in color of the inhibitor that correlated with potency of inhibition. In addition, the compound activity varied depending on vendor source. We hypothesized, and then confirmed by synthesis of the compound, that the actual inhibitor of DUSP5 was a dimeric form of the original inhibitor compound, formed upon exposure to light and oxygen. This compound has an IC 50 of 36 μM for DUSP5, and is a competitive inhibitor. Testing against PTP1B, for selectivity, demonstrated the dimeric compound was actually a more potent inhibitor of PTP1B, with an IC 50 of 2.1 μM. The compound, an azo-bridged dimer of sulfonated naphthol rings, resembles previously reported PTP inhibitors, but with 18-fold selectivity for PTP1B versus DUSP5. We report the identification of a potent PTP1B inhibitor that was initially identified in a screen for DUSP5, implying common mechanism of inhibitory action for these scaffolds.

Small Molecule Neuropilin-1 Antagonists Combine Antiangiogenic and Antitumor Activity with Immune Modulation through Reduction of Transforming Growth Factor Beta (TGFβ) Production in Regulatory T-Cells

PubMed Central

2018-01-01

We report the design, synthesis, and biological evaluation of some potent small-molecule neuropilin-1 (NRP1) antagonists. NRP1 is implicated in the immune response to tumors, particularly in Treg cell fragility, required for PD1 checkpoint blockade. The design of these compounds was based on a previously identified compound EG00229. The design of these molecules was informed and supported by X-ray crystal structures. Compound 1 (EG01377) was identified as having properties suitable for further investigation. Compound 1 was then tested in several in vitro assays and was shown to have antiangiogenic, antimigratory, and antitumor effects. Remarkably, 1 was shown to be selective for NRP1 over the closely related protein NRP2. In purified Nrp1+, FoxP3+, and CD25+ populations of Tregs from mice, 1 was able to block a glioma-conditioned medium-induced increase in TGFβ production. This comprehensive characterization of a small-molecule NRP1 antagonist provides the basis for future in vivo studies. PMID:29648813

Structure-Activity Correlations with Compounds Related to Abscisic Acid 1

PubMed Central

Sondheimer, Ernest; Walton, Daniel C.

1970-01-01

Inhibition of cell expansion of excised embryonic axes of Phaseolus vulgaris was used to evaluate the growth-inhibiting activity of abscisic acid and related compounds. None of the 13 compounds tested was as active as abscisic acid. 4-Hydroxyisophorone, a substance representative of the abscisic acid ring system was essentially inactive; cis, trans-3-methylsorbic acid, a compound resembling the side chain of abscisic acid, had low activity; and cis, trans-β-ionylideneacetic acid was one-sixth as active. Loss of the ring double bond results in a drastic decrease in biological activity. Comparison of our results with those reported previously leads to the suggestion that the double bond of the cyclohexyl moiety may have an important function in determining the degree of activity of cis, trans-ionylideneacetic acids. Two modes of action are discussed. It seems possible that the ring double bond is involved in covalent bonding in binding of the abscisic acid analogue to macromolecules. This may require formation of an intermediate epoxide. It can also be argued that stereochemical differences between cyclohexane derivatives are important factors in determining the degree of biological activity. PMID:5423465

In vitro mutagenic, antimutagenic, and antioxidant activities evaluation and biotransformation of some bioactive 4-substituted 1-(2-methoxyphenyl)piperazine derivatives.

PubMed

Słoczyńska, Karolina; Pańczyk, Katarzyna; Waszkielewicz, Anna M; Marona, Henryk; Pękala, Elżbieta

2016-12-01

In vitro mutagenic, antimutagenic, and antioxidant potency evaluation and biotransformation of six novel 4-substituted 1-(2-methoxyphenyl)piperazine derivatives demonstrating antidepressant-like activity were investigated. Mutagenic and antimutagenic properties were assessed using the Ames test; free radical scavenging activity was evaluated with 2,2-diphenyl-1-picrylhydrazyl radical scavenging assay and biotransformation was performed with liver microsomes. It was found that all tested compounds are not mutagenic in bacterial strains TA100 and TA1535 and exhibit antimutagenic effects in the Ames test. Noteworthy, compounds possessing propyl linker between phenoxyl and N-(2-methoxyphenyl)piperazine displayed more pronounced antimutagenic properties than derivatives with ethoxyethyl linker. Additionally, compounds 2 and 6 in vitro biotransformation showed that primarily their hydroxylated or O-dealkylated metabolites are formed. Some of the compounds exhibited intrinsic clearance values lower than those reported previously for antidepressant imipramine. To sum up, the results of the present study might represent a valuable step in designing and planning future studies with piperazine derivatives. © 2016 Wiley Periodicals, Inc.

Imaging flow cytometry for the screening of compounds that disrupt the Plasmodium falciparum digestive vacuole.

PubMed

Chia, Wan Ni; Lee, Yan Quan; Tan, Kevin Shyong-Wei

2017-01-01

Malaria, despite being one of the world's oldest infectious diseases, remains difficult to eradicate because the parasite is rapidly developing resistance to frontline chemotherapies. Previous studies have shown that the parasite exhibits features resembling programmed cell death upon treatment with drugs that disrupt its digestive vacuole (DV), providing a phenotypic readout that can be detected using the imaging flow cytometer. Large compound collections can thus be screened to identify drugs that are able to disrupt the DV of the malaria parasite using this high-content high-throughput screening platform. As a proof-of-concept, 4440 compounds were screened using this platform in 4months and 254 hits (5.7% hit rate) were obtained. Additionally, 25 compounds (0.6% top hit rate) were observed to retain potent DV disruption activity that was comparable to the canonical DV disruptive drug chloroquine when tested at a ten-fold lower concentration from the original screen. This pilot study demonstrates the robustness and high-throughput capability of the imaging flow cytometer and we report herein the methodology of this screening assay. Copyright © 2016 Elsevier Inc. All rights reserved.

Development of Thioaryl-Based Matrix Metalloproteinase-12 Inhibitors with Alternative Zinc-Binding Groups: Synthesis, Potentiometric, NMR, and Crystallographic Studies.

PubMed

Nuti, Elisa; Cuffaro, Doretta; Bernardini, Elisa; Camodeca, Caterina; Panelli, Laura; Chaves, Sílvia; Ciccone, Lidia; Tepshi, Livia; Vera, Laura; Orlandini, Elisabetta; Nencetti, Susanna; Stura, Enrico A; Santos, M Amélia; Dive, Vincent; Rossello, Armando

2018-05-24

Matrix metalloproteinase-12 (MMP-12) selective inhibitors could play a role in the treatment of lung inflammatory and cardiovascular diseases. In the present study, the previously reported 4-methoxybiphenylsulfonyl hydroxamate and carboxylate based inhibitors (1b and 2b) were modified to enhance their selectivity for MMP-12. In the newly synthesized thioaryl derivatives, the nature of the zinc binding group (ZBG) and the sulfur oxidation state were changed. Biological assays carried out in vitro on human MMPs with the resulting compounds led to identification of a sulfide, 4a, bearing an N-1-hydroxypiperidine-2,6-dione (HPD) group as new ZBG. Compound 4a is a promising hit compound since it displayed a nanomolar affinity for MMP-12 with a marked selectivity over MMP-9, MMP-1, and MMP-14. Solution complexation studies with Zn 2+ were performed to characterize the chelating abilities of the new compounds and confirmed the bidentate binding mode of HPD derivatives. X-ray crystallography studies using MMP-12 and MMP-9 catalytic domains were carried out to rationalize the biological results.

Average and local structure of the Pb-free ferroelectric perovskites ( Sr , Sn ) TiO 3 and ( Ba , Ca , Sn ) TiO 3

DOE Office of Scientific and Technical Information (OSTI.GOV)

Laurita, Geneva; Page, Katharine; Suzuki, Shoichiro

2015-12-16

The characteristic structural off -centering of Pb 2+ in oxides, associated with its 6s 2 lone pair, allows it to play a dominant role in polar materials, and makes it a somewhat ubiquitous component of ferroelectrics. In this work, we examine the compounds Sr 0.9Sn 0.1TiO 3 and Ba 0.79Ca 0.16Sn 0.05TiO 3 using neutron total scattering techniques with data acquired at di erent temperatures. In these compounds, previously reported as ferroelectrics, Sn 2+ appears to display some of the characteristics of Pb 2+. We compare the local and long-range structures of the Sn2+-substituted compositions to the unsubstituted parent compoundsmore » SrTiO 3 and BaTiO 3. Lastly, we find that even at these small substitution levels, the Sn 2+ lone pairs drive the local ordering behavior, with the local structure of both compounds more similar to the structure of PbTiO 3 rather than the parent compounds.« less

Chemical constituents of Hericium erinaceum associated with the inhibitory activity against cellular senescence in human umbilical vascular endothelial cells.

PubMed

Noh, Hyung Jun; Yang, Hyo Hyun; Kim, Geum Soog; Lee, Seung Eun; Lee, Dae Young; Choi, Je Hun; Kim, Seung Yu; Lee, Eun Suk; Ji, Seung Heon; Kang, Ki Sung; Park, Hye-Jin; Kim, Jae-Ryong; Kim, Ki Hyun

2015-12-01

Hericium erinaceum is an edible and medicinal mushroom widely used in Korea, Japan, and China. On the search for biologically active compounds supporting the medicinal usage, the MeOH extract of the fruiting bodies of H. erinaceum was investigated for its chemical constituents. Six compounds were isolated and identified as hericenone D (1), (22E,24R)-5α,8α-epidioxyergosta-6,22-dien-3β-ol (2), erinacerin B (3), hericenone E (4), hericenone F (5) and isohericerin (6) by comparing their spectroscopic data with previously reported values. The inhibitory effects on adriamycin-induced cellular senescence in human dermal fibroblasts (HDFs) and human umbilical vein endothelial cells (HUVECs) of the isolates (1-6) were studied. Among the isolated compounds, ergosterol peroxide (2) reduced senescence associated β-galactosidase (SA-β-gal) activity increased in HUVECs treated with adriamycin. According to experimental data obtained, the active compound may inspire the development of a new pharmacologically useful substance to be used in the treatment and prevention of age-related diseases.

Chemical constituents from Hericium erinaceus and their ability to stimulate NGF-mediated neurite outgrowth on PC12 cells.

PubMed

Zhang, Cheng-Chen; Yin, Xia; Cao, Chen-Yu; Wei, Jing; Zhang, Qiang; Gao, Jin-Ming

2015-11-15

One new meroterpenoid, named hericenone K (11), along with 10 known compounds (1-10), ergosterol peroxide (1), cerevisterol (2), 3β,5α,9α-trihydroxy-ergosta-7,22-dien-6-one (3), inoterpene A (4), astradoric acid C (5), betulin (6), oleanolic acid (7), ursolic acid (8), hemisceramide (9), and 3,4-dihydro-5-methoxy-2-methyl-2-(4'-methyl-2'-oxo-3'-pentenyl)-9(7H)-oxo-2H-furo[3,4-h]benzopyran (10), was isolated from the fruiting bodies of the mushroom Hericium erinaceus. Their structures were characterized on the basis of spectroscopic methods, as well as through comparison with previously reported data. Compounds 3-6, 8, and 9 were isolated from Hericium species for the first time. Compounds 10 and 11 was suggested to be racemic by the CD spectrum data and specific rotations, which ware resolved by chiral HPLC into respective enantiomers. Compounds 1-3, (±)-10, (-)-10 and (+)-10 in the presence of NGF (20 ng/mL) exerted a significant increase in neurite-bearing cells. Copyright © 2015 Elsevier Ltd. All rights reserved.

Reactions Involved in the Lower Pathway for Degradation of 4-Nitrotoluene by Mycobacterium Strain HL 4-NT-1

PubMed Central

He, Zhongqi; Spain, Jim C.

2000-01-01

In spite of the variety of initial reactions, the aerobic biodegradation of aromatic compounds generally yields dihydroxy intermediates for ring cleavage. Recent investigation of the degradation of nitroaromatic compounds revealed that some nitroaromatic compounds are initially converted to 2-aminophenol rather than dihydroxy intermediates by a number of microorganisms. The complete pathway for the metabolism of 2-aminophenol during the degradation of nitrobenzene by Pseudomonas pseudoalcaligenes JS45 has been elucidated previously. The pathway is parallel to the catechol extradiol ring cleavage pathway, except that 2-aminophenol is the ring cleavage substrate. Here we report the elucidation of the pathway of 2-amino-4-methylphenol (6-amino-m-cresol) metabolism during the degradation of 4-nitrotoluene by Mycobacterium strain HL 4-NT-1 and the comparison of the substrate specificities of the relevant enzymes in strains JS45 and HL 4-NT-1. The results indicate that the 2-aminophenol ring cleavage pathway in strain JS45 is not unique but is representative of the pathways of metabolism of other o-aminophenolic compounds. PMID:10877799

Heterometallic titanium–gold complexes inhibit renal cancer cells in vitro and in vivo † †This paper is dedicated to Prof. Roberto Sánchez-Delgado, great mentor and excellent friend, on the occasion of his 65th birthday. ‡ ‡Electronic supplementary information (ESI) available: Stability studies of the new compounds by NMR, UV-vis spectroscopy and MS spectrometry, crystallographic data for compound 6, DFT calculations for compounds 4–7, IC50 values in human renal cells at both 24 and 72 h, details on migration studies, TrxR inhibition studies for 3, 5 and AF at different times, inhibition studies of compound 5 against a panel of 35 protein kinases, effects of AF on MAPKAPK-3 in Caki-1 cells, effects of compound 3 in Caki-1 mouse xenografts. CCDC 1400886. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c5sc01753j Click here for additional data file. Click here for additional data file.

PubMed Central

Fernández-Gallardo, Jacob; Elie, Benelita T.; Sadhukha, Tanmoy; Prabha, Swayam; Sanaú, Mercedes; Rotenberg, Susan A.

2015-01-01

Following recent work on heterometallic titanocene–gold complexes as potential chemotherapeutics for renal cancer, we report here on the synthesis, characterization and stability studies of new titanocene complexes containing a methyl group and a carboxylate ligand (mba = S–C6H4–COO–) bound to gold(i)-phosphane fragments through a thiolate group [(η-C5H5)2TiMe(μ-mba)Au(PR3)]. The compounds are more stable in physiological media than those previously reported and are highly cytotoxic against human cancer renal cell lines. We describe here preliminary mechanistic data involving studies on the interaction of selected compounds with plasmid (pBR322) DNA used as a model nucleic acid, and with selected protein kinases from a panel of 35 protein kinases having oncological interest. Preliminary mechanistic studies in Caki-1 renal cells indicate that the cytotoxic and anti-migration effects of the most active compound 5 [(η-C5H5)2TiMe(μ-mba)Au(PPh3)] involve inhibition of thioredoxin reductase and loss of expression of protein kinases that drive cell migration (AKT, p90-RSK, and MAPKAPK3). The co-localization of both titanium and gold metals (1 : 1 ratio) in Caki-1 renal cells was demonstrated for 5 indicating the robustness of the heterometallic compound in vitro. Two compounds were selected for further in vivo studies on mice based on their selectivity in vitro against renal cancer cell lines when compared to non-tumorigenic human kidney cell lines (HEK-293T and RPTC) and the favourable preliminary toxicity profile in C57BL/6 mice. Evaluation of Caki-1 xenografts in NOD.CB17-Prkdc SCID/J mice showed an impressive tumor reduction (67%) after treatment for 28 days (3 mg per kg per every other day) with heterometallic compound 5 as compared with the previously described [(η-C5H5)2Ti{OC(O)-4-C6H4-P(Ph2)AuCl}2] 3 which was non-inhibitory. These findings indicate that structural modifications on the ligand scaffold affect the in vivo efficacy of this class of compounds. PMID:27213034

Time‐ and concentration‐dependent genomic responses of the rat airway to inhaled nickel sulfate

PubMed Central

Campbell, J. L.; Dodd, D. E.; Oller, A. R.; Clewell, H. J.

2017-01-01

While insoluble nickel subsulfide (Ni3S2) was carcinogenic in the lung in a 2‐year rat bioassay, soluble nickel sulfate hexahydrate (NiSO4*6H2O) was not. To investigate whether differences in the cellular responses to these two nickel compounds could underlie their differential activities, we conducted parallel studies to determine the gene expression changes in micro‐dissected lung distal airway cells from Fischer 344 rats following inhalation of the two compounds for one and four weeks (6 hr per day, 5 days per week). The results of the Ni3S2 study have been reported previously; this paper reports the results for NiSO4 and provides a comparative analysis. The cellular responses to NiSO4 were highly similar to those previously reported for Ni3S2, and a set of genes was identified whose expression could be used as biomarkers for comparing cellular nickel effects from in vitro or in vivo studies with soluble NiSO4 and particulate Ni3S2. Evaluation of the genomic concentration‐responses for the two compounds suggests that the highest inhaled concentration in the tumor bioassay for NiSO4, which was limited by toxicity, may not have achieved the Ni concentrations at which tumors were observed in the Ni3S2 bioassay. However, several key differences in the immune responses to NiSO4 and Ni3S2 were identified that may result from the differential intracellular disposition of Ni from NiSO4 entering the cell as an ion rather than as a slowly soluble Ni3S2 particle. These differences may also contribute to the observation of tumors in the bioassay for Ni3S2 but not NiSO4. Environ. Mol. Mutagen. 58:607–618, 2017. © 2017 The Authors Environmental and Molecular Mutagenesis published by Wiley Periodicals, Inc. on behalf of Environmental Mutagen Society PMID:28862355

Large drought-induced variations in oak leaf volatile organic compound emissions during PINOT NOIR 2012

DOE PAGES

Geron, Chris; Gu, Lianhong; Daly, Ryan; ...

2015-12-17

Here, leaf-level isoprene and monoterpene emissions were collected and analyzed from five of the most abundant oak (Quercus) species in Central Missouri's Ozarks Region in 2012 during PINOT NOIR (Particle Investigations at a Northern Ozarks Tower – NOx, Oxidants, Isoprene Research). June measurements, prior to the onset of severe drought, showed isoprene emission rates and leaf temperature responses similar to those previously reported in the literature and used in Biogenic Volatile Organic Compound (BVOC) emission models. During the peak of the drought in August, isoprene emission rates were substantially reduced, and response to temperature was dramatically altered, especially for themore » species in the red oak subgenus (Erythrobalanus).« less

Preisocalamendiol, Shyobunol and Related Oxygenated Sesquiterpenes from Bolivian Schinus molle Essential Oil.

PubMed

St-Gelais, Alexis; Mathieu, Michel; Levasseur, Virginie; Ovando, Jesús Flores; Escamilla, Ruben; Marceau, Hubert

2016-04-01

Five batches of Bolivian Schinus molle essential oils were obtained from pilot and industrial-scale hydrodiffusions. They were analyzed by gas chromatography to find 80 known compounds and two unknown molecules. In particular, preisocalamendiol (5.6-11.0 %) was found to be an important constituent of these oils, along with shyobunol (0.6-3.2 %) and several other related oxygenated sesquiterpenes. These compounds, usually found in Acorus calamus, had not been reported altogether in S. molle essential oils previously. These findings, in light of the GABAA positive modulating effect of shyobunone and preisocalamendiol, along with some traditional uses of S. molle, suggest that further investigation of the tranquilizing properties of these Bolivian oils would be of interest.

L-Asparaginase Production by the Rumen Anaerobe Vibrio succinogenes

PubMed Central

Kafkewitz, David; Goodman, David

1974-01-01

The rumen anaerobe Vibrio succinogenes possesses a constitutive L-asparaginase. The amount of enzyme produced is affected by the compound supplied to the organism to generate the fumaric acid it requires as a terminal electron acceptor. When nitrate is provided as the terminal electron acceptor, the amount of enzyme produced is affected by the compound provided to satisfy the nutritional requirement of the organism for succinic acid. Specific activities of up to 8.4 IU/mg of protein in cell-free extracts have been obtained. This specific activity is higher than has been previously reported for any organism. The enzyme has an apparent Km of 1.7 × 10-5 M and low activity towards L-glutamine when assayed at pH 8.5. PMID:4855647

Disulfides with Anti-inflammatory Activity from the Brown Alga Dictyopteris membranacea.

PubMed

Dimou, Maria; Ioannou, Efstathia; Daskalaki, Maria G; Tziveleka, Leto A; Kampranis, Sotirios C; Roussis, Vassilios

2016-03-25

Six new (1, 2, and 4-7) and two previously reported (3 and 8) disulfides, along with 4-butyl-2,6-cycloheptadienone, γ-tocopherol, and δ-tocopherol, were isolated from an organic extract of the brown alga Dictyopteris membranacea, collected at Gerolimenas Bay, Greece. The structure elucidation of the isolated natural products was based on analysis of their spectroscopic data. Compounds 1, 3-6, and 8 were evaluated for their antibacterial and anti-inflammatory activities. None of the compounds displayed antibacterial activity against two resistant strains of Staphylococcus aureus and one strain of Escherichia coli. In contrast, metabolite 5 was able to cause strong inhibition of NO production with an IC50 value of 3.8 μM using an LPS stimulation assay.

(Tl, Sb) and (Tl, Bi) binary surface reconstructions on Ge(111) substrate

NASA Astrophysics Data System (ADS)

Gruznev, D. V.; Bondarenko, L. V.; Tupchaya, A. Y.; Yakovlev, A. A.; Mihalyuk, A. N.; Zotov, A. V.; Saranin, A. A.

2018-03-01

2D compounds made of Group-III and Group-V elements on the surface of silicon and germanium attract considerable attention due to prospects of creating III-V binary monolayers, which are predicted to hold advanced physical properties. In the present work, we have investigated two such systems, (Tl, Sb)/Ge(111) and (Tl, Bi)/Ge(111) using scanning tunneling microscopy, low energy electron diffraction observations and density-functional-theory calculations. In addition to the previously reported surface structures of 2D (Tl, Sb) and (Tl, Bi) compounds on Si(111), we found new ones, namely, √{ 7} × √{ 7} and 3 × 3. Formation processes and plausible models of their atomic arrangements are discussed.

Bioactive natural compounds from the plant endophytic fungi Pestalotiopsis spp.

PubMed

Wang, Kuiwu; Lei, Jinxiu; Wei, Jiguang; Yao, Nan

2012-11-01

The plant-endophytic strains of the fungus Pestalotiopsis (Amphisphaeriaceae) are distributed throughout the world. Previous chemical investigation of members of the genus resulted in the discovery of various bioactive secondary metabolites including chromones, cytosporones, polyketides, terpenoids and coumarins with diverse structural features. The present report reviews the papers, which have appeared in the literature till now, concerning the isolation, structural elucidation, and biological activities of the secondary metabolites from Pestalotiopsis species.

Iridoids from Pentas lanceolata.

PubMed

Schripsema, Jan; Caprini, Geisa Paulino; van der Heijden, Rob; Bino, Raoul; de Vos, Ric; Dagnino, Denise

2007-09-01

From the aerial parts of Pentas lanceolata, belonging to the family Rubiaceae, a series of iridoid glucosides was isolated by preparative HPLC. Seven iridoid glucosides were identified. Besides asperuloside and asperulosidic acid, characteristic iridoids for Rubiaceae, five new iridoids were isolated, namely, tudoside (1), 13R-epi-gaertneroside (2), 13R-epi-epoxygaertneroside (3), and a mixture of E-uenfoside (4) and Z-uenfoside (5). Further, it was shown that the compound reported as citrifolinin B (6) is in fact the same as tudoside and should be revised. Also, the configuration of the previously reported iridoids gaertneroside and epoxygaertneroside has been elucidated.

Discovery and characterization of a novel series of N-phenylsulfonyl-1H-pyrrole picolinamides as positive allosteric modulators of the metabotropic glutamate receptor 4 (mGlu4).

PubMed

Gogliotti, Rocco D; Blobaum, Anna L; Morrison, Ryan M; Daniels, J Scott; Salovich, James M; Cheung, Yiu-Yin; Rodriguez, Alice L; Loch, Matthew T; Conn, P Jeffrey; Lindsley, Craig W; Niswender, Colleen M; Hopkins, Corey R

2016-07-01

Herein we report the synthesis and characterization of a novel series of N-phenylsulfonyl-1H-pyrrole picolinamides as novel positive allosteric modulators of mGlu4. We detail our work towards finding phenyl replacements for the core scaffold of previously reported phenyl sulfonamides and phenyl sulfone compounds. Our efforts culminated in the identification of N-(1-((3,4-dimethylphenyl)sulfonyl)-1H-pyrrol-3-yl)picolinamide as a potent PAM of mGlu4. Copyright © 2016 Elsevier Ltd. All rights reserved.

New lignan glycosides from Justicia procumbens.

PubMed

Jin, Hong; Yang, Shu; Dong, Jun-Xing

2017-01-01

Four new lignan glycosides (1-4), named procumbenosides I, K, L, and M, together with cleistanthin B (5) reported for the first time in the genus Justicia, and 5 other known arylnaphthalene lignan glycosides (6-10) were isolated from the whole plant of Justicia procumbens. The structures of the new compounds were elucidated by extensive one-dimensional (1D) and two-dimensional (2D) NMR experiments and mass spectrometry. Procumbenoside M (4) was a rare sesquilignan glycoside never previously reported in the species of Justicia. The paper also provided insight into the conformational equilibria existing in the lignan glycosides of the plant.

Prediction of multi-target networks of neuroprotective compounds with entropy indices and synthesis, assay, and theoretical study of new asymmetric 1,2-rasagiline carbamates.

PubMed

Romero Durán, Francisco J; Alonso, Nerea; Caamaño, Olga; García-Mera, Xerardo; Yañez, Matilde; Prado-Prado, Francisco J; González-Díaz, Humberto

2014-09-24

In a multi-target complex network, the links (L(ij)) represent the interactions between the drug (d(i)) and the target (t(j)), characterized by different experimental measures (K(i), K(m), IC50, etc.) obtained in pharmacological assays under diverse boundary conditions (c(j)). In this work, we handle Shannon entropy measures for developing a model encompassing a multi-target network of neuroprotective/neurotoxic compounds reported in the CHEMBL database. The model predicts correctly >8300 experimental outcomes with Accuracy, Specificity, and Sensitivity above 80%-90% on training and external validation series. Indeed, the model can calculate different outcomes for >30 experimental measures in >400 different experimental protocolsin relation with >150 molecular and cellular targets on 11 different organisms (including human). Hereafter, we reported by the first time the synthesis, characterization, and experimental assays of a new series of chiral 1,2-rasagiline carbamate derivatives not reported in previous works. The experimental tests included: (1) assay in absence of neurotoxic agents; (2) in the presence of glutamate; and (3) in the presence of H2O2. Lastly, we used the new Assessing Links with Moving Averages (ALMA)-entropy model to predict possible outcomes for the new compounds in a high number of pharmacological tests not carried out experimentally.

Journal Article: the National Dioxin Air Monitoring Network ...

EPA Pesticide Factsheets

The U.S. EPA has established a National Dioxin Air Monitoring Network (NDAMN) to determine the temporal and geographical variability of atmospheric CDDs, CDFs and coplanar PCBs at rural and nonimpacted locations throughout the United States. Currently operating at 32 sampling stations, NDAMN has three primary purposes: (1) to determine the atmospheric levels and occurrences of dioxin-like compounds in rural and agricultural areas where livestock, poultry and animal feed crops are grown; (2) to provide measurements of atmospheric levels of dioxin-like compounds in different geographic regions of the U.S.; and (3) to provide information regarding the long-range transport of dioxin-like compounds in air over the U.S. Designed in 1997, NDAMN has been implemented in phases, with the first phase consisting of 9 monitoring stations. Previously EPA has reported on the preliminary results of monitoring at 9 rural locations from June1998 through June 19991. The one-year measurement at the 9 stations indicated an annual mean TEQDF–WHO98 air concentration of 12 fg m-3. Since this reporting, NDAMN has been extended to include additional stations. The following is intended to be an update to this national monitoring effort. We are reporting the air monitoring results of 22 NDAMN stations operational over 9 sampling moments from June 1998 to December 1999. Fifteen stations are in rural areas, and 6 are located in National Parks. One station is located in suburban Wa

Search for Unique Organic Biomarkers in ALH84001

NASA Technical Reports Server (NTRS)

Zare, Richard N.

1999-01-01

Four goals were outlined for this project. These were: [1] to reproduce the measurement of polycyclic aromatic hydrocarbons (PAHS) in ALH84001 with both a higher spatial resolution and sensitivity than has been previously reported; [2] to extend such measurements to include other members of the Martian SNC (Shergotties, Nahklites, and Chassigny) meteorite clan, in particular the Antarctic Martian meteorite EETA79001; [3] to address issues of potential organic contamination, because at present very little is known about the effect of terrestrial weathering in the Antarctic environment as it pertains to perturbing an indigenous organic distribution within a meteoritic matrix; and [4] to diversify the range of organic compounds studied to include species that can serve as unique biological markers - "molecular fossils" - derived from once living organisms. In order to achieve this, three specific goals were outlined for the funding period 06/01/97 to 02/28/98. They were: [1] to investigate the effects of terrestrial weathering and organic contamination of meteoritic samples collected from Antarctica; [2] to reproduce and extend upon the measurements of PAHs in ALH84001 with the aim of establishing or refuting the indigeneity of these species; and [3] to extend the analysis of organic compounds in ALH84001 and EETA79001 to address compounds that are considered to be more biologically relevant than PAHS. All three were successfully accomplished, as detailed in the previous performance report. In brief, however, the results achieved were to establish that the PAHs found in ALH84001 were indigenous and not due to contamination, and to determine that a novel and sensitive technique in meteoritic work, capillary zone electrophoresis (CE), could indeed detect amino acids, a potential class of biomarker.

Optimization of benzoxazole-based inhibitors of Cryptosporidium parvum inosine 5′-monophosphate dehydrogenase

PubMed Central

Gorla, Suresh Kumar; Kavitha, Mandapati; Zhang, Minjia; Chin, James En Wai; Liu, Xiaoping; Striepen, Boris; Makowska-Grzyska, Magdalena; Kim, Youngchang; Joachimiak, Andrzej; Hedstrom, Lizbeth; Cuny, Gregory D.

2013-01-01

Cryptosporidium parvum is an enteric protozoan parasite that has emerged as a major cause of diarrhea, malnutrition and gastroenteritis as well as posing a potential bioterrorism threat. C. parvum synthesizes guanine nucleotides from host adenosine in a streamlined pathway that relies on inosine 5′-monophosphate dehydrogenase (IMPDH). We have previously identified several parasite-selective C. parvum IMPDH (CpIMPDH) inhibitors by high-throughput screening. In this paper, we report the structure-activity relationship (SAR) for a series of benzoxazole derivatives with many compounds demonstrating CpIMPDH IC50 values in the nanomolar range and > 500-fold selectivity over human IMPDH (hIMPDH). Unlike previously reported CpIMPDH inhibitors, these compounds are competitive inhibitors versus NAD+. The SAR study reveals that pyridine and other small heteroaromatic substituents are required at the 2-position of the benzoxazole for potent inhibitory activity. In addition, several other SAR conclusions are highlighted with regard to the benzoxazole and the amide portion of the inhibitor, including preferred stereochemistry. An x-ray crystal structure of a representative E•IMP•inhibitor complex is also presented. Overall, the secondary amine derivative 15a (Q67) demonstrated excellent CpIMPDH inhibitory activity (IC50 = 0.5 ± 0.1 nM) and moderate stability (t1/2 = 44 min) in mouse liver microsomes. Compound 73, the racemic version of 15a, also displayed superb antiparasitic activity in a Toxoplasma gondii strain that relies on CpIMPDH (EC50 = 20 ± 20 nM), and selectivity versus a wild-type T. gondii strain (200-fold). No toxicity was observed (LD50 > 50 μM) against a panel of four mammalian cells lines. PMID:23668331

Liquid chromatography coupled to different atmospheric pressure ionization sources-quadrupole-time-of-flight mass spectrometry and post-column addition of metal salt solutions as a powerful tool for the metabolic profiling of Fusarium oxysporum.

PubMed

Cirigliano, Adriana M; Rodriguez, M Alejandra; Gagliano, M Laura; Bertinetti, Brenda V; Godeas, Alicia M; Cabrera, Gabriela M

2016-03-25

Fusarium oxysporum L11 is a non-pathogenic soil-borne fungal strain that yielded an extract that showed antifungal activity against phytopathogens. In this study, reversed-phase high-performance liquid chromatography (RP-HPLC) coupled to different atmospheric pressure ionization sources-quadrupole-time-of-flight mass spectrometry (API-QTOF-MS) was applied for the comprehensive profiling of the metabolites from the extract. The employed sources were electrospray (ESI), atmospheric pressure chemical ionization (APCI) and atmospheric pressure photoionization (APPI). Post-column addition of metal solutions of Ca, Cu and Zn(II) was also tested using ESI. A total of 137 compounds were identified or tentatively identified by matching their accurate mass signals, suggested molecular formulae and MS/MS analysis with previously reported data. Some compounds were isolated and identified by NMR. The extract was rich in cyclic peptides like cyclosporins, diketopiperazines and sansalvamides, most of which were new, and are reported here for the first time. The use of post-column addition of metals resulted in a useful strategy for the discrimination of compound classes since specific adducts were observed for the different compound families. This technique also allowed the screening for compounds with metal binding properties. Thus, the applied methodology is a useful choice for the metabolic profiling of extracts and also for the selection of metabolites with potential biological activities related to interactions with metal ions. Copyright © 2015 Elsevier B.V. All rights reserved.

Olfactory cues from plants infected by powdery mildew guide foraging by a mycophagous ladybird beetle.

PubMed

Tabata, Jun; De Moraes, Consuelo M; Mescher, Mark C

2011-01-01

Powdery mildews (Erysiphales) are economically important plant pathogens that attack many agricultural crops. Conventional management strategies involving fungicide application face challenges, including the evolution of resistance and concerns over impacts on non-target organisms, that call for investigation of more sustainable alternatives. Mycophagous ladybird beetles (Coleoptera: Coccinellidae) feed on powdery mildew and have considerable potential as biological control agents; however, the foraging ecology and behavior of these beetles is not well understood. Here we document the olfactory cues presented by squash plants (Cucurbita moschata) infected by powdery mildew (Podosphaera sp.) and the behavioral responses of twenty-spotted ladybird beetles (Psyllobora vigintimaculata) to these cues. Volatile analyses through gas chromatography revealed a number of volatile compounds characteristic of infected plants, including 3-octanol and its analogues 1-octen-3-ol and 3-octanone. These compounds are typical "moldy" odorants previously reported in volatiles collected from other fungi. In addition, infected plants exhibited elevated emissions of several compounds also observed in collections from healthy leaves, including linalool and benzyl alcohol, which are reported to have anti-fungal properties. In Y-tube choice assays, P. vigintimaculata beetles displayed a significant preference for the odors of infected plants compared to those of healthy plants. Moreover, beetles exhibited strong attraction to one individual compound, 1-octen-3-ol, which was the most abundant of the characteristic fungal compounds identified. These results enhance our understanding of the olfactory cues that guide foraging by mycophagous insects and may facilitate the development of integrated disease-management strategies informed by an understanding of underlying ecological mechanisms.

Olfactory Cues from Plants Infected by Powdery Mildew Guide Foraging by a Mycophagous Ladybird Beetle

PubMed Central

Tabata, Jun; De Moraes, Consuelo M.; Mescher, Mark C.

2011-01-01

Powdery mildews (Erysiphales) are economically important plant pathogens that attack many agricultural crops. Conventional management strategies involving fungicide application face challenges, including the evolution of resistance and concerns over impacts on non-target organisms, that call for investigation of more sustainable alternatives. Mycophagous ladybird beetles (Coleoptera: Coccinellidae) feed on powdery mildew and have considerable potential as biological control agents; however, the foraging ecology and behavior of these beetles is not well understood. Here we document the olfactory cues presented by squash plants (Cucurbita moschata) infected by powdery mildew (Podosphaera sp.) and the behavioral responses of twenty-spotted ladybird beetles (Psyllobora vigintimaculata) to these cues. Volatile analyses through gas chromatography revealed a number of volatile compounds characteristic of infected plants, including 3-octanol and its analogues 1-octen-3-ol and 3-octanone. These compounds are typical “moldy” odorants previously reported in volatiles collected from other fungi. In addition, infected plants exhibited elevated emissions of several compounds also observed in collections from healthy leaves, including linalool and benzyl alcohol, which are reported to have anti-fungal properties. In Y-tube choice assays, P. vigintimaculata beetles displayed a significant preference for the odors of infected plants compared to those of healthy plants. Moreover, beetles exhibited strong attraction to one individual compound, 1-octen-3-ol, which was the most abundant of the characteristic fungal compounds identified. These results enhance our understanding of the olfactory cues that guide foraging by mycophagous insects and may facilitate the development of integrated disease-management strategies informed by an understanding of underlying ecological mechanisms. PMID:21876772

Integrated Computational Approach for Virtual Hit Identification against Ebola Viral Proteins VP35 and VP40.

PubMed

Mirza, Muhammad Usman; Ikram, Nazia

2016-10-26

The Ebola virus (EBOV) has been recognised for nearly 40 years, with the most recent EBOV outbreak being in West Africa, where it created a humanitarian crisis. Mortalities reported up to 30 March 2016 totalled 11,307. However, up until now, EBOV drugs have been far from achieving regulatory (FDA) approval. It is therefore essential to identify parent compounds that have the potential to be developed into effective drugs. Studies on Ebola viral proteins have shown that some can elicit an immunological response in mice, and these are now considered essential components of a vaccine designed to protect against Ebola haemorrhagic fever. The current study focuses on chemoinformatic approaches to identify virtual hits against Ebola viral proteins (VP35 and VP40), including protein binding site prediction, drug-likeness, pharmacokinetic and pharmacodynamic properties, metabolic site prediction, and molecular docking. Retrospective validation was performed using a database of non-active compounds, and early enrichment of EBOV actives at different false positive rates was calculated. Homology modelling and subsequent superimposition of binding site residues on other strains of EBOV were carried out to check residual conformations, and hence to confirm the efficacy of potential compounds. As a mechanism for artefactual inhibition of proteins through non-specific compounds, virtual hits were assessed for their aggregator potential compared with previously reported aggregators. These systematic studies have indicated that a few compounds may be effective inhibitors of EBOV replication and therefore might have the potential to be developed as anti-EBOV drugs after subsequent testing and validation in experiments in vivo.

Unusual superconducting state at 49 K in electron-doped CaFe2As2 at ambient pressure

PubMed Central

Lv, Bing; Deng, Liangzi; Gooch, Melissa; Wei, Fengyan; Sun, Yanyi; Meen, James K.; Xue, Yu-Yi; Lorenz, Bernd; Chu, Ching-Wu

2011-01-01

We report the detection of unusual superconductivity up to 49 K in single crystalline CaFe2As2 via electron-doping by partial replacement of Ca by rare-earth. The superconducting transition observed suggests the possible existence of two phases: one starting at 49 K, which has a low critical field < 4 Oe, and the other at 21 K, with a much higher critical field > 5 T. Our observations are in strong contrast to previous reports of doping or pressurizing layered compounds AeFe2As2 (or Ae122), where Ae = Ca, Sr, or Ba. In Ae122, hole-doping has been previously observed to generate superconductivity with a transition temperature (Tc) only up to 38 K and pressurization has been reported to produce superconductivity with a Tc up to 30 K. The unusual 49 K phase detected will be discussed. PMID:21911404

Intracellular conversion and in vivo dose response of favipiravir (T-705) in rodents infected with Ebola virus.

PubMed

Bixler, Sandra L; Bocan, Thomas M; Wells, Jay; Wetzel, Kelly S; Van Tongeren, Sean A; Garza, Nicole L; Donnelly, Ginger; Cazares, Lisa H; Soloveva, Veronica; Welch, Lisa; Epstein, Carol; Liang, Li-Fang; Giesing, Dennis; Lenk, Robert; Bavari, Sina; Warren, Travis K

2018-03-01

During the 2013-2016 Ebola virus (EBOV) outbreak in West Africa, our team at USAMRIID evaluated the antiviral activity of a number of compounds, including favipiravir (T-705), in vitro and in mouse and nonhuman primate (NHP) models of Ebola virus disease. In this short communication, we present our findings for favipiravir in cell culture and in mice, while an accompanying paper presents the results of NHP studies. We confirmed previous reports that favipiravir has anti-EBOV activity in mice. Additionally, we found that the active form of favipiravir is generated in mice in tissues relevant for the pathogenesis of EBOV infection. Finally, we observed that protection can be achieved in mice down to 8 mg/kg/day, which is lower than the dosing regimens previously reported. An accompanying paper reports the results of treating nonhuman primates infected with EBOV or with Marburg virus with oral or intravenous favipiravir. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

Comparison of EMIT II, CEDIA, and DPC RIA assays for the detection of lysergic acid diethylamide in forensic urine samples.

PubMed

Wiegand, Russell F; Klette, Kevin L; Stout, Peter R; Gehlhausen, Jay M

2002-10-01

In an effort to determine a practical, efficient, and economical alternative for the use of a radioimmunoassay (RIA) for the detection of lysergic acid diethylamide (LSD) in human urine, the performance of two photometric immunoassays (Dade Behring EMIT II and Microgenics CEDIA) and the Diagnostics Products Corp. (DPC) RIA were compared. Precision, accuracy, and linearity of the 3 assays were determined by testing 60 replicates (10 for RIA) at 5 different concentrations below and above the 500-pg/mL LSD cut-off. The CEDIA and RIA exhibited better accuracy and precision than the EMIT II immunoassay. In contrast, the EMIT II and CEDIA demonstrated superior linearity r2 = 0.9809 and 0.9540, respectively, as compared with the RIA (r2 = 0.9062). The specificity of the three assays was assessed using compounds that have structural and chemical properties similar to LSD, common over-the-counter products, prescription drugs and some of their metabolites, and other drugs of abuse. Of the 144 compounds studied, the EMIT II cross-reacted with twice as many compounds as did the CEDIA and RIA. Specificity was also assessed in 221 forensic human urine specimens that previously screened positive for LSD by the EMIT II assay. Of these, only 11 tested positive by CEDIA, and 3 were positive by RIA. This indicated a comparable specificity performance between CEDIA and RIA. This also was consistent with a previously reported high false-positive rate of EMIT II (low specificity). Each of the immunoassays correctly identified LSD in 23 out of 24 human urine specimens that had previously been found to contain LSD by gas chromatography-mass spectrometry at a cut-off concentration of 200 pg/mL. The CEDIA exhibited superior precision, accuracy, and decreased cross-reactivity to compounds other than LSD as compared with the EMIT II assay and does not necessitate the handling of radioactive materials.

Studies on the Red Sea Sponge Haliclona sp. for its Chemical and Cytotoxic Properties.

PubMed

Al-Massarani, Shaza Mohamed; El-Gamal, Ali Ali; Al-Said, Mansour Sulaiman; Abdel-Kader, Maged S; Ashour, Abdelkader E; Kumar, Ashok; Abdel-Mageed, Wael M; Al-Rehaily, Adnan Jathlan; Ghabbour, Hazem A; Fun, Hoong-Kun

2016-01-01

A great number of novel compounds with rich chemical diversity and significant bioactivity have been reported from Red Sea sponges. To isolate, identify, and evaluate the cytotoxic activity of the chemical constituents of a sponge belonging to genus Haliclona collected from the Eastern coast of the Red Sea. The total ethanolic extract of the titled sponge was subjected to intensive chromatographic fractionation and purification guided by cytotoxic bioassay toward various cancer cell lines. The structures of the isolated compounds were elucidated using spectroscopic techniques including one-dimension and two-dimension nuclear magnetic resonance, mass spectrometry, ultraviolet, and infrared data, as well as comparison with the reported spectral data for the known compounds. X-ray single-crystal structure determination was performed to determine the absolute configuration of compound 4. The screening of antiproliferative activity of the compounds was carried on three tumor cell lines, namely the human cervical cancer (HeLa), human hepatocellular carcinoma (HepG2), and human medulloblastoma (Daoy) cells using MTT assay. This investigation resulted in the isolation of a new indole alkaloid, 1-(1H-indol-3-yloxy) propan-2-ol (1), with the previously synthesized pyrrolidine alkaloid, (2R, 3S, 4R, 5R) pyrrolidine-(1-hydroxyethyl)-3,4-diol hydrochloride (4), isolated here from a natural source for the first time. In addition, six known compounds tetillapyrone (2), nortetillapyrone (3), 2-methyl maleimide-5-oxime (5), maleimide-5-oxime (6), 5-(hydroxymethyl) dihydrofuran-2 (3H)-one (7), and ergosta-5,24 (28)-dien-3-ol (8) were also identified. Most of the isolated compounds exhibited weak cytotoxic activity against HepG-2, Daoy, and HeLa cancer cell lines. This is the first report of the occurrence of the indole and pyrrolidine alkaloids, 1-(1H-indol-2-yloxy) propan-2-ol (1), and the - (1-hydroxyethyl)-3,4-diol hydrochloride (4), in the Red Sea Haliclona sp. From the Red Sea Haliclona sp. two alkaloids with indole and pyrrolidine nuclei, 1-(1H-indol-2-yloxy) propan-2-ol-(1) and pyrrolidine-(1-hydroxyethyl)-3,4-diol hydrochloride (4) were isolated and fully characterized; in addition to six known compounds (2, 3, 5-8)The absolute configuration and the three-dimension stereo-molecular structure of compound 4 were determined by X-ray crystallographyThe different extracts and isolated compounds showed weak cytotoxic activity against HepG-2, Daoy, and HeLa cancer cell lines.

Isolation and purification of antialgal compounds from the red alga Gracilaria lemaneiformis for activity against common harmful red tide microalgae.

PubMed

Sun, Ying-Ying; Meng, Kun; Su, Zhen-Xia; Guo, Gan-Lin; Pu, Yin-Fang; Wang, Chang-Hai

2017-02-01

Seven antialgal compounds (1-7) were successfully isolated from the red alga Gracilaria lemaneiformis through a combination of silica gel column chromatography and repeated preparative thin-layer chromatography. On the basis of the spectral data, the compounds were identified as gossonorol (1), 7,10-epoxy-ar-bisabol-11-ol (2), glycerol monopalmitate (3), stigmasterol (4), 15-hydroxymethyl-2, 6, 10, 18, 22, 26, 30-heptamethyl-14-methylene-17-hentriacontene (5), 4-hydroxyphenethyl alcohol (6), and margaric acid (7). These seven compounds were isolated from G. lemaneiformis for the first time, while the compounds 4, 6, and 7 were isolated from marine macroalgae for the first time. Furthermore, a quantitative relationship between the inhibition of algal growth and the concentration of each antialgal compound was determined and important parameters for future practical HAB control, e.g., EC 50-96h , were also obtained. The results indicated that isolated compounds 1-7 possess selective antialgal activity against the growth of several red tide microalgae (including Amphidinium carterae, Heterosigma akashiwo, Karenia mikimitoi, Phaeocystis globsa, Prorocentrum donghaiense, and Skeletonema costatum). Their antialgal activity against test red tide microalgae has not been previously reported. Furthermore, the EC 50-96h of one or more of the compounds towards the tested red microalgae was not only significantly less than 10 μg/mL but also was smaller than that of the characteristic antialgal agent potassium dichromate. The study demonstrates that compounds 1-7 possess significant application potential as antialgal agents against several harmful red tide microalgae.

Fragment-Based Identification of Influenza Endonuclease Inhibitors

PubMed Central

2016-01-01

The influenza virus is responsible for millions of cases of severe illness annually. Yearly variance in the effectiveness of vaccination, coupled with emerging drug resistance, necessitates the development of new drugs to treat influenza infections. One attractive target is the RNA-dependent RNA polymerase PA subunit. Herein we report the development of inhibitors of influenza PA endonuclease derived from lead compounds identified from a metal-binding pharmacophore (MBP) library screen. Pyromeconic acid and derivatives thereof were found to be potent inhibitors of endonuclease. Guided by modeling and previously reported structural data, several sublibraries of molecules were elaborated from the MBP hits. Structure–activity relationships were established, and more potent molecules were designed and synthesized using fragment growth and fragment merging strategies. This approach ultimately resulted in the development of a lead compound with an IC50 value of 14 nM, which displayed an EC50 value of 2.1 μM against H1N1 influenza virus in MDCK cells. PMID:27291165

Design and modeling of an SJ infrared solar cell approaching upper limit of theoretical efficiency

NASA Astrophysics Data System (ADS)

Sahoo, G. S.; Mishra, G. P.

2018-01-01

Recent trends of photovoltaics account for the conversion efficiency limit making them more cost effective. To achieve this we have to leave the golden era of silicon cell and make a path towards III-V compound semiconductor groups to take advantages like bandgap engineering by alloying these compounds. In this work we have used a low bandgap GaSb material and designed a single junction (SJ) cell with a conversion efficiency of 32.98%. SILVACO ATLAS TCAD simulator has been used to simulate the proposed model using both Ray Tracing and Transfer Matrix Method (under 1 sun and 1000 sun of AM1.5G spectrum). A detailed analyses of photogeneration rate, spectral response, potential developed, external quantum efficiency (EQE), internal quantum efficiency (IQE), short-circuit current density (JSC), open-circuit voltage (VOC), fill factor (FF) and conversion efficiency (η) are discussed. The obtained results are compared with previously reported SJ solar cell reports.

Study of the therapeutic benefit of cationic copolymer administration to vascular endothelium under mechanical stress

PubMed Central

Giantsos-Adams, Kristina; Lopez-Quintero, Veronica; Kopeckova, Pavla; Kopecek, Jindrich; Tarbell, John M.; Dull, Randal

2015-01-01

Pulmonary edema and the associated increases in vascular permeability continue to represent a significant clinical problem in the intensive care setting, with no current treatment modality other than supportive care and mechanical ventilation. Therapeutic compound(s) capable of attenuating changes in vascular barrier function would represent a significant advance in critical care medicine. We have previously reported the development of HPMA-based copolymers, targeted to endothelial glycocalyx that are able to enhance barrier function. In this work, we report the refinement of copolymer design and extend our physiological studies todemonstrate that the polymers: 1) reduce both shear stress and pressure-mediated increase in hydraulic conductivity, 2) reduce nitric oxide production in response to elevated hydrostatic pressure and, 3) reduce the capillary filtration coefficient (Kfc) in an isolated perfused mouse lung model. These copolymers represent an important tool for use in mechanotransduction research and a novel strategy for developing clinically useful copolymers for the treatment of vascular permeability. PMID:20932573

Investigational Antimicrobial Agents of 2013

PubMed Central

Pucci, Michael J.

2013-01-01

SUMMARY New antimicrobial agents are always needed to counteract the resistant pathogens that continue to be selected by current therapeutic regimens. This review provides a survey of known antimicrobial agents that were currently in clinical development in the fall of 2012 and spring of 2013. Data were collected from published literature primarily from 2010 to 2012, meeting abstracts (2011 to 2012), government websites, and company websites when appropriate. Compared to what was reported in previous surveys, a surprising number of new agents are currently in company pipelines, particularly in phase 3 clinical development. Familiar antibacterial classes of the quinolones, tetracyclines, oxazolidinones, glycopeptides, and cephalosporins are represented by entities with enhanced antimicrobial or pharmacological properties. More importantly, compounds of novel chemical structures targeting bacterial pathways not previously exploited are under development. Some of the most promising compounds include novel β-lactamase inhibitor combinations that target many multidrug-resistant Gram-negative bacteria, a critical medical need. Although new antimicrobial agents will continue to be needed to address increasing antibiotic resistance, there are novel agents in development to tackle at least some of the more worrisome pathogens in the current nosocomial setting. PMID:24092856

Alkaloids from psychotria target sirtuins: in silico and in vitro interaction studies.

PubMed

Sacconnay, Lionel; Ryckewaert, Lucie; Dos Santos Passos, Carolina; Guerra, Maria Cristina; Kato, Lucilia; Alves de Oliveira, Cecilia Maria; Henriques, Amélia; Carrupt, Pierre-Alain; Simões-Pires, Claudia; Nurisso, Alessandra

2015-04-01

Epigenetic enzymes such as histone deacetylases play a crucial role in the development of ageing-related diseases. Among the 18 histone deacetylase isoforms found in humans, class III histone deacetylases, also known as sirtuins, seem to be promising targets for treating neurodegenerative conditions. Recently, Psychotria alkaloids, mainly monoterpene indoles, have been reported for their inhibitory properties against central nervous system cholinesterase and monoamine oxidase proteins. Given the multifunctional profile of these alkaloids in the central nervous system, and the fact that the indole scaffold has been previously associated with sirtuin inhibition, we hypothesized that these indole derivatives could also interact with sirtuins. In the present study, alkaloids previously isolated from Psychotria spp. were evaluated for their potential interaction with human sirtuin 1 and sirtuin 2 by molecular docking and molecular dynamics simulation approaches. The in silico results allowed for the selection of five potentially active compounds, namely, prunifoleine, 14-oxoprunifoleine, E-vallesiachotamine, Z-vallesiachotamine, and vallesiachotamine lactone. The sirtuin inhibition of these compounds was confirmed in vitro in a dose-response manner, with preliminary information on their pharmacokinetics properties. Georg Thieme Verlag KG Stuttgart · New York.

Phenolic Component Profiles of Mustard Greens, Yu Choy, and 15 Other Brassica Vegetables

PubMed Central

Lin, Long-Ze; Harnly, James M

2013-01-01

A liquid chromatography–mass spectrometry (LC-MS) profiling method was used to characterize the phenolic components of 17 leafy vegetables from Brassica species other than Brassica oleracea. The vegetables studied were mustard green, baby mustard green, gai choy, baby gai choy, yu choy, yu choy tip, bok choy, bok choy tip, baby bok choy, bok choy sum, Taiwan bok choy, Shanghai bok choy, baby Shanghai bok choy, rapini broccoli, turnip green, napa, and baby napa. This work led to the tentative identification of 71 phenolic compounds consisting of kaempferol 3-O-diglucoside-7-O-glucoside derivatives, isorhamnetin 3-O-glucoside-7-O-glucoside hydroxycinnamoyl gentiobioses, hydroxycinnamoylmalic acids, and hydroxycinnamoylquinic acids. Ten of the compounds, 3-O-diacyltriglucoside-7-O-glucosides of kaempferol and quercetin, had not been previously reported. The phenolic component profiles of these vegetables were significantly different than those of the leafy vegetables from B. oleracea. This is the first comparative study of these leafy vegetables. Ten of the vegetables had never been previously studied by LC-MS. PMID:20465307

Characterization of organic aromatic compounds in soils affected by an uncontrolled tire landfill fire through the use of comprehensive two-dimensional gas chromatography-time-of-flight mass spectrometry.

PubMed

Escobar-Arnanz, J; Mekni, S; Blanco, G; Eljarrat, E; Barceló, D; Ramos, L

2018-02-09

Discarded vehicle tires have become an increasing concern worldwide due to the enormous amount of wastes generated and the increasing evidence of health problems associated to their disposal and accidental combustion. Previous studies conducted involving either simulated or open uncontrolled tire fires have identified aromatics belonging to two main classes, volatile organic compounds and polycyclic aromatic compounds (PAHs), as the most relevant chemicals generated in these burning processes. As a consequence, and due to their recognized toxicity, most studies reported up to now have mainly focused on these two categories of compounds being information concerning the possible occurrence of other aromatic classes rather limited. In this study, the enhanced separation power and structural confirmation capabilities provided by comprehensive two-dimensional gas chromatography-time-of-flight mass spectrometry (GC×GC-ToF MS) has been used, for the first time, for the non-targeted analysis of soils impacted by a tire fire and an ash collected at the scene of the fire. In total, 118 volatile and semi-volatile aromatic compounds have been differentiated. Among them, 104 compounds have been either positively or tentatively identified. PAHs with 3-5 rings and their alkyl-derivatives were the most numerous and relevant classes in the investigated samples. A significant number of sulfur, oxygen- and nitrogen-containing PAHs were also detected in the samples. The application of a script function to the raw GC×GC-ToF MS data allowed the fast filtering and automatic recognition of compounds containing halogens in their structure. This part of the study evidenced that only a limited number of regulated persistent organic pollutants were present in the investigated samples. However, it also revealed the presence of emerging organophosphorous flame retardants, whose levels in tire fire impacted soils are reported for the first time. Copyright © 2017 Elsevier B.V. All rights reserved.

Crystal growth and physical properties of SrCu2As2, SrCu2Sb2, and BaCu2Sb2

DOE Office of Scientific and Technical Information (OSTI.GOV)

Anand, V.K.; Perera, P. Kanchana; Pandey, Abhishek

2012-06-25

We report the growth of single crystals of SrCu2As2, SrCu2Sb2, SrCu2(As0.84Sb0.16)2, and BaCu2Sb2 using the self-flux technique and their structural, magnetic, thermal, and transport properties that were investigated by powder x-ray diffraction (XRD), magnetic susceptibility χ, specific heat Cp, and electrical resistivity ρ measurements versus temperature T from 1.8 to 350 K. Rietveld refinements of XRD patterns for crushed crystals confirm that SrCu2As2 crystallizes in the ThCr2Si2-type body-centered tetragonal structure (space group I4/mmm) and SrCu2Sb2 crystallizes in the CaBe2Ge2-type primitive tetragonal structure (space group P4/nmm). However, as reported previously, BaCu2Sb2 is found to have a large unit cell consisting ofmore » three blocks. Here a ThCr2Si2-type block is sandwiched between two CaBe2Ge2-type blocks along the c axis with an overall symmetry of I4/mmm, as reported, but likely with a monoclinic distortion. The χ data of all these compounds are diamagnetic and reveal nearly T-independent anisotropic behavior. The χ of SrCu2As2 is found to be larger in the ab plane than along the c axis, as also previously reported for pure and doped BaFe2As2, whereas the χ values of SrCu2Sb2 and BaCu2Sb2 are larger along the c axis. This difference in anisotropy appears to arise from the differences between the crystal structures. The finite values of the Sommerfeld linear specific heat coefficients γ and the T dependences of ρ reveal metallic character of all four compounds. The electronic and magnetic properties indicate that these compounds are sp metals with Cu in the nonmagnetic 3d10 electronic configuration corresponding to the oxidation state Cu+1, as previously predicted theoretically for SrCu2As2 by Singh [ Phys. Rev. B 79 153102 (2009)]. We present a brief review of theoretical and experimental work on the doping character of transition metals for Fe in BaFe2As2. The As–As covalent interlayer bond distances in the collapsed-tetragonal (Ca,Sr,Ba)Cu2As2 compounds are much shorter than the nonbonding As–As distances in BaFe2As2. Thus, the electronic character of the Cu and the strength of the As–As interlayer bonding are both expected to drastically change between weakly Cu-substituted BaFe2As2 and pure BaCu2As2, perhaps via a first-order lattice instability such as a miscibility gap in the Ba(Fe1−xCux)2As2 system.« less

Early severe scoliosis in a patient with atypical progressive pseudorheumatoid dysplasia (PPD): Identification of two WISP3 mutations, one previously unreported.

PubMed

Montané, Lucia Sentchordi; Marín, Oliver R; Rivera-Pedroza, Carlos I; Vallespín, Elena; Del Pozo, Ángela; Heath, Karen E

2016-06-01

Progressive pseudorheumatoid dysplasia (PPD) is a rare autosomal recessive disorder characterized by spondyloepiphyseal dysplasia associated with pain and stiffness of multiple joints, enlargement of the interphalangeal joints, normal inflammatory parameters, and absence of extra-skeletal manifestations. Homozygous or compound heterozygous WISP3 mutations cause PPD. We report two siblings from a non-consanguineous Ecuadorian family with a late-onset spondyloepiphyseal dysplasia. Mutation screening was undertaken in the two affected siblings using a customized skeletal dysplasia next generation sequencing (NGS) panel and confirmed by Sanger sequencing. Two compound heterozygous mutations were identified in WISP3 exon 2, c.[190G>A];[197G>A] (p.[(Gly64Arg)];[(Ser66Asn)]) in the two siblings, both of which had been inherited. The p. (Gly64Arg) mutation has not been previously described whilst the p. (Ser66Asn) mutation has been reported in two PPD families. The two siblings presented with atypical PPD, as they presented during late childhood, yet the severity was different between them. The progression was particularly aggressive in the male sibling who suffered severe scoliosis by the age of 13 years. This case reaffirms the clinical heterogeneity of this disorder and the clinical utility of NGS to genetically diagnose skeletal dysplasias, enabling adequate management, monitorization, and genetic counseling. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Detection of semi-volatile organic compounds (SVOCs) in surface water, soil, and groundwater in a chemical industrial park in Eastern China.

PubMed

Liu, Benhua; Li, Yuehua; Ma, Jianfeng; Huang, Linxian; Chen, Liang

2016-01-01

China is suffering from serious water and soil pollution, especially in the North China Plain. This work investigated semi-volatile organic compounds (SVOCs) in surface water, groundwater and soil within a chemical industrial park in Eastern China, for which the volatile organic compound (VOC) results have been previously reported. A total of 20 samples were collected from the field, and analyzed in the laboratory. A 100% detection frequency of SVOCs in samples from this chemical industrial park was observed (same as VOCs). Moreover, the detection frequency of 113 SVOCs in each sample reached 15.93, 12.39 and 20.35% for surface water, groundwater and soil, respectively. The most detected SVOCs in the park included N-containing SVOCs, polycyclic aromatic hydrocarbons, phthalates, organic pesticides and polychlorodiphenyls. The elevated detecting frequencies and concentration levels of SVOCs identified in the groundwater were attributed to the intensive chemical production activities in the park. In addition, the agricultural activities in the area might also have contributed to the SVOCs to the groundwater. The results of VOCs and SVOCs from this and previous studies suggest that the groundwater in this industrial park has been severely contaminated, and the contamination likely spreads beyond the park. Imminent hydrogeological assessments and remedial actions are warranted to eliminate the source and mitigate the potential plume expansion beyond the park boundary.

Detection and Monitoring of Neurotransmitters - a Spectroscopic Analysis

NASA Astrophysics Data System (ADS)

Manciu, Felicia; Lee, Kendall; Durrer, William; Bennet, Kevin

2012-10-01

In this work we demonstrate the capability of confocal Raman mapping spectroscopy for simultaneously and locally detecting important compounds in neuroscience such as dopamine, serotonin, and adenosine. The Raman results show shifting of the characteristic vibrations of the compounds, observations consistent with previous spectroscopic studies. Although some vibrations are common in these neurotransmitters, Raman mapping was achieved by detecting non-overlapping characteristic spectral signatures of the compounds, as follows: for dopamine the vibration attributed to C-O stretching, for serotonin the indole ring stretching vibration, and for adenosine the adenine ring vibrations. Without damage, dyeing, or preferential sample preparation, confocal Raman mapping provided positive detection of each neurotransmitter, allowing association of the high-resolution spectra with specific micro-scale image regions. Such information is particularly important for complex, heterogeneous samples, where modification of the chemical or physical composition can influence the neurotransmission processes. We also report an estimated dopamine diffusion coefficient two orders of magnitude smaller than that calculated by the flow-injection method.

Antivirulence C-Mannosides as Antibiotic-Sparing, Oral Therapeutics for Urinary Tract Infections.

PubMed

Mydock-McGrane, Laurel; Cusumano, Zachary; Han, Zhenfu; Binkley, Jana; Kostakioti, Maria; Hannan, Thomas; Pinkner, Jerome S; Klein, Roger; Kalas, Vasilios; Crowley, Jan; Rath, Nigam P; Hultgren, Scott J; Janetka, James W

2016-10-27

Gram-negative uropathogenic Escherichia coli (UPEC) bacteria are a causative pathogen of urinary tract infections (UTIs). Previously developed antivirulence inhibitors of the type 1 pilus adhesin, FimH, demonstrated oral activity in animal models of UTI but were found to have limited compound exposure due to the metabolic instability of the O-glycosidic bond (O-mannosides). Herein, we disclose that compounds having the O-glycosidic bond replaced with carbon linkages had improved stability and inhibitory activity against FimH. We report on the design, synthesis, and in vivo evaluation of this promising new class of carbon-linked C-mannosides that show improved pharmacokinetic (PK) properties relative to O-mannosides. Interestingly, we found that FimH binding is stereospecifically modulated by hydroxyl substitution on the methylene linker, where the R-hydroxy isomer has a 60-fold increase in potency. This new class of C-mannoside antagonists have significantly increased compound exposure and, as a result, enhanced efficacy in mouse models of acute and chronic UTI.

A Drosophila Gustatory Receptor Required for Strychnine Sensation

PubMed Central

Lee, Youngseok; Moon, Seok Jun; Wang, Yijin

2015-01-01

Strychnine is a potent, naturally occurring neurotoxin that effectively protects plants from animal pests by deterring feeding behavior. In insects, such as the fruit fly, Drosophila melanogaster, bitter-tasting aversive compounds are detected primarily through a family of gustatory receptors (GRs), which are expressed in gustatory receptor neurons. We previously described multiple GRs that eliminate the behavioral avoidance to all bitter compounds tested, with the exception of strychnine. Here, we report the identity of a strychnine receptor, referred to as GR47a. We generated a mutation in Gr47a and found that it eliminated strychnine repulsion and strychnine-induced action potentials. GR47a was narrowly tuned, as the responses to other avoidance compounds were unaffected in the mutant animals. This analysis supports an emerging model that Drosophila GRs fall broadly into two specificity classes—one class is comprised of core receptors that are broadly required, whereas the other class, which includes GR47a, consists of narrowly tuned receptors that define chemical specificity. PMID:26187906

Chrodrimanins K-N and Related Meroterpenoids from the Fungus Penicillium sp. SCS-KFD09 Isolated from a Marine Worm, Sipunculus nudus.

PubMed

Kong, Fan-Dong; Ma, Qing-Yun; Huang, Sheng-Zhuo; Wang, Pei; Wang, Jun-Feng; Zhou, Li-Man; Yuan, Jing-Zhe; Dai, Hao-Fu; Zhao, You-Xing

2017-04-28

Six new meroterpenoids, chrodrimanins K-N (1-4), including two uncommon chlorinated ones (1 and 2), and verruculides B2 (5) and B3 (6), as well as seven known ones (7-13), were isolated from the fermentation broth of Penicillium sp. SCS-KFD09 isolated from a marine worm, Sipunculus nudus, from Haikou Bay, China. The structures including the absolute configurations of the new compounds were unambiguously elucidated by spectroscopic data, X-ray diffraction analysis, and ECD spectra analysis along with quantum ECD calculations. In addition, the X-ray crystal structures and absolute configurations of two previously reported meroterpenoids, chrodrimanins F (9) and A (11), are described for the first time. Compounds 1, 4, and 7 displayed anti-H1N1 activity with IC 50 values of 74, 58, and 34 μM, respectively, while compound 5 showed weak inhibitory activity against Staphylococcus aureus with an MIC of 32 μg/mL.

Selective accumulation of harmful compounds by the DNA-inorganic hybrid-immobilized glass bead.

PubMed

Yamada, Masanori; Hamai, Akari

2009-08-11

Previously, we reported the DNA-inorganic hybrid material including double-stranded DNA by mixing the aqueous DNA solution and silane coupling reagents. Here, we immobilized the DNA-inorganic hybrid material onto the glass bead and prepared the DNA-immobilized glass bead column. The DNA-immobilized glass beads were stable in water and the amount of eluted DNA from the DNA-glass beads did not change for more than 1 week. Additionally, this DNA-immobilized column selectively accumulated the harmful compounds with the planar structure, such as dioxin- and polychlorinated biphenyl (PCB)-derivatives, and these accumulation percentages were 50-70%. Furthermore, the DNA-immobilized glass bead was recycled nine times by the application of ethanol solution and the accumulative ratio was maintained at more than 60% and did not appear to be decreasing. Therefore, these DNA-columns might have a potential for the selective removal and separation of DNA-intercalating molecules and harmful compounds with the planar structure from experimental or industrial drainages.

Antisite occupation induced single anionic redox chemistry and structural stabilization of layered sodium chromium sulfide

DOE PAGES

Shadike, Zulipiya; Zhou, Yong -Ning; Chen, Lan -Li; ...

2017-08-30

The intercalation compounds with various electrochemically active or inactive elements in the layered structure have been the subject of increasing interest due to their high capacities, good reversibility, simple structures and ease of synthesis. However, their reversible intercalation/deintercalation redox chemistries in all previous compounds involve a single cationic redox reaction or a cumulative cationic and anionic redox reaction. Here we report an anionic redox only chemistry and structural stabilization of layered sodium chromium sulfide. It is discovered that sulfur in sodium chromium sulfide is electrochemical active undergoing oxidation/reduction of sulfur rather than chromium. Significantly, sodium ions can successfully move outmore » and into without changing its lattice parameter c, which is explained in terms of the occurrence of chromium/sodium vacancy antisite during desodiation and sodiation processes. Here, our present work not only enriches the electrochemistry of layered intercalation compounds, but also extends the scope of investigation on high-capacity electrodes.« less

Cryogenic terahertz spectrum of (+)-methamphetamine hydrochloride and assignment using solid-state density functional theory.

PubMed

Hakey, Patrick M; Allis, Damian G; Ouellette, Wayne; Korter, Timothy M

2009-04-30

The cryogenic terahertz spectrum of (+)-methamphetamine hydrochloride from 10.0 to 100.0 cm(-1) is presented, as is the complete structural analysis and vibrational assignment of the compound using solid-state density functional theory. This cryogenic investigation reveals multiple spectral features that were not previously reported in room-temperature terahertz studies of the title compound. Modeling of the compound employed eight density functionals utilizing both solid-state and isolated-molecule methods. The results clearly indicate the necessity of solid-state simulations for the accurate assignment of solid-state THz spectra. Assignment of the observed spectral features to specific atomic motions is based on the BP density functional, which provided the best-fit solid-state simulation of the experimental spectrum. The seven experimental spectral features are the result of thirteen infrared-active vibrational modes predicted at a BP/DNP level of theory with more than 90% of the total spectral intensity associated with external crystal vibrations.

Residues of organochlorine pesticides and polychloribiphenyls [sic] in starlings (Sturnus vulgaris), from the continental United States, 1982

USGS Publications Warehouse

Bunck, C.M.; Prouty, R.M.; Krynitsky, A.J.

1987-01-01

Starlings were collected from 129 sites throughout the contiguous United States in the fall of 1982 and analyzed for organochlorine compounds as part of a nationwide monitoring program. Residues of 14 organochlorine compounds were found. Only DDE, polychlorobiphenyls (PCB), dieldrin, and heptachlor epoxide occurred in more than 50% of the lO-starling pools. Geographical variation in the occurrence of seven organochlorine compounds was noted. Mean DDE levels were higher in the southwestern United States. Mean PCB levels were higher in the eastern United States. The occurrence frequency of most organochlorines in 1982 was similar to that which was reported in the previous nationwide study in 1979. A slight increase in occurrence was noted for trans-nonachlor. Mean DDE level I in 1982 was similar to that of 1979. Mean PCB level in 1982 was lower than the 1979 mean, but this change may not reflect a decrease in environmental PCB levels.

Acute Toxicity of the Antifouling Compound Butenolide in Non-Target Organisms

PubMed Central

Chandramouli, Kondethimmanahalli H.; Xu, Ying; Pan, Ke; Wang, Wen-Xiong; Qian, Pei-Yuan

2011-01-01

Butenolide [5-octylfuran-2(5H)-one] is a recently discovered and very promising anti-marine-fouling compound. In this study, the acute toxicity of butenolide was assessed in several non-target organisms, including micro algae, crustaceans, and fish. Results were compared with previously reported results on the effective concentrations used on fouling (target) organisms. According to OECD's guideline, the predicted no effect concentration (PNEC) was 0.168 µg l−1, which was among one of the highest in representative new biocides. Mechanistically, the phenotype of butenolide-treated Danio rerio (zebrafish) embryos was similar to the phenotype of the pro-caspase-3 over-expression mutant with pericardial edema, small eyes, small brains, and increased numbers of apoptotic cells in the bodies of zebrafish embryos. Butenolide also induced apoptosis in HeLa cells, with the activation of c-Jun N-terminal kinases (JNK), Bcl-2 family proteins, and caspases and proteasomes/lysosomes involved in this process. This is the first detailed toxicity and toxicology study on this antifouling compound. PMID:21897857

Antisite occupation induced single anionic redox chemistry and structural stabilization of layered sodium chromium sulfide

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shadike, Zulipiya; Zhou, Yong -Ning; Chen, Lan -Li

The intercalation compounds with various electrochemically active or inactive elements in the layered structure have been the subject of increasing interest due to their high capacities, good reversibility, simple structures and ease of synthesis. However, their reversible intercalation/deintercalation redox chemistries in all previous compounds involve a single cationic redox reaction or a cumulative cationic and anionic redox reaction. Here we report an anionic redox only chemistry and structural stabilization of layered sodium chromium sulfide. It is discovered that sulfur in sodium chromium sulfide is electrochemical active undergoing oxidation/reduction of sulfur rather than chromium. Significantly, sodium ions can successfully move outmore » and into without changing its lattice parameter c, which is explained in terms of the occurrence of chromium/sodium vacancy antisite during desodiation and sodiation processes. Here, our present work not only enriches the electrochemistry of layered intercalation compounds, but also extends the scope of investigation on high-capacity electrodes.« less

A new phenylpropanoid and an alkylglycoside from Piper retrofractum leaves with their antioxidant and α-glucosidase inhibitory activity.

PubMed

Luyen, Bui Thi Thuy; Tai, Bui Huu; Thao, Nguyen Phuong; Yang, Seo Young; Cuong, Nguyen Manh; Kwon, Young In; Jang, Hae Dong; Kim, Young Ho

2014-09-01

Two new compounds, piperoside (1) and isoheptanol 2(S)-O-β-D-xylopyranosyl (1→6)-O-β-D-glucopyranoside (11), along with 10 known compounds 3,4-dihydroxyallylbenzene (2), 1,2-di-O-β-D-glucopyranosyl-4-allylbenzene (3), tachioside (4), benzyl-O-β-D-glucopyranoside (5), icariside F2 (6), dihydrovomifoliol-3'-O-β-D-glucopyranoside (7), isopropyl O-β-D-glucopyranoside (8), isopropyl primeveroside (9), n-butyl O-β-D-glucopyranoside (10), isoheptanol 2(S)-O-β-D-apiofuranosyl-(1→6)-O-β-D-glucopyranoside (12), were isolated from the leaves of Piper retrofractum. Their structures were determined from 1D-NMR, 2D-NMR, and HR-ESI-MS spectral, a modified Mosher's method, and comparisons with previous reports. All of the isolated compounds showed modest α-glucosidase inhibitory (4.60±1.74% to 11.97±3.30%) and antioxidant activities under the tested conditions. Copyright © 2014 Elsevier Ltd. All rights reserved.

Novel quinolinone-phosphonic acid AMPA antagonists devoid of nephrotoxicity.

PubMed

Cordi, Alex A; Desos, Patrice; Ruano, Elisabeth; Al-Badri, Hashim; Fugier, Claude; Chapman, Astrid G; Meldrum, Brian S; Thomas, Jean-Yves; Roger, Anita; Lestage, Pierre

2002-10-01

We reported previously the synthesis and structure-activity relationships (SAR) in a series of 2-(1H)-oxoquinolines bearing different acidic functions in the 3-position. Exploiting these SAR, we were able to identify 6,7-dichloro-2-(1H)-oxoquinoline-3-phosphonic acid compound 3 (S 17625) as a potent, in vivo active AMPA antagonist. Unfortunately, during the course of the development, nephrotoxicity was manifest at therapeutically effective doses. Considering that some similitude exists between S 17625 and probenecid, a compound known to protect against the nephrotoxicity and/or slow the clearance of different drugs, we decided to synthesise some new analogues of S 17625 incorporating some of the salient features of probenecid. Replacement of the chlorine in position 6 by a sulfonylamine led to very potent AMPA antagonists endowed with good in vivo activity and lacking nephrotoxicity potential. Amongst the compounds evaluated, derivatives 7a and 7s appear to be the most promising and are currently evaluated in therapeutically relevant stroke models.

Phenolic profile, antioxidant activity and palynological analysis of stingless bee honey from Amazonas, Northern Brazil.

PubMed

da Silva, Isnandia Andréa Almeida; da Silva, Tania Maria Sarmento; Camara, Celso Amorim; Queiroz, Neide; Magnani, Marciane; de Novais, Jaílson Santos; Soledade, Luiz Edmundo Bastos; Lima, Edeltrudes de Oliveira; de Souza, Antonia Lucia; de Souza, Antonio Gouveia

2013-12-15

In this study honey samples produced by Melipona (Michmelia) seminigra merrillae, collected in seven counties distributed in the central and southern region of Amazonas state in Brazil, were analysed for their botanical origin, content and profile of phenolic compounds, and antioxidant and antimicrobial activities. Twenty-two pollen types were identified. The total phenolic content ranged from 17 to 66 mg GAE/g of extract; the highest contents were found in honeys produced from pollen types such as Clidemia and Myrcia. The antioxidant activity was higher in the samples that contained higher quantities of phenolic compounds. In relation to the antibacterial activity, samples CAD3, CAD4 and SAD3 presented the best results. Fourteen phenolic compounds were determined. Among them, we identified the flavonoid taxifolin, which has not previously been described in honeys from stingless bees, and we report the identification of catechol in Brazilian honey samples for the first time. Copyright © 2013 Elsevier Ltd. All rights reserved.

Advancement into the Arctic Region for Bioactive Sponge Secondary Metabolites

PubMed Central

Abbas, Samuel; Kelly, Michelle; Bowling, John; Sims, James; Waters, Amanda; Hamann, Mark

2011-01-01

Porifera have long been a reservoir for the discovery of bioactive compounds and drug discovery. Most research in the area has focused on sponges from tropical and temperate waters, but more recently the focus has shifted to the less accessible colder waters of the Antarctic and, to a lesser extent, the Arctic. The Antarctic region in particular has been a more popular location for natural products discovery and has provided promising candidates for drug development. This article reviews groups of bioactive compounds that have been isolated and reported from the southern reaches of the Arctic Circle, surveys the known sponge diversity present in the Arctic waters, and details a recent sponge collection by our group in the Aleutian Islands, Alaska. The collection has yielded previously undescribed sponge species along with primary activity against opportunistic infectious diseases, malaria, and HCV. The discovery of new sponge species and bioactive crude extracts gives optimism for the isolation of new bioactive compounds from a relatively unexplored source. PMID:22163194

A Novel Access to Arylated and Heteroarylated Beta-Carboline Based PDE5 Inhibitors

PubMed Central

Ahmed, Nermin S.; Gary, Bernard D.; Piazza, Gary A.; Tinsley, Heather N.; Laufer, Stefan; Abadi, Ashraf H.

2016-01-01

Starting from a previously reported lead compound GR30040X (a hydantoin tetrahydro-β-carboline derivative with a 4- pyridinyl ring at C- 5), a series of structurally related tetrahydro-β-carboline derivatives were prepared. The tet-rahydro-β-carboline skeleton was fused either to a hydantoin or to a piperazindione ring, the pendant aryl group attached to C-5 or C-6 was changed to a 3, 4-dimethoxyphenyl or a 3-pyridinyl ring; different N-substituents on the terminal ring were introduced, a straight chain ethyl group, a branched tert. butyl and P-chlorophenyl group rather than n-butyl group of the lead compound. All four possible diastereomers of target tetrahydro-β-carboline derivatives were prepared, separated by column chromatography and the significance of these stereochemical manipulations was studied. Synthesized compounds were evaluated for their inhibitory effect versus PDE5. Seven hits were obtained with appreciable inhibitory activity versus PDE5 with IC50s 0.14 - 4.99 μM. PMID:21054274

Environmental Chemistry Compound Identification Using High ...

EPA Pesticide Factsheets

There is a growing need for rapid chemical screening and prioritization to inform regulatory decision-making on thousands of chemicals in the environment. We have previously used high-resolution mass spectrometry to examine household vacuum dust samples using liquid chromatography time-of-flight mass spectrometry (LC-TOF/MS). Using a combination of exact mass, isotope distribution, and isotope spacing, molecular features were matched with a list of chemical formulas from the EPA’s Distributed Structure-Searchable Toxicity (DSSTox) database. This has further developed our understanding of how openly available chemical databases, together with the appropriate searches, could be used for the purpose of compound identification. We report here on the utility of the EPA’s iCSS Chemistry Dashboard for the purpose of compound identification using searches against a database of over 720,000 chemicals. We also examine the benefits of QSAR prediction for the purpose of retention time prediction to allow for alignment of both chromatographic and mass spectral properties. This abstract does not reflect U.S. EPA policy presentation at the Eastern Analytical Symposium.

Selective arylsulfonamide inhibitors of ADAM-17: hit optimization and activity in ovarian cancer cell models.

PubMed

Nuti, Elisa; Casalini, Francesca; Santamaria, Salvatore; Fabbi, Marina; Carbotti, Grazia; Ferrini, Silvano; Marinelli, Luciana; La Pietra, Valeria; Novellino, Ettore; Camodeca, Caterina; Orlandini, Elisabetta; Nencetti, Susanna; Rossello, Armando

2013-10-24

Activated leukocyte cell adhesion molecule (ALCAM) is expressed at the surface of epithelial ovarian cancer (EOC) cells and is released in a soluble form (sALCAM) by ADAM-17-mediated shedding. This process is relevant to EOC cell motility and invasiveness, which is reduced by inhibitors of ADAM-17. In addition, ADAM-17 plays a key role in EGFR signaling and thus may represent a useful target in anticancer therapy. Herein we report our hit optimization effort to identify potent and selective ADAM-17 inhibitors, starting with previously identified inhibitor 1. A new series of secondary sulfonamido-based hydroxamates was designed and synthesized. The biological activity of the newly synthesized compounds was tested in vitro on isolated enzymes and human EOC cell lines. The optimization process led to compound 21, which showed an IC50 of 1.9 nM on ADAM-17 with greatly increased selectivity. This compound maintained good inhibitory properties on sALCAM shedding in several in vitro assays.

Rational design of bioactive, modularly assembled aminoglycosides targeting the RNA that causes myotonic dystrophy type 1.

PubMed

Childs-Disney, Jessica L; Parkesh, Raman; Nakamori, Masayuki; Thornton, Charles A; Disney, Matthew D

2012-12-21

Myotonic dystrophy type 1 (DM1) is caused when an expanded r(CUG) repeat (r(CUG)(exp)) binds the RNA splicing regulator muscleblind-like 1 protein (MBNL1) as well as other proteins. Previously, we reported that modularly assembled small molecules displaying a 6'-N-5-hexynoate kanamycin A RNA-binding module (K) on a peptoid backbone potently inhibit the binding of MBNL1 to r(CUG)(exp). However, these parent compounds are not appreciably active in cell-based models of DM1. The lack of potency was traced to suboptimal cellular permeability and localization. To improve these properties, second-generation compounds that are conjugated to a d-Arg(9) molecular transporter were synthesized. These modified compounds enter cells in higher concentrations than the parent compounds and are efficacious in cell-based DM1 model systems at low micromolar concentrations. In particular, they improve three defects that are the hallmarks of DM1: a translational defect due to nuclear retention of transcripts containing r(CUG)(exp); pre-mRNA splicing defects due to inactivation of MBNL1; and the formation of nuclear foci. The best compound in cell-based studies was tested in a mouse model of DM1. Modest improvement of pre-mRNA splicing defects was observed. These studies suggest that a modular assembly approach can afford bioactive compounds that target RNA.

Rational Design of Bioactive, Modularly Assembled Aminoglycosides Targeting the RNA that Causes Myotonic Dystrophy Type 1

PubMed Central

Childs-Disney, Jessica L.; Parkesh, Raman; Nakamori, Masayuki; Thornton, Charles A.; Disney, Matthew D.

2012-01-01

Myotonic dystrophy type 1 (DM1) is caused when an expanded r(CUG) repeat (r(CUG)exp) binds the RNA splicing regulator muscleblind-like 1 protein (MBNL1) as well as other proteins. Previously, we reported that modularly assembled small molecules displaying a 6′-N-5-hexynoate kanamycin A RNA-binding module (K) on a peptoid backbone potently inhibit the binding of MBNL1 to r(CUG)exp. However, these parent compounds are not appreciably active in cell-based models of DM1. The lack of potency was traced to suboptimal cellular permeability and localization. To improve these properties, second-generation compounds that are conjugated to a D-Arg9 molecular transporter were synthesized. These modified compounds enter cells in higher concentrations than the parent compounds and are efficacious in cell-based DM1 model systems at low micromolar concentrations. In particular, they improve three defects that are the hallmarks of DM1: a translational defect due to nuclear retention of transcripts containing r(CUG)exp; pre-mRNA splicing defects due to inactivation of MBNL1; and the formation of nuclear foci. The best compound in cell-based studies was tested in a mouse model of DM1. Modest improvement of pre-mRNA splicing defects was observed. These studies suggest that a modular assembly approach can afford bioactive compounds that target RNA. PMID:23130637

Molecular-level characterization of crude oil compounds combining reversed-phase high-performance liquid chromatography with off-line high-resolution mass spectrometry

USGS Publications Warehouse

Sim, Arum; Cho, Yunju; Kim, Daae; Witt, Matthias; Birdwell, Justin E.; Kim, Byung Ju; Kim, Sunghwan

2014-01-01

A reversed-phase separation technique was developed in a previous study (Loegel et al., 2012) and successfully applied to the de-asphalted fraction of crude oil. However, to the best of our knowledge, the molecular-level characterization of oil fractions obtained by reversed-phase high-performance liquid chromatography (HPLC) coupled with high-resolution mass spectrometry (MS) has not yet been reported. A detailed characterization of the oil fractions prepared by reversed-phase HPLC was performed in this study. HPLC fractionation was carried out on conventional crude oil and an oil shale pyrolysate. The analyses of the fractions showed that the carbon number of alkyl chains and the double bond equivalent (DBE) value were the major factors determining elution order. The compounds with larger DBE (presumably more condensed aromatic structures) and smaller carbon number (presumably compounds with short side chains) were eluted earlier but those compounds with lower DBE values (presumably less aromatic structures) and higher carbon number (presumably compounds with longer alkyl chains) eluted later in the chromatograms. This separation behavior is in good agreement with that expected from the principles of reversed-phase separation. The data presented in this study show that reversed-phase chromatography is effective in separating crude oil compounds and can be combined with ultrahigh-resolution MS data to better understand natural oils and oil shale pyrolysates.

Design, synthesis, and anticancer evaluation of long-chain alkoxylated mono-carbonyl analogues of curcumin.

PubMed

Weng, Qiaoyou; Fu, Lili; Chen, Gaozhi; Hui, Junguo; Song, Jingjing; Feng, Jianpeng; Shi, Dengjian; Cai, Yuepiao; Ji, Jiansong; Liang, Guang

2015-10-20

Curcumin is a nontoxic phenolic compound that modulates the activity of several cellular targets that have been linked with cancers and other chronic diseases. However, the efficacy of curcumin in the clinic has been limited by its poor bioavailability and rapid metabolism in vivo. We have previously reported the design and discovery of series of 5-carbon linker-containing mono-carbonyl analogues of curcumin (MACs) as anti-cancer agents. In continuation of our ongoing research, we designed and synthesized 37 novel long-chain alkoxylated MACs for anti-cancer evaluation here. The MTS assay was used to determine the cytotoxicity of compounds in gastrointestinal cancer cells. Compounds 5, 28, and 29 showed strongest inhibition against gastric cancer cell proliferation and were subjected to further analysis. The effects of 5, 28, and 29 on cell apoptosis were measured by flow cytometry. Expression levels of Bcl-2, cleaved poly ADP-ribose polymerase (PARP), and pro-caspase-3 were detected by western blotting. Compounds 5, 28, and 29 induced apoptosis in human gastric carcinoma cells, increased PARP cleavage, and decreased expression of Bcl-2 and pro-caspase-3 protein. We then showed that compound 28, which possessed the strongest activity among the test compounds in vitro, exhibited significant tumor inhibition in SGC7901-driven xenograft mouse model. Taken together, the novel compound 28 could be further explored as an effective anticancer agent for the treatment of human gastric cancer. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Size-induced chemical and magnetic ordering in individual Fe-Au nanoparticles.

PubMed

Mukherjee, Pinaki; Manchanda, Priyanka; Kumar, Pankaj; Zhou, Lin; Kramer, Matthew J; Kashyap, Arti; Skomski, Ralph; Sellmyer, David; Shield, Jeffrey E

2014-08-26

Formation of chemically ordered compounds of Fe and Au is inhibited in bulk materials due to their limited mutual solubility. However, here we report the formation of chemically ordered L12-type Fe3Au and FeAu3 compounds in Fe-Au sub-10 nm nanoparticles, suggesting that they are equilibrium structures in size-constrained systems. The stability of these L12-ordered Fe3Au and FeAu3 compounds along with a previously discovered L10-ordered FeAu has been explained by a size-dependent equilibrium thermodynamic model. Furthermore, the spin ordering of these three compounds has been computed using ab initio first-principle calculations. All ordered compounds exhibit a substantial magnetization at room temperature. The Fe3Au had a high saturation magnetization of about 143.6 emu/g with a ferromagnetic spin structure. The FeAu3 nanoparticles displayed a low saturation magnetization of about 11 emu/g. This suggests a antiferromagnetic spin structure, with the net magnetization arising from uncompensated surface spins. First-principle calculations using the Vienna ab initio simulation package (VASP) indicate that ferromagnetic ordering is energetically most stable in Fe3Au, while antiferromagnetic order is predicted in FeAu and FeAu3, consistent with the experimental results.

Secondary Metabolites from the Culture of the Marine Sponge-Associated Fungi Talaromyces tratensis and Sporidesmium circinophorum.

PubMed

Buttachon, Suradet; May Zin, War War; Dethoup, Tida; Gales, Luís; Pereira, José A; Silva, Artur M S; Kijjoa, Anake

2016-06-01

Wortmin (1), meso-1,4-bis(4-methoxybenzyl)-2,3-butanediol (2), and a new isocoumarin derivative tratenopyrone (3) were isolated from the marine sponge-associated fungus Talaromyces tratensis KUFA 0091. A new diphenyl ether derivative, circinophoric acid (4), was isolated, together with the previously reported anthraquinones catenarin and physcion, the benzophenone monomethylsoluchrin, and β-ergosterol-5,8-endoperoxide, from the marine sponge-associated fungus Sporidesmium circinophorum KUFA 0043. The structures of the new compounds were established based on an extensive analysis of 1D and 2D NMR spectra, and, in the case of compounds 2-4, also by X-ray analysis. All of the isolated compounds were tested for their antibacterial activity against Gram-positive and Gram-negative bacteria, and multidrug-resistant isolates from the environment, as well as for their anti-quorum sensing based on the pigment production of Chromobacterium violaceum ATCC 31523. None of the compounds exhibited either antibacterial (MIC > 256 µg/mL) or anti-quorum sensing activities. The compounds were also inactive in the antifungal (MIC > 512 µg/mL) and cancer cell line (GI50 > 150 µM) assays. Georg Thieme Verlag KG Stuttgart · New York.

Aryloxyalkanoic Acids as Non-Covalent Modifiers of the Allosteric Properties of Hemoglobin

PubMed Central

Omar, Abdelsattar M.; Mahran, Mona A.; Ghatge, Mohini S.; Bamane, Faida H. A.; Ahmed, Mostafa H.; El-Araby, Moustafa E.; Abdulmalik, Osheiza; Safo, Martin K.

2017-01-01

Hemoglobin (Hb) modifiers that stereospecifically inhibit sickle hemoglobin polymer formation and/or allosterically increase Hb affinity for oxygen have been shown to prevent the primary pathophysiology of sickle cell disease (SCD), specifically, Hb polymerization and red blood cell sickling. Several such compounds are currently being clinically studied for the treatment of SCD. Based on the previously reported non-covalent Hb binding characteristics of substituted aryloxyalkanoic acids that exhibited antisickling properties, we designed, synthesized and evaluated 18 new compounds (KAUS II series) for enhanced antisickling activities. Surprisingly, select test compounds showed no antisickling effects or promoted erythrocyte sickling. Additionally, the compounds showed no significant effect on Hb oxygen affinity (or in some cases, even decreased the affinity for oxygen). The X-ray structure of deoxygenated Hb in complex with a prototype compound, KAUS-23, revealed that the effector bound in the central water cavity of the protein, providing atomic level explanations for the observed functional and biological activities. Although the structural modification did not lead to the anticipated biological effects, the findings provide important direction for designing candidate antisickling agents, as well as a framework for novel Hb allosteric effectors that conversely, decrease the protein affinity for oxygen for potential therapeutic use for hypoxic- and/or ischemic-related diseases. PMID:27529207

Environmental Chemicals Modulate Polar Bear (Ursus maritimus) Peroxisome Proliferator-Activated Receptor Gamma (PPARG) and Adipogenesis in Vitro.

PubMed

Routti, Heli; Lille-Langøy, Roger; Berg, Mari K; Fink, Trine; Harju, Mikael; Kristiansen, Kurt; Rostkowski, Pawel; Rusten, Marte; Sylte, Ingebrigt; Øygarden, Lene; Goksøyr, Anders

2016-10-04

We studied interactions between polar bear peroxisome proliferator-activated receptor gamma (pbPPARG) and selected compounds using a luciferase reporter assay and predictions through molecular docking. Furthermore, we studied adipogenesis by liver and adipose tissue extracts from a polar bear and three synthetic mixtures of contaminants in murine 3T3-L1 preadipocytes and polar bear adipose tissue-derived stem cells (pbASCs). PCB153 and p,p'-DDE antagonized pbPPARG, although their predicted receptor-ligand affinity was weak. PBDEs, tetrabromobisphenol A, and PCB170 had a weak agonistic effect on pbPPARG, while hexabromocyclododecane, bisphenol A, oxychlordane, and endosulfan were weak antagonists. pbPPARG-mediated luciferase activity was suppressed by synthetic contaminant mixtures reflecting levels measured in polar bear adipose tissue, as were transcript levels of PPARG and the PPARG target gene fatty acid binding protein 4 (FABP4) in pbASCs. Contaminant extracts from polar bear tissues enhanced triglyceride accumulation in murine 3T3-L1 cells and pbASCs, whereas triglyceride accumulation was not affected by the synthetic mixtures. Chemical characterization of extracts using nontarget methods revealed presence of exogenous compounds that have previously been reported to induce adipogenesis. These compounds included phthalates, tonalide, and nonylphenol. In conclusion, major legacy contaminants in polar bear adipose tissue exert antagonistic effects on PPARG, but adipogenesis by a mixture containing emerging compounds may be enhanced through PPARG or other pathways.

Comparing metabolic effects of six different commercial trivalent chromium compounds.

PubMed

Preuss, Harry G; Echard, Bobby; Perricone, Nicholas V; Bagchi, Debasis; Yasmin, Taharat; Stohs, Sidney J

2008-11-01

Recent reports provide cogent evidence that the average individual becomes chromium deficient with age. Unfortunately, chromium deficiency is strongly associated with many aspects of the Metabolic Syndrome, including insulin resistance and type 2 diabetes. Since replacement of chromium, per os, often ameliorates many deleterious manifestations associated with insulin resistance and diabetes, it is not surprising that many different, commercial trivalent chromium compounds are available on the market. However, previous reports have shown that the form of trivalent chromium (negative charges) can influence effectiveness markedly. We compared various commercial forms of trivalent chromium commonly used alone or in formulations, to examine whether they are equally effective and non-toxic. In the first study, five different chromium products were examined - citrate, amino acid chelate (AAC), chelavite, polynicotinate (NBC), and nicotinate. In the second study, effects of NBC and picolinate were assessed. Results demonstrated that only chelavite and NBC improved insulin sensitivity, and only NBC decreased systolic blood pressure (SBP) significantly. In the second study, both picolinate and NBC significantly decreased SBP compared to control. NBC and picolinate decreased malonyldialdehyde concentrations (free radical formation) and DNA fragmentation in hepatic and renal tissues. No evidence of adverse effects was noted with any of the compounds tested. In conclusion, while all the trivalent chromium compounds tested seem safe, only three enhanced insulin sensitivity (NBC, chelavite, and picolinate) and only two decreased SBP significantly (NBC and picolinate). Furthermore, both NBC and picolinate were protective in lessening free radical formation and DNA damage in the liver and kidneys.

Trivalent metal ions based on inorganic compounds with in vitro inhibitory activity of matrix metalloproteinase 13.

PubMed

Wen, Hanyu; Qin, Yuan; Zhong, Weilong; Li, Cong; Liu, Xiang; Shen, Yehua

2016-10-01

Collagenase-3 (MMP-13) inhibitors have attracted considerable attention in recent years and have been developed as a therapeutic target for a variety of diseases, including cancer. Matrix metalloproteinases (MMPs) can be inhibited by a multitude of compounds, including hydroxamic acids. Studies have shown that materials and compounds containing trivalent metal ions, particularly potassium hexacyanoferrate (III) (K3[Fe(CN)6]), exhibit cdMMP-13 inhibitory potential with a half maximal inhibitory concentration (IC50) of 1.3μM. The target protein was obtained by refolding the recombinant histidine-tagged cdMMP-13 using size exclusion chromatography (SEC). The secondary structures of the refolded cdMMP-13 with or without metal ions were further analyzed via circular dichroism and the results indicate that upon binding with metal ions, an altered structure with increased domain stability was obtained. Furthermore, isothermal titration calorimetry (ITC) experiments demonstrated that K3[Fe(CN)6]is able to bind to MMP-13 and endothelial cell tube formation tests provide further evidence for this interaction to exhibit anti-angiogenesis potential. To the best of our knowledge, no previous report of an inorganic compound featuring a MMP-13 inhibitory activity has ever been reported in the literature. Our results demonstrate that K3[Fe(CN)6] is useful as a new effective and specific inhibitor for cdMMP-13 which may be of great potential for future drug screening applications. Copyright © 2016. Published by Elsevier Inc.

Covalent dimers of 1,3-diphenylisobenzofuran for singlet fission: synthesis and electrochemistry.

PubMed

Akdag, Akin; Wahab, Abdul; Beran, Pavel; Rulíšek, Lubomír; Dron, Paul I; Ludvík, Jiří; Michl, Josef

2015-01-02

The synthesis of covalent dimers in which two 1,3-diphenylisobenzofuran units are connected through one phenyl substituent on each is reported. In three of the dimers, the subunits are linked directly, and in three others, they are linked via an alkane chain. A seventh new compound in which two 1,3-diphenylisobenzofuran units share a phenyl substituent is also described. These materials are needed for investigations of the singlet fission process, which promises to increase the efficiency of solar cells. The electrochemical oxidation and reduction of the monomer, two previously known dimers, and the seven new compounds have been examined, and reversible redox potentials have been compared with results obtained from density functional theory. Although the overall agreement is satisfactory, some discrepancies are noted and discussed.

Cytotoxicity of three new triazolo-pyrimidine derivatives against the plant trypanosomatid: Phytomonas sp. isolated from Euphorbia characias.

PubMed

Magán, Rosa; Marín, Clotilde; Salas, Juan M; Barrera-Pérez, Mario; Rosales, Maria J; Sánchez-Moreno, Manuel

2004-10-01

There is no effective chemotherapy against diseases caused by Phytomonas sp., a plant trypanosomatid responsible for economic losses in major crops. We tested three triazolo-pyrimidine complexes [two with Pt(II), and another with Ru(III)] against promastigotes of Phytomonas sp. isolated from Euphorbia characias. The incorporation of radiolabelled precursors, ultrastructural alterations and changes in the pattern of metabolite excretion were examined. Different degrees of toxicity were found for each complex: the platinum compound showed an inhibition effect on nucleic acid synthesis, provoking alterations on the levels of mitochondria, nucleus and glycosomes. These results, together with others reported previously in our laboratory about the activity of pyrimidine derivatives, reflect the potential of these compounds as agents in the treatment of Phytomonas sp.

Real-time electrochemical detection of extracellular nitric oxide in tobacco cells exposed to cryptogein, an elicitor of defence responses

PubMed Central

Besson-Bard, Angélique; Griveau, Sophie; Bedioui, Fethi; Wendehenne, David

2008-01-01

It was previously reported that cryptogein, an elicitor of defence responses, induces an intracellular production of nitric oxide (NO) in tobacco. Here, the possibility was explored that cryptogein might also trigger an increase of NO extracellular content through two distinct approaches, an indirect method using the NO probe 4,5-diaminofluorescein (DAF-2) and an electrochemical method involving a chemically modified microelectrode probing free NO in biological media. While the chemical nature of DAF-2-reactive compound(s) is still uncertain, the electrochemical modified microelectrodes provide real-time evidence that cryptogein induces an increase of extracellular NO. Direct measurement of free extracellular NO might offer important new insights into its role in plants challenged by biotic stresses. PMID:18653691

Experimental and theoretical investigation on the molecular structure, spectroscopic and electric properties of 2,4-dinitrodiphenylamine, 2-nitro-4-(trifluoromethyl)aniline and 4-bromo-2-nitroaniline

NASA Astrophysics Data System (ADS)

Hernández-Paredes, Javier; Hernández-Negrete, Ofelia; Carrillo-Torres, Roberto C.; Sánchez-Zeferino, Raúl; Duarte-Moller, Alberto; Alvarez-Ramos, Mario E.

2015-10-01

2,4-Dinitrodiphenylamine (I), 2-nitro-4-(trifluoromethyl)aniline (II) and 4-bromo-2-nitroaniline (III) have been investigated by DFT and experimental FTIR, Raman and UV-Vis spectroscopies. The gas-phase molecular geometries were consistent with similar compounds already reported in the literature. From the vibrational analysis, the main functional groups were identified and their absorption bands were assigned. Some differences were found between the calculated and the experimental UV-Vis spectra. These differences were analyzed and explained in terms of the TD-DFT/B3LYP limitations, which were mainly attributed to charge-transfer (CT) effects. These findings were in agreement with previous works, which reported that TD-DFT/B3LYP calculations diverge from experimental results when the electronic transitions involve CT. Despite this, TD-DFT/B3LYP calculations provided satisfactory results and a detailed description of the electronic transitions involved in the absorption bands of the UV-Vis spectra. In terms of the NLO properties, it was found that compound (I) is a good candidate for NLO applications and deserves further study due to its good β values. However, the β values for compounds (II) and (III) were negatively affected compared to those found on o-nitroaniline.

Resolving the smell of wood - identification of odour-active compounds in Scots pine (Pinus sylvestris L.).

PubMed

Schreiner, Linda; Bauer, Patrick; Buettner, Andrea

2018-05-29

Being one of the most common trees in forests, Pinus sylvestris L. is a frequently used raw material for wood products. Its specific odour is, however, mostly unresolved to date. Accordingly, we investigated Scots pine wood samples grown in Germany for their main odorant composition. We employed dedicated odorant analysis techniques such as gas chromatography-olfactometry (GC-O) and aroma extract dilution analysis (AEDA) and successfully detected 44 odour-active compounds; of these, 39 substances were successfully identified by gas chromatography-mass spectrometry/olfactometry (GC-MS/O) and two-dimensional gas chromatography-mass spectrometry/olfactometry (2D-GC-MS/O). Among the main odorants found were (E,E)-nona-2,4-dienal, vanillin, phenylacetic acid, 3-phenylpropanoic acid, δ-octalactone and α-pinene, all of them having been detected with high flavour dilution factors during GC-O analyses. The majority of the identified odorants were fatty acid degradation products, plus some terpenoic substances and odorous substances resulting from the degradation of lignin. Although some of the detected substances have previously been reported as constituents of wood, 11 substances are reported here for the first time as odour-active compounds in wood, amongst them heptanoic acid, γ-octalactone, δ-nonalactone and (E,Z,Z)-trideca-2,4,7-trienal.

Constructional Meanings of Verb-Noun Compounds in Spanish: "Limpiabotas vs. Tientaparedes"

ERIC Educational Resources Information Center

Yoon, Jiyoung

2009-01-01

This study examines Spanish [Verb + Noun (V + N)] compounds based on insights drawn from Construction Grammar. In contrast to previous studies that treat Spanish [V + N] compounds as having one common structural and semantic property, this study proposes two types of [V + N] compound constructions in Spanish, each with its own respective…

Inuloxins A-D and derivatives as antileishmanial agents: structure-activity relationship study

USDA-ARS?s Scientific Manuscript database

Inuloxins A-D (1-4) and a-costic acid (5), the phytotoxic compounds previously isolated from Inula viscosa, as well as synthetic derivatives of inuloxin A (compounds 6-10), inuloxin C (compound 11) and inuloxin D (compound 12) were tested in vitro for their activity against Leishmania donovani, the ...

2-Hydroxyterpenylic acid: An oxygenated marker compound for a-pinene secondary organic aerosol in ambient fine aerosol

EPA Science Inventory

An oxygenated MW 188 compound is commonly observed in substantial abundance in atmospheric aerosol samples and was proposed in previous studies as an α-pinene-related marker compound that is associated with aging processes. Owing to difficulties in producing this compound in suff...

Sesquiterpenes with TRAIL-resistance overcoming activity from Xanthium strumarium.

PubMed

Karmakar, Utpal K; Ishikawa, Naoki; Toume, Kazufumi; Arai, Midori A; Sadhu, Samir K; Ahmed, Firoj; Ishibashi, Masami

2015-08-01

The ability of TRAIL to selectively induce apoptosis in cancer cells while sparing normal cells makes it an attractive target for the development of new cancer therapy. In search of bioactive natural products for overcoming TRAIL-resistance from natural resources, we previously reported a number of active compounds. In our screening program on natural resources targeting overcoming TRAIL-resistance, activity-guided fractionations of the extract of Xanthium strumarium led to the isolation of five sesquiterpene compounds (1-5). 11α,13-dihydroxanthinin (2) and 11α,13-dihydroxanthuminol (3) were first isolated from natural resources and xanthinosin (1), desacetylxanthanol (4), and lasidiol p-methoxybenzoate (5) were known compounds. All compounds (1-5) showed potent TRAIL-resistance overcoming activity at 8, 20, 20, 16, and 16 μM, respectively, in TRAIL-resistant AGS cells. Compounds 1 and 5 enhanced the levels of apoptosis inducing proteins DR4, DR5, p53, CHOP, Bax, cleaved caspase-3, cleaved caspase-8, and cleaved caspase-9 and also decreased the levels of cell survival protein Bcl-2 in TRAIL-resistant AGS cells in a dose-dependent manner. Compound 1 also enhanced the levels of DR4 and DR5 proteins in a time-dependent manner. Thus, compounds 1 and 5 were found to induce both extrinsic and intrinsic apoptotic cell death. Compound 1 also exhibit TRAIL-resistance overcoming activity in DLD1, DU145, HeLa, and MCF7 cells but did not decrease viability in non-cancer HEK293 cells up to 8 μM. Copyright © 2015 Elsevier Ltd. All rights reserved.

Isolation and characterisation of 13 pterosins and pterosides from bracken (Pteridium aquilinum (L.) Kuhn) rhizome.

PubMed

Mohammad, Rizgar Hassan; Nur-E-Alam, Mohammad; Lahmann, Martina; Parveen, Ifat; Tizzard, Graham J; Coles, Simon J; Fowler, Mark; Drake, Alex F; Heyes, Derren; Thoss, Vera

2016-08-01

Systematic phytochemical investigations of the underground rhizome of Pteridium aquilinum (L.) Kuhn (Dennstaedtiaceae) afforded thirty-five pterosins and pterosides. By detailed analysis of one- and two-dimensional nuclear magnetic resonance spectroscopy, circular dichroism (CD) and high-resolution mass spectrometric data, thirteen previously undescribed pterosins and pterosides have been identified. Interestingly, for the first time 12-O-β-D-glucopyranoside substituted pterosins, rhedynosides C and D, and the sulfate-containing pterosin, rhedynosin H, alongside the two known compounds, histiopterosin A and (2S)-pteroside A2, were isolated from the rhizomes of subsp. aquilinum of bracken. In addition, six-membered cyclic ether pterosins and pterosides, rhedynosin A and rhedynoside A, are the first examples of this type of pterosin-sesquiterpenoid. Additionally, the three previously reported compounds (rhedynosin I, (2S)-2-hydroxymethylpterosin E and (2S)-12-hydroxypterosin A) were obtained for the first time from plants as opposed to mammalian metabolic products. Single crystal X-ray diffraction analysis was applied to the previously undescribed compounds (2R)-rhedynoside B, (2R)-pteroside B and (2S)-pteroside K, yielding the first crystal structures for pterosides, and three known pterosins, (2S)-pterosin A, trans-pterosin C and cis-pterosin C. Rhedynosin C is the only example of the cyclic lactone pterosins with a keto group at position C-14. Six selected pterosins ((2S)-pterosin A, (2R)-pterosin B and trans-pterosin C) and associated glycosides ((2S)-pteroside A, (2R)-pteroside B and pteroside Z) were assessed for their anti-diabetic activity using an intestinal glucose uptake assay; all were found to be inactive at 300 μM. Copyright © 2016 Elsevier Ltd. All rights reserved.

Studies on tridecaptin B(1), a lipopeptide with activity against multidrug resistant Gram-negative bacteria.

PubMed

Cochrane, Stephen A; Lohans, Christopher T; van Belkum, Marco J; Bels, Manon A; Vederas, John C

2015-06-07

Previously other groups had reported that Paenibacillus polymyxa NRRL B-30507 produces SRCAM 37, a type IIA bacteriocin with antimicrobial activity against Campylobacter jejuni. Genome sequencing and isolation of antimicrobial compounds from this P. polymyxa strain show that the antimicrobial activity is due to polymyxins and tridecaptin B1. The complete structural assignment, synthesis, and antimicrobial profile of tridecaptin B1 is reported, as well as the putative gene cluster responsible for its biosynthesis. This peptide displays strong activity against multidrug resistant Gram-negative bacteria, a finding that is timely to the current problem of antibiotic resistance.

The influence of allosteric modulators and transmembrane mutations on desensitisation and activation of α7 nicotinic acetylcholine receptors

PubMed Central

Chatzidaki, Anna; D'Oyley, Jarryl M.; Gill-Thind, JasKiran K.; Sheppard, Tom D.; Millar, Neil S.

2015-01-01

Acetylcholine activates nicotinic acetylcholine receptors (nAChRs) by binding at an extracellular orthosteric site. Previous studies have described several positive allosteric modulators (PAMs) that are selective for homomeric α7 nAChRs. These include type I PAMs, which exert little or no effect on the rate of receptor desensitisation, and type II PAMs, which cause a dramatic loss of agonist-induced desensitisation. Here we report evidence that transmembrane mutations in α7 nAChRs have diverse effects on receptor activation and desensitisation by allosteric ligands. It has been reported previously that the L247T mutation, located toward the middle of the second transmembrane domain (at the 9′ position), confers reduced levels of desensitisation. In contrast, the M260L mutation, located higher up in the TM2 domain (at the 22′ position), does not show any difference in desensitisation compared to wild-type receptors. We have found that in receptors containing the L247T mutation, both type I PAMs and type II PAMs are converted into non-desensitising agonists. In contrast, in receptors containing the M260L mutation, this effect is seen only with type II PAMs. These findings, indicating that the M260L mutation has a selective effect on type II PAMs, have been confirmed both with previously described PAMs and also with a series of novel α7-selective PAMs. The novel PAMs examined in this study have close chemical similarity but diverse pharmacological properties. For example, they include compounds displaying effects on receptor desensitisation that are typical of classical type I and type II PAMs but, in addition, they include compounds with intermediate properties. PMID:25998276

The influence of allosteric modulators and transmembrane mutations on desensitisation and activation of α7 nicotinic acetylcholine receptors.

PubMed

Chatzidaki, Anna; D'Oyley, Jarryl M; Gill-Thind, JasKiran K; Sheppard, Tom D; Millar, Neil S

2015-10-01

Acetylcholine activates nicotinic acetylcholine receptors (nAChRs) by binding at an extracellular orthosteric site. Previous studies have described several positive allosteric modulators (PAMs) that are selective for homomeric α7 nAChRs. These include type I PAMs, which exert little or no effect on the rate of receptor desensitisation, and type II PAMs, which cause a dramatic loss of agonist-induced desensitisation. Here we report evidence that transmembrane mutations in α7 nAChRs have diverse effects on receptor activation and desensitisation by allosteric ligands. It has been reported previously that the L247T mutation, located toward the middle of the second transmembrane domain (at the 9' position), confers reduced levels of desensitisation. In contrast, the M260L mutation, located higher up in the TM2 domain (at the 22' position), does not show any difference in desensitisation compared to wild-type receptors. We have found that in receptors containing the L247T mutation, both type I PAMs and type II PAMs are converted into non-desensitising agonists. In contrast, in receptors containing the M260L mutation, this effect is seen only with type II PAMs. These findings, indicating that the M260L mutation has a selective effect on type II PAMs, have been confirmed both with previously described PAMs and also with a series of novel α7-selective PAMs. The novel PAMs examined in this study have close chemical similarity but diverse pharmacological properties. For example, they include compounds displaying effects on receptor desensitisation that are typical of classical type I and type II PAMs but, in addition, they include compounds with intermediate properties. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

Degree of Response to Homeopathic Potencies Correlates with Dipole Moment Size in Molecular Detectors: Implications for Understanding the Fundamental Nature of Serially Diluted and Succussed Solutions.

PubMed

Cartwright, Steven J

2018-02-01

 The use of solvatochromic dyes to investigate homeopathic potencies holds out the promise of understanding the nature of serially succussed and diluted solutions at a fundamental physicochemical level. Recent studies have shown that a range of different dyes interact with potencies and, moreover, the nature of the interaction is beginning to allow certain specific characteristics of potencies to be delineated.  The study reported in this article takes previous investigations further and aims to understand more about the nature of the interaction between potencies and solvatochromic dyes. To this end, the UV-visible spectra of a wide range of potential detectors of potencies have been examined using methodologies previously described.  Results presented demonstrate that solvatochromic dyes are a sub-group of a larger class of compounds capable of demonstrating interactions with potencies. In particular, amino acids containing an aromatic bridge also show marked optical changes in the presence of potencies. Several specific features of molecular detectors can now be shown to be necessary for significant interactions with homeopathic potencies. These include systems with a large dipole moment, electron delocalisation, polarizability and molecular rigidity.  Analysis of the optical changes occurring on interaction with potencies suggests that in all cases potencies increase the polarity of molecular detectors to a degree that correlates with the size of the compound's permanent or ground dipole moment. These results can be explained by inferring that potencies themselves have polarity. Possible candidates for the identity of potencies, based on these and previously reported results, are discussed. The Faculty of Homeopathy.

Copper Selenidophosphates Cu4P2Se6, Cu4P3Se4, Cu4P4Se3, and CuP2Se, Featuring Zero-, One-, and Two-Dimensional Anions.

PubMed

Kuhn, Alexander; Schoop, Leslie M; Eger, Roland; Moudrakovski, Igor; Schwarzmüller, Stefan; Duppel, Viola; Kremer, Reinhard K; Oeckler, Oliver; Lotsch, Bettina V

2016-08-15

Five new compounds in the Cu/P/Se phase diagram have been synthesized, and their crystal structures have been determined. The crystal structures of these compounds comprise four previously unreported zero-, one-, and two-dimensional selenidophosphate anions containing low-valent phosphorus. In addition to two new modifications of Cu4P2Se6 featuring the well-known hexaselenidohypodiphosphate(IV) ion, there are three copper selenidophosphates with low-valent P: Cu4P3Se4 contains two different new anions, (i) a monomeric (zero-dimensional) selenidophosphate anion [P2Se4](4-) and (ii) a one-dimensional selenidophosphate anion [Formula: see text], which is related to the well-known gray-Se-like [Formula: see text] Zintl anion. Cu4P4Se3 contains one-dimensional [Formula: see text] polyanions, whereas CuP2Se contains the 2D selenidophosphate [Formula: see text] polyanion. It consists of charge-neutral CuP2Se layers separated by a van der Waals gap which is very rare for a Zintl-type phase. Hence, besides black P, CuP2Se constitutes a new possible source of 2D oxidized phosphorus containing layers for intercalation or exfoliation experiments. Additionally, the electronic structures and some fundamental physical properties of the new compounds are reported. All compounds are semiconducting with indirect band gaps of the orders of around 1 eV. The phases reported here add to the structural diversity of chalcogenido phosphates. The structural variety of this family of compounds may translate into a variety of tunable physical properties.

QSAR analyses of conformationally restricted 1,5-diaryl pyrazoles as selective COX-2 inhibitors: application of connection table representation of ligands.

PubMed

Prasanna, S; Manivannan, E; Chaturvedi, S C

2005-04-15

As a part of our continuing efforts in discerning the structural and physicochemical requirements for selective COX-2 over COX-1 inhibition among the fused pyrazole ring systems, herein we report the QSAR analyses of the title compounds. The conformational flexibility of the title compounds was examined using a simple connection table representation. The conformational investigation was aided by calculating a connection table parameter called fraction of rotable bonds, b_rotR encompassing the number of rotable bonds and b_count, the number of bonds including implicit hydrogens of each ligand. The hydrophobic and steric correlation of the title compounds towards selective COX-2 inhibition was reported previously in one of our recent publications. In this communication, we attempt to calculate Wang-Ford charges of the non-hydrogen common atoms of AM1 optimized geometries of the title compounds. Owing to the partial conformational flexibility of title compounds, conformationally restricted and unrestricted descriptors were calculated from MOE. Correlation analysis of these 2D, 3D and Wang-Ford charges was accomplished by linear regression analysis. 2D molecular descriptor b_single, 3D molecular descriptors glob, std_dim3 showed significant contribution towards COX-2 inhibitory activity. Balaban J, a connectivity topological index showed a negative and positive contribution towards COX-1 and selective COX-2 over COX-1 inhibition, respectively. Wang-Ford charges calculated on C(7) showed a significant contribution towards COX-1 inhibitory activity whereas charges calculated on C(8) were crucial in governing the selectivity of COX-2 over COX-1 inhibition among these congeners.

Characterization of fatty acid amide hydrolase activity by a fluorescence-based assay.

PubMed

Dato, Florian M; Maaßen, Andreas; Goldfuß, Bernd; Pietsch, Markus

2018-04-01

Fatty acid amide hydrolase (FAAH) is involved in many human diseases, particularly cancer, pain and inflammation as well as neurological, metabolic and cardiovascular disorders. Therefore, FAAH is an attractive target for the development of low-molecular-weight inhibitors as therapeutics, which requires robust assays that can be used for high-throughput screening (HTS) of compound libraries. Here, we report the development of a fluorometric assay based on FAAH's ability to effectively hydrolyze medium-chain fatty acid amides, introducing N-decanoyl-substituted 5-amino-2-methoxypyridine (D-MAP) as new amide substrate. D-MAP is cleaved by FAAH with an 8-fold larger specificity constant than the previously reported octanoyl-analog Oc-MAP (V max /K m of 1.09 and 0.134 mL min -1 mg -1 , respectively), with both MAP derivatives possessing superior substrate properties and much increased aqueous solubility compared to the respective p-nitroaniline compounds D-pNA and Oc-pNA. The new assay with D-MAP as substrate is highly sensitive using a lower enzyme concentration (1 μg mL -1 ) than literature-reported fluorimetric FAAH assays. In addition, D-MAP was validated in comparison to the substrate Oc-MAP for the characterization of FAAH inhibitors by means of the reference compounds URB597 and TC-F2 and was shown to be highly suitable for HTS in both kinetic and endpoint assays (Z' factors of 0.81 and 0.78, respectively). Copyright © 2018 Elsevier Inc. All rights reserved.

Partition coefficients of organic compounds between water and imidazolium-, pyridinium-, and phosphonium-based ionic liquids.

PubMed

Padró, Juan M; Pellegrino Vidal, Rocío B; Reta, Mario

2014-12-01

The partition coefficients, P IL/w, of several compounds, some of them of biological and pharmacological interest, between water and room-temperature ionic liquids based on the imidazolium, pyridinium, and phosphonium cations, namely 1-octyl-3-methylimidazolium hexafluorophosphate, N-octylpyridinium tetrafluorophosphate, trihexyl(tetradecyl)phosphonium chloride, trihexyl(tetradecyl)phosphonium bromide, trihexyl(tetradecyl)phosphonium bis(trifluoromethylsulfonyl)imide, and trihexyl(tetradecyl)phosphonium dicyanamide, were accurately measured. In this way, we extended our database of partition coefficients in room-temperature ionic liquids previously reported. We employed the solvation parameter model with different probe molecules (the training set) to elucidate the chemical interactions involved in the partition process and discussed the most relevant differences among the three types of ionic liquids. The multiparametric equations obtained with the aforementioned model were used to predict the partition coefficients for compounds (the test set) not present in the training set, most being of biological and pharmacological interest. An excellent agreement between calculated and experimental log P IL/w values was obtained. Thus, the obtained equations can be used to predict, a priori, the extraction efficiency for any compound using these ionic liquids as extraction solvents in liquid-liquid extractions.

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

PubMed

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

2015-03-16

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

Discovery of New Compounds Active against Plasmodium falciparum by High Throughput Screening of Microbial Natural Products.

PubMed

Pérez-Moreno, Guiomar; Cantizani, Juan; Sánchez-Carrasco, Paula; Ruiz-Pérez, Luis Miguel; Martín, Jesús; El Aouad, Noureddine; Pérez-Victoria, Ignacio; Tormo, José Rubén; González-Menendez, Víctor; González, Ignacio; de Pedro, Nuria; Reyes, Fernando; Genilloud, Olga; Vicente, Francisca; González-Pacanowska, Dolores

2016-01-01

Due to the low structural diversity within the set of antimalarial drugs currently available in the clinic and the increasing number of cases of resistance, there is an urgent need to find new compounds with novel modes of action to treat the disease. Microbial natural products are characterized by their large diversity provided in terms of the chemical complexity of the compounds and the novelty of structures. Microbial natural products extracts have been underexplored in the search for new antiparasitic drugs and even more so in the discovery of new antimalarials. Our objective was to find new druggable natural products with antimalarial properties from the MEDINA natural products collection, one of the largest natural product libraries harboring more than 130,000 microbial extracts. In this work, we describe the optimization process and the results of a phenotypic high throughput screen (HTS) based on measurements of Plasmodium lactate dehydrogenase. A subset of more than 20,000 extracts from the MEDINA microbial products collection has been explored, leading to the discovery of 3 new compounds with antimalarial activity. In addition, we report on the novel antiplasmodial activity of 4 previously described natural products.

Occurrence of organic wastewater contaminants, pharmaceuticals, and personal care products in selected water supplies, Cape Cod, Massachusetts, June 2004

USGS Publications Warehouse

Zimmerman, Marc J.

2005-01-01

In June 2004, the U.S. Geological Survey, in cooperation with the Barnstable County Department of Health and Environment, sampled water from 14 wastewater sources and drinking-water supplies on Cape Cod, Massachusetts, for the presence of organic wastewater contaminants, pharmaceuticals, and personal care products. The geographic distribution of sampling locations does not represent the distribution of drinking-water supplies on Cape Cod. The environmental presence of the analyte compounds is mostly unregulated; many of the compounds are suspected of having adverse ecological and human health effects. Of the 85 different organic analyte compounds, 43 were detected, with 13 detected in low concentrations (less than 1 microgram per liter) from drinking-water supplies thought to be affected by wastewater because of previously detected high nitrate concentrations. (Phenol and d-limonene, detected in equipment blanks at unacceptably high concentrations, are not included in counts of detections in this report.) Compounds detected in the drinking-water supplies included the solvent, tetrachloroethylene; the analgesic, acetaminophen; the antibiotic, sulfamethoxazole; and the antidepressant, carbamazapine. Nitrate nitrogen, an indicator of wastewater, was detected in water supplies in concentrations ranging from 0.2 to 8.8 milligrams per liter.

Bioactive products from singlet oxygen photooxygenation of cannabinoids.

PubMed

Galal Osman, Ahmed; Elokely, Khaled M; Yadav, Vivek K; Carvalho, Paulo; Radwan, Mohamed; Slade, Desmond; Gul, Waseem; Khan, Shabana; Dale, Olivia R; Husni, Afeef S; Klein, Michael L; Cutler, Stephen J; Ross, Samir A; ElSohly, Mahmoud A

2018-01-01

Photooxygenation of Δ 8 tetrahydrocannabinol (Δ 8 -THC), Δ 9 tetrahydrocannabinol (Δ 9 -THC), Δ 9 tetrahydrocannabinolic acid (Δ 9 -THCA) and some derivatives (acetate, tosylate and methyl ether) yielded 24 oxygenated derivatives, 18 of which were new and 6 were previously reported, including allyl alcohols, ethers, quinones, hydroperoxides, and epoxides. Testing these compounds for their modulatory effect on cannabinoid receptors CB 1 and CB 2 led to the identification of 7 and 21 as CB 1 partial agonists with Ki values of 0.043 μM and 0.048 μM, respectively and 23 as a cannabinoid with high binding affinity for CB 2 with Ki value of 0.0095 μM, but much less affinity towards CB 1 (Ki 0.467 μM). The synthesized compounds showed cytotoxic activity against cancer cell lines (SK-MEL, KB, BT-549, and SK-OV-3) with IC 50 values ranging from 4.2 to 8.5 μg/mL. Several of those compounds showed antimicrobial, antimalarial and antileishmanial activities, with compound 14 being the most potent against various pathogens. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Notable decomposition products of senescing Lake Michigan Cladophora glomerata

USGS Publications Warehouse

Peller, Julie R.; Byappanahalli, Muruleedhara N.; Shively, Dawn A.; Sadowsky, Michael J.; Chun, Chan Lan; Whitman, Richard L.

2013-01-01

Massive accumulations of Cladophora, a ubiquitous, filamentous green alga, have been increasingly reported along Great Lakes shorelines, negatively affecting beach aesthetics, recreational activities, public health and beachfront property values. Previously, the decomposition byproducts of decaying algae have not been thoroughly examined. To better understand the negative consequences and potential merit of the stranded Cladophora, a three month mesocosm study of the dynamic chemical environment of the alga was conducted using fresh samples collected from southern Lake Michigan beaches. Typical fermentation products, such as organic acids, sulfide compounds, and alcohols were detected in the oxygen–deprived algae. Short chain carboxylic acids peaked on day seven, in correspondence with the lowest pH value. Most low molecular mass carbon compounds were eventually consumed, but 4-methylphenol, indole, and 3-methylindole were detected throughout the incubation period. Natural oils were detected in fresh and decomposing algae, indicating the stable nature of these compounds. The mesocosm experiment was validated by directly sampling the fluid within decomposing Cladophora mats in the field; many of the same compounds were found. This study suggests that the problematic Cladophora accumulations may be harvested for useful byproducts, thereby reducing the odiferous and potentially harmful mats stranded along the shorelines.

Correlating wine quality indicators to chemical and sensory measurements.

PubMed

Hopfer, Helene; Nelson, Jenny; Ebeler, Susan E; Heymann, Hildegarde

2015-05-12

Twenty-seven commercial Californian Cabernet Sauvignon wines of different quality categories were analyzed with sensory and chemical methods. Correlations between five quality proxies-points awarded during a wine competition, wine expert scores, retail price, vintage, and wine region-were correlated to sensory attributes, volatile compounds, and elemental composition. Wine quality is a multi-faceted construct, incorporating many different layers. Depending on the quality proxy studied, significant correlations between quality and attributes, volatiles and elements were found, some of them previously reported in the literature.

Targeted Delivery of Carbon Nanotubes to Cancer Cells

DTIC Science & Technology

2009-01-01

were thiolated by incubation for 1 h at room temperature with a 20:1 molar excess of Traut’s reagent. After incubation, the reaction was quenched...0.1 mM EDTA, pH 7.4. The thiolated MAb was conjugated to the activated NA at a molar ratio of 1:2 for 2 h at room temperature with gentle shaking...previous reports, this was achieved by coating CNTs with biocompatible compounds, such as hydrophilic uncharged polymers including poly-(ethylene glycol

Improving the throughput of batch photochemical reactions using flow: Dual photoredox and nickel catalysis in flow for C(sp2)C(sp3) cross-coupling.

PubMed

Abdiaj, Irini; Alcázar, Jesús

2017-12-01

We report herein the transfer of dual photoredox and nickel catalysis for C(sp 2 )C(sp 3 ) cross coupling form batch to flow. This new procedure clearly improves the scalability of the previous batch reaction by the reactor's size and operating time reduction, and allows the preparation of interesting compounds for drug discovery in multigram amounts. Copyright © 2016 Elsevier Ltd. All rights reserved.

Near Infrared Spectra of H2O/HCN Mixtures

NASA Technical Reports Server (NTRS)

Mastrapa, R. M.; Bernstein, M. P.; Sanford, S. A.

2006-01-01

Cassini's VIMS has already returned exciting results interpreting spectra of Saturn's icy satellites. The discovery of unidentified features possibly due to CN compounds inspired the work reported here. We wanted to test HCN as a possibility for explaining these features, and also explore how the features of HCN change when mixed with H2O. We have previously noted that mixing H20 and CO2 produces new spectral features and that those features change with temperature and mixing ratio.

Ferroelasticity in the LnNbO/sub 4/-type rare earth niobates

DOE Office of Scientific and Technical Information (OSTI.GOV)

Brixner, L.H.; Whitney, J.F.; Zumsteg, F.C.

1977-01-01

The previously reported phase transitions for the isostructural rare earth niobates between 500/sup 0/C and 850/sup 0/C correspond to a point group transformation 4/mF2/m, which is purely ferroelastic. The correct room temperature point group for all LnNbO/sub 4/ compounds is 2/m. Crystal growth and domain wall behavior is discussed for LaNbO/sub 4/. The high temperature phase transition is described for YbNbO/sub 4/.

Proceedings of the Topical Meeting on the Microphysics of Surfaces, Beams, and Adsorbates (2nd) Held in Sante Fe, New Mexico on 16-18 February 1987

DTIC Science & Technology

1987-10-31

SECURITY CLASSIFICATION AUTHORITY 3 DISTRIBUTIONi AVAILABILITY OF REPORT 2b DECLASSIFICATION/DOWNGRADING SCHEDULE Approved for public release...of a compound similar to a Ziegler-Natta catalyst, 2 In previous publications 6 we discussed the mechanism and (2) laser-chemical-vapor deposition of...first crossed these publications . To shed more light onto this intriguing beams studies on the Si(Cl2 ,Ar’ ) system Coburn and Winters2 observed that

Efforts towards the optimization of a bi-aryl class of potent IRAK4 inhibitors

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hanisak, Jennifer; Seganish, W. Michael; McElroy, William T.

2016-09-01

IRAK4 has been identified as potential therapeutic target for inflammatory and autoimmune diseases. Herein we report the identification and initial SAR studies of a new class of pyrazole containing IRAK4 inhibitors designed to expand chemical diversity and improve off target activity of a previously identified series. These compounds maintain potent IRAK4 activity and desirable ligand efficiency. Rat clearance and a variety of off target activities were also examined, resulting in encouraging data with tractable SAR.

Internal energy deposition with silicon nanoparticle-assisted laser desorption/ionization (SPALDI) mass spectrometry

NASA Astrophysics Data System (ADS)

Dagan, Shai; Hua, Yimin; Boday, Dylan J.; Somogyi, Arpad; Wysocki, Ronald J.; Wysocki, Vicki H.

2009-06-01

The use of silicon nanoparticles for laser desorption/ionization (LDI) is a new appealing matrix-less approach for the selective and sensitive mass spectrometry of small molecules in MALDI instruments. Chemically modified silicon nanoparticles (30 nm) were previously found to require very low laser fluence in order to induce efficient LDI, which raised the question of internal energy deposition processes in that system. Here we report a comparative study of internal energy deposition from silicon nanoparticles to previously explored benzylpyridinium (BP) model compounds during LDI experiments. The internal energy deposition in silicon nanoparticle-assisted laser desorption/ionization (SPALDI) with different fluorinated linear chain modifiers (decyl, hexyl and propyl) was compared to LDI from untreated silicon nanoparticles and from the organic matrix, [alpha]-cyano-4-hydroxycinnamic acid (CHCA). The energy deposition to internal vibrational modes was evaluated by molecular ion survival curves and indicated that the ions produced by SPALDI have an internal energy threshold of 2.8-3.7 eV. This is slightly lower than the internal energy induced using the organic CHCA matrix, with similar molecular survival curves as previously reported for LDI off silicon nanowires. However, the internal energy associated with desorption/ionization from the silicon nanoparticles is significantly lower than that reported for desorption/ionization on silicon (DIOS). The measured survival yields in SPALDI gradually decrease with increasing laser fluence, contrary to reported results for silicon nanowires. The effect of modification of the silicon particle surface with semifluorinated linear chain silanes, including fluorinated decyl (C10), fluorinated hexyl (C6) and fluorinated propyl (C3) was explored too. The internal energy deposited increased with a decrease in the length of the modifier alkyl chain. Unmodified silicon particles exhibited the highest analyte internal energy deposition. These findings may suggest a role of the modifier as a moderator in the energy dissipation and relaxation process. The relatively low internal energy content of SPALDI-produced ions indicates that this is a "soft" desorption technique, with potential advantages in the analysis of labile compounds.

Perturbation Theory/Machine Learning Model of ChEMBL Data for Dopamine Targets: Docking, Synthesis, and Assay of New l-Prolyl-l-leucyl-glycinamide Peptidomimetics.

PubMed

Ferreira da Costa, Joana; Silva, David; Caamaño, Olga; Brea, José M; Loza, Maria Isabel; Munteanu, Cristian R; Pazos, Alejandro; García-Mera, Xerardo; González-Díaz, Humbert

2018-06-25

Predicting drug-protein interactions (DPIs) for target proteins involved in dopamine pathways is a very important goal in medicinal chemistry. We can tackle this problem using Molecular Docking or Machine Learning (ML) models for one specific protein. Unfortunately, these models fail to account for large and complex big data sets of preclinical assays reported in public databases. This includes multiple conditions of assays, such as different experimental parameters, biological assays, target proteins, cell lines, organism of the target, or organism of assay. On the other hand, perturbation theory (PT) models allow us to predict the properties of a query compound or molecular system in experimental assays with multiple boundary conditions based on a previously known case of reference. In this work, we report the first PTML (PT + ML) study of a large ChEMBL data set of preclinical assays of compounds targeting dopamine pathway proteins. The best PTML model found predicts 50000 cases with accuracy of 70-91% in training and external validation series. We also compared the linear PTML model with alternative PTML models trained with multiple nonlinear methods (artificial neural network (ANN), Random Forest, Deep Learning, etc.). Some of the nonlinear methods outperform the linear model but at the cost of a notable increment of the complexity of the model. We illustrated the practical use of the new model with a proof-of-concept theoretical-experimental study. We reported for the first time the organic synthesis, chemical characterization, and pharmacological assay of a new series of l-prolyl-l-leucyl-glycinamide (PLG) peptidomimetic compounds. In addition, we performed a molecular docking study for some of these compounds with the software Vina AutoDock. The work ends with a PTML model predictive study of the outcomes of the new compounds in a large number of assays. Therefore, this study offers a new computational methodology for predicting the outcome for any compound in new assays. This PTML method focuses on the prediction with a simple linear model of multiple pharmacological parameters (IC 50 , EC 50 , K i , etc.) for compounds in assays involving different cell lines used, organisms of the protein target, or organism of assay for proteins in the dopamine pathway.

Inhibition of Staphyloxanthin Virulence Factor Biosynthesis in Staphylococcus aureus: In Vitro, in Vivo, and Crystallographic Results†

PubMed Central

Song, Yongcheng; Liu, Chia-I; Lin, Fu-Yang; No, Joo Hwan; Hensler, Mary; Liu, Yi-Liang; Jeng, Wen-Yih; Low, Jennifer; Liu, George Y.; Nizet, Victor; Wang, Andrew H.-J.; Oldfield, Eric

2009-01-01

The gold color of Staphylococcus aureus is derived from the carotenoid staphyloxanthin, a virulence factor for the organism. Here, we report the synthesis and activity of a broad variety of staphyloxanthin biosynthesis inhibitors that inhibit the first committed step in its biosynthesis, condensation of two farnesyl diphosphate (FPP) molecules to dehydrosqualene, catalyzed by the enzyme dehydrosqualene synthase (CrtM). The most active compounds are phosphonoacetamides that have low nanomolar Ki values for CrtM inhibition and are active in whole bacterial cells and in mice, where they inhibit S. aureus disease progression. We also report the X-ray crystallographic structure of the most active compound, N-3-(3-phenoxyphenyl)propylphosphonoacetamide (IC50 = 8 nM, in cells), bound to CrtM. The structure exhibits a complex network of hydrogen bonds between the polar headgroup and the protein, while the 3-phenoxyphenyl side chain is located in a hydrophobic pocket previously reported to bind farnesyl thiodiphosphate (FsPP), as well as biphenyl phosphonosulfonate inhibitors. Given the good enzymatic, whole cell, and in vivo pharmacologic activities, these results should help guide the further development of novel antivirulence factor-based therapies for S. aureus infections. PMID:19456099

Bibliography of work on the heterogeneous photocatalytic removal of hazardous compounds from water and air: Update Number 1 to June, 1995

DOE Office of Scientific and Technical Information (OSTI.GOV)

Blake, D.M.

1995-11-01

This report is an update of a bibliography, published in May, 1994, of research performed on the photocatalytic oxidation of organic or inorganic compounds in air or water and on the photocatalytic reduction of metal-containing ions in water. The general focus of the research is on removing hazardous contaminants from air water to meet environmental or health regulations. The processes covered are based on the application of heterogeneous photocatalysts. The current state-of-the-art in catalysts are forms of titanium dioxide or modifications of titanium dioxide, but work on other heterogeneous catalysts is also included in this compilation. This update contains 574more » references, most published between January, 1993 and June, 1995, but some references are from earlier work that were not included in the previous report. A new section has been added which gives information about companies that are active in providing products based on photocatalytic processes or that can provide pilot, demonstration, or commercial-scale water- or air-treatment systems. Key words, assigned by the author of this report, have been included with the citations in the listing of the bibliography.« less

Novel biallelic mutations in MSH6 and PMS2 genes: gene conversion as a likely cause of PMS2 gene inactivation.

PubMed

Auclair, Jessie; Leroux, Dominique; Desseigne, Françoise; Lasset, Christine; Saurin, Jean Christophe; Joly, Marie Odile; Pinson, Stéphane; Xu, Xiao Li; Montmain, Gilles; Ruano, Eric; Navarro, Claudine; Puisieux, Alain; Wang, Qing

2007-11-01

Since the first report by our group in 1999, more than 20 unrelated biallelic mutations in DNA mismatch repair genes (MMR) have been identified. In the present report, we describe two novel cases: one carrying compound heterozygous mutations in the MSH6 gene; and the other, compound heterozygous mutations in the PMS2 gene. Interestingly, the inactivation of one PMS2 allele was likely caused by gene conversion. Although gene conversion has been suggested to be a mutation mechanism underlying PMS2 inactivation, this is the first report of its involvement in a pathogenic mutation. The clinical features of biallelic mutation carriers were similar to other previously described patients, with the presence of café-au-lait spots (CALS), early onset of brain tumors, and colorectal neoplasia. Our data provide further evidence of the existence, although rare, of a distinct recessively inherited syndrome on the basis of MMR constitutional inactivation. The identification of this syndrome should be useful for genetic counseling, especially in families with atypical hereditary nonpolyposis colon cancer (HNPCC) associated with childhood cancers, and for the clinical surveillance of these mutation carriers. 2007 Wiley-Liss, Inc.

Selective Cytotoxicity against Human Osteosarcoma Cells by a Novel Synthetic C-1 Analogue of 7-Deoxypancratistatin Is Potentiated by Curcumin

PubMed Central

Ma, Dennis; Tremblay, Phillip; Mahngar, Kevinjeet; Collins, Jonathan; Hudlicky, Tomas; Pandey, Siyaram

2011-01-01

The natural compound pancratistatin (PST) is a non-genotoxic inducer of apoptosis in a variety of cancers. It exhibits cancer selectivity as non-cancerous cells are markedly less sensitive to PST. Nonetheless, PST is not readily synthesized and is present in very low quantities in its natural source to be applied clinically. We have previously synthesized and evaluated several synthetic analogues of 7-deoxypancratistatin, and found that JC-TH-acetate-4 (JCTH-4), a C-1 acetoxymethyl analogue, possessed similar apoptosis inducing activity compared to PST. In this study, notoriously chemoresistant osteosarcoma (OS) cells (Saos-2, U-2 OS) were substantially susceptible to JCTH-4-induced apoptosis through mitochondrial targeting; JCTH-4 induced collapse of mitochondrial membrane potential (MMP), increased reactive oxygen species (ROS) production in isolated mitochondria, and caused release of apoptosis inducing factor (AIF) and endonuclease G (EndoG) from isolated mitochondria. Furthermore, JCTH-4 selectively induced autophagy in OS cells. Additionally, we investigated the combinatory effect of JCTH-4 with the natural compound curcumin (CC), a compound found in turmeric spice, previously shown to possess antiproliferative properties. CC alone had no observable effect on Saos-2 and U-2 OS cells. However, when present with JCTH-4, CC was able to enhance the cytotoxicity of JCTH-4 selectively in OS cells. Such cytotoxicity by JCTH-4 alone and in combination with CC was not observed in normal human osteoblasts (HOb) and normal human fetal fibroblasts (NFF). Therefore, this report illustrates a new window in combination therapy, utilizing a novel synthetic analogue of PST with the natural compound CC, for the treatment of OS. PMID:22205968

Cosmetic Preservatives as Therapeutic Corneal and Scleral Tissue Cross-Linking Agents

PubMed Central

Babar, Natasha; Kim, MiJung; Cao, Kerry; Shimizu, Yukari; Kim, Su-Young; Takaoka, Anna; Trokel, Stephen L.; Paik, David C.

2015-01-01

Purpose. Previously, aliphatic β-nitroalcohols (BNAs) have been studied as a means to chemically induce tissue cross-linking (TXL) of cornea and sclera. There are a number of related and possibly more potent agents, known as formaldehyde releasers (FARs), that are in commercial use as preservatives in cosmetics and other personal care products. The present study was undertaken in order to screen such compounds for potential clinical utility as therapeutic TXL agents. Methods. A chemical registry of 62 FARs was created from a literature review and included characteristics relevant to TXL such as molecular weight, carcinogenicity/mutagenicity, toxicity, hydrophobicity, and commercial availability. From this registry, five compounds [diazolidinyl urea (DAU), imidazolidinyl urea (IMU), sodium hydroxymethylglycinate (SMG), DMDM hydantoin (DMDM), 5-Ethyl-3,7-dioxa-1-azabicyclo [3.3.0] octane (OCT)] were selected for efficacy screening using two independent systems, an ex vivo rabbit corneal cross-linking simulation setup and incubation of cut scleral tissue pieces. Treatments were conducted at pH 7.4 or 8.5 for 30 minutes. Efficacy was evaluated using thermal denaturation temperature (Tm), and cell toxicity was studied using the trypan blue exclusion method. Results. Cross-linking effects in the five selected FARs were pH and concentration dependent. Overall, the Tm shifts were in agreement with both cornea and sclera. By comparison with BNAs previously reported upon, the FARs identified in this study were significantly more potent but with similar or better cytotoxicity. Conclusions. The FARs, a class of compounds well known to the cosmetic industry, may have utility as therapeutic TXL agents. The compounds studied thus far show promise and will be further tested. PMID:25634979

Additivity of Pyrethroid Actions on Sodium Influx in Cerebrocortical Neurons in Primary Culture

PubMed Central

Cao, Zhengyu; Shafer, Timothy J.; Crofton, Kevin M.; Gennings, Chris

2011-01-01

Background: Pyrethroid insecticides bind to voltage-gated sodium channels and modify their gating kinetics, thereby disrupting neuronal function. Although previous work has tested the additivity of pyrethroids in vivo, this has not been assessed directly at the primary molecular target using a functional measure. Objectives: We investigated the potency and efficacy of 11 structurally diverse food-use pyrethroids to evoke sodium (Na+) influx in neurons and tested the hypothesis of dose additivity for a mixture of these same 11 compounds. Methods: We determined pyrethroid-induced increases in Na+ influx in primary cultures of cerebrocortical neurons using the Na+-sensitive dye sodium-binding benzofuran isophthalate (SBFI). Concentration-dependent responses for 11 pyrethroids were determined, and the response to dilutions of a mixture of all 11 compounds at an equimolar mixing ratio was assessed. Additivity was tested assuming a dose-additive model. Results: Seven pyrethroids produced concentration-dependent, tetrodotoxin-sensitive Na+ influx. The rank order of potency was deltamethrin > S-bioallethrin > β-cyfluthrin > λ-cyhalothrin > esfenvalerate > tefluthrin > fenpropathrin. Cypermethrin and bifenthrin produced modest increases in Na+ influx, whereas permethrin and resmethrin were inactive. When all 11 pyrethroids were present at an equimolar mixing ratio, their actions on Na+ influx were consistent with a dose-additive model. Conclusions: These data provide in vitro relative potency and efficacy measurements for 7 pyrethroid compounds in intact mammalian neurons. Despite differences in individual compound potencies, we found the action of a mixture of all 11 pyrethroids to be additive when we used an appropriate statistical model. These results are consistent with a previous report of the additivity of pyrethroids in vivo. PMID:21665567

In Vitro Effects of Chronic Spirolide Treatment on Human Neuronal Stem Cell Differentiation and Cholinergic System Development.

PubMed

Boente-Juncal, Andrea; Méndez, Aida G; Vale, Carmen; Vieytes, Mercedes R; Botana, Luis M

2018-06-20

Spirolides (SPX) are marine toxins, produced by dinoflagellates that act as potent antagonists of nicotinic acetylcholine receptors. These compounds are not toxic for humans, and since there are no reports of human intoxications caused by this group of toxins they are not yet currently regulated in Europe. Currently 13-desmethyl spirolide C, 13,19-didesmethyl spirolide C, and 20-methyl spirolide G are commercially available as reference materials. Previous work in our laboratory has demonstrated that after 4 days of treatment of primary mice cortical neurons with 13-desmethyl spirolide C, the compound ameliorated the glutamate induced toxicity and increased acetylcholine levels and the expression of the acetylcholine synthesizing enzyme being useful both in vitro and in vivo to decrease the brain pathology associated with Alzheimer's disease. In this work, we aimed to extend the study of the neuronal effects of spirolides in human neuronal cells. To this end, human neuronal progenitor cells CTX0E16 were employed to evaluate the in vitro effect of spirolides on neuronal development. The results presented here indicate that long-term exposure (30 days) of human neuronal stem cells to SPX compounds, at concentrations up to 50 nM, ameliorated the MPP + -induced neurotoxicity and increased the expression of neuritic and dendritic markers, the levels of the choline acetyltransferase enzyme and the protein levels of the α7 subunit of nicotinic acetylcholine receptors. These effects are presumably due to the previously described interaction of these compounds with nicotinic receptors containing both α7 and α4 subunits. All together, these data emphasize the idea that SPX could be attractive lead molecules against neurodegenerative disorders.

Effects of intermediates between vitamins K(2) and K(3) on mammalian DNA polymerase inhibition and anti-inflammatory activity.

PubMed

Mizushina, Yoshiyuki; Maeda, Jun; Irino, Yasuhiro; Nishida, Masayuki; Nishiumi, Shin; Kondo, Yasuyuki; Nishio, Kazuyuki; Kuramochi, Kouji; Tsubaki, Kazunori; Kuriyama, Isoko; Azuma, Takeshi; Yoshida, Hiromi; Yoshida, Masaru

2011-02-10

Previously, we reported that vitamin K(3) (VK(3)), but not VK(1) or VK(2) (=MK-4), inhibits the activity of human DNA polymerase γ (pol γ). In this study, we chemically synthesized three intermediate compounds between VK(2) and VK(3), namely MK-3, MK-2 and MK-1, and investigated the inhibitory effects of all five compounds on the activity of mammalian pols. Among these compounds, MK-2 was the strongest inhibitor of mammalian pols α, κ and λ, which belong to the B, Y and X families of pols, respectively; whereas VK(3) was the strongest inhibitor of human pol γ, an A-family pol. MK-2 potently inhibited the activity of all animal species of pol tested, and its inhibitory effect on pol λ activity was the strongest with an IC(50) value of 24.6 μM. However, MK-2 did not affect the activity of plant or prokaryotic pols, or that of other DNA metabolic enzymes such as primase of pol α, RNA polymerase, polynucleotide kinase or deoxyribonuclease I. Because we previously found a positive relationship between pol λ inhibition and anti-inflammatory action, we examined whether these compounds could inhibit inflammatory responses. Among the five compounds tested, MK-2 caused the greatest reduction in 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced acute inflammation in mouse ear. In addition, in a cell culture system using mouse macrophages, MK-2 displayed the strongest suppression of the production of tumor necrosis factor (TNF)-α induced by lipopolysaccharide (LPS). Moreover, MK-2 was found to inhibit the action of nuclear factor (NF)-κB. In an in vivo mouse model of LPS-evoked acute inflammation, intraperitoneal injection of MK-2 in mice led to suppression of TNF-α production in serum. In conclusion, this study has identified VK(2) and VK(3) intermediates, such as MK-2, that are promising anti-inflammatory candidates.

Chemical characterization of territorial marking fluid of male Bengal tiger, Panthera tigris.

PubMed

Burger, B V; Viviers, M Z; Bekker, J P I; le Roux, M; Fish, N; Fourie, W B; Weibchen, G

2008-05-01

The territorial marking fluid of the male Bengal tiger, Panthera tigris, consists of a mixture of urine and a small quantity of lipid material that may act as a controlled-release carrier for the volatile constituents of the fluid. Using gas chromatography and gas chromatography-mass spectrometry, 98 volatile compounds and elemental sulfur were identified in the marking fluid. Another 16 volatiles were tentatively identified. The majority of these compounds were alkanols, alkanals, 2-alkanones, branched and unbranched alkanoic acids, dimethyl esters of dicarboxylic acids, gamma- and delta-lactones, and compounds containing nitrogen or sulfur. Several samples of the marking fluid contained pure (R)-3-methyl-2-octanone, (R)-3-methyl-2-nonanone, and (R)-3-methyl-2-decanone, but these ketones were partly or completely racemized in other samples. The gamma-lactone (S)-(+)-(Z)-6-dodecen-4-olide and the C(8) to C(16) saturated (R)-gamma-lactones and (S)-delta-lactones were present in high enantiomeric purities. The chiral carboxylic acids, 2-methylnonanoic acid, 2-methyldecanoic acid, 2-methylundecanoic acid, and 2-ethylhexanoic acid were racemates. Cadaverine, putrescine, and 2-acetylpyrroline, previously reported as constituents of tiger urine, were not detected. The dominant contribution of some ketones, fatty acids, and lactones to the composition of the headspace of the marking fluid suggests that these compounds may be important constituents of the pheromone. Although it constitutes only a small proportion, the lipid fraction of the fluid contained larger quantities of the volatile organic compounds than the aqueous fraction (urine). The lipid derives its role as controlled-release carrier of the chemical message left by the tiger, from its affinity for the volatiles of the marking fluid. Six proteins with masses ranging from 16 to 69 kDa, inter alia, the carboxylesterase-like urinary protein known as cauxin, previously identified in the urine of the domestic cat and other felid species, were identified in the urine fraction of the marking fluid.

2-Substituted 3β-Aryltropane Cocaine Analogs Produce Atypical Effects without Inducing Inward-Facing Dopamine Transporter Conformations.

PubMed

Hong, Weimin C; Kopajtic, Theresa A; Xu, Lifen; Lomenzo, Stacey A; Jean, Bernandie; Madura, Jeffry D; Surratt, Christopher K; Trudell, Mark L; Katz, Jonathan L

2016-03-01

Previous structure-activity relationship studies indicate that a series of cocaine analogs, 3β-aryltropanes with 2β-diarylmethoxy substituents, selectively bind to the dopamine transporter (DAT) with nanomolar affinities that are 10-fold greater than the affinities of their corresponding 2α-enantiomers. The present study compared these compounds to cocaine with respect to locomotor effects in mice, and assessed their ability to substitute for cocaine (10 mg/kg, i.p.) in rats trained to discriminate cocaine from saline. Despite nanomolar DAT affinity, only the 2β-Ph2COCH2-3β-4-Cl-Ph analog fully substituted for cocaine-like discriminative effects. Whereas all of the 2β compounds increased locomotion, only the 2β-(4-ClPh)PhCOCH2-3β-4-Cl-Ph analog had cocaine-like efficacy. None of the 2α-substituted compounds produced either of these cocaine-like effects. To explore the molecular mechanisms of these drugs, their effects on DAT conformation were probed using a cysteine-accessibility assay. Previous reports indicate that cocaine binds with substantially higher affinity to the DAT in its outward (extracellular)- compared with inward-facing conformation, whereas atypical DAT inhibitors, such as benztropine, have greater similarity in affinity to these conformations, and this is postulated to explain their divergent behavioral effects. All of the 2β- and 2α-substituted compounds tested altered cysteine accessibility of DAT in a manner similar to cocaine. Furthermore, molecular dynamics of in silico inhibitor-DAT complexes suggested that the 2-substituted compounds reach equilibrium in the binding pocket in a cocaine-like fashion. These behavioral, biochemical, and computational results show that aryltropane analogs can bind to the DAT and stabilize outward-facing DAT conformations like cocaine, yet produce effects that differ from those of cocaine. U.S. Government work not protected by U.S. copyright.

A rapid and rational approach to generating isomorphous heavy-atom phasing derivatives

PubMed Central

Lu, Jinghua; Sun, Peter D.

2014-01-01

In attempts to replace the conventional trial-and-error heavy-atom derivative search method with a rational approach, we previously defined heavy metal compound reactivity against peptide ligands. Here, we assembled a composite pH and buffer-dependent peptide reactivity profile for each heavy metal compound to guide rational heavy-atom derivative search. When knowledge of the best-reacting heavy-atom compound is combined with mass spectrometry-assisted derivatization, and with a quick-soak method to optimize phasing, it is likely that the traditional heavy-atom compounds could meet the demand of modern high-throughput X-ray crystallography. As an example, we applied this rational heavy-atom phasing approach to determine a previously unknown mouse serum amyloid A2 crystal structure. PMID:25040395

Known and Newly Identified Semi-Volatile Organic Compounds from Biomass Burning in Amazonia: Variability and Relationship to Aerosol Physical Properties

NASA Astrophysics Data System (ADS)

Wernis, R. A.; Yee, L.; Isaacman-VanWertz, G. A.; Kreisberg, N. M.; de Sá, S. S.; Liu, Y.; Martin, S. T.; Alexander, M. L. L.; Palm, B. B.; Hu, W.; Campuzano-Jost, P.; Day, D. A.; Jimenez, J. L.; Artaxo, P.; Viegas, J.; Manzi, A. O.; Souza, R. A. F. D.; Hering, S. V.; Goldstein, A. H.

2016-12-01

Aerosols are a source of great uncertainty in radiative forcing predictions and have poorly understood impacts on human health. In many environments, biomass burning contributes a significant source of primary aerosol as well as reactive gas-phase precursors that can form secondary organic aerosol (SOA). One class of these precursors, semi-volatile organic compounds (SVOCs), has been shown to have a large contribution to the amount of SOA formed from fire emissions. At present, SVOC emissions from biomass burning are poorly constrained and understanding their contributions to SOA formation is an important research challenge. In the Amazonian dry season, biomass burning is a major source of gases and aerosols reducing regional air quality. As part of the GoAmazon 2014/5 field campaign, we deployed the Semi-Volatile Thermal desorption Aerosol Gas Chromatograph (SV-TAG) instrument at the rural T3 site, 60 km to the west of Manaus, Brazil to measure hourly concentrations of SVOCs in the gas and particle phases. This comprehensive technique detects thousands of compounds, enabling the discovery of previously unidentified compounds. In this work we explore compounds for which a correlation with well-known biomass burning tracers is observed to discover the identities of new markers. We discuss contributions to the total organic aerosol from over 30 well-known, rarely reported and newly identified biomass burning markers. We examine the relationship between biomass burning aerosol composition and aerosol physical properties as measured at the T3 site. Additionally, we report gas-particle partitioning of all identified compounds with comparison to theoretical predictions. We find that the commonly used biomass burning tracer levoglucosan existed entirely in the particle phase and contributed 0.6% and 0.3% of total organic aerosol mass in the dry and wet seasons, respectively.

Toxic Diatom Aldehydes Affect Defence Gene Networks in Sea Urchins

PubMed Central

Varrella, Stefano; Ruocco, Nadia; Ianora, Adrianna; Bentley, Matt G.; Costantini, Maria

2016-01-01

Marine organisms possess a series of cellular strategies to counteract the negative effects of toxic compounds, including the massive reorganization of gene expression networks. Here we report the modulated dose-dependent response of activated genes by diatom polyunsaturated aldehydes (PUAs) in the sea urchin Paracentrotus lividus. PUAs are secondary metabolites deriving from the oxidation of fatty acids, inducing deleterious effects on the reproduction and development of planktonic and benthic organisms that feed on these unicellular algae and with anti-cancer activity. Our previous results showed that PUAs target several genes, implicated in different functional processes in this sea urchin. Using interactomic Ingenuity Pathway Analysis we now show that the genes targeted by PUAs are correlated with four HUB genes, NF-κB, p53, δ-2-catenin and HIF1A, which have not been previously reported for P. lividus. We propose a working model describing hypothetical pathways potentially involved in toxic aldehyde stress response in sea urchins. This represents the first report on gene networks affected by PUAs, opening new perspectives in understanding the cellular mechanisms underlying the response of benthic organisms to diatom exposure. PMID:26914213

Capture compound mass spectrometry sheds light on the molecular mechanisms of liver toxicity of two Parkinson drugs.

PubMed

Fischer, Jenny J; Michaelis, Simon; Schrey, Anna K; Graebner, Olivia Graebner nee; Glinski, Mirko; Dreger, Mathias; Kroll, Friedrich; Koester, Hubert

2010-01-01

Capture compound mass spectrometry (CCMS) is a novel technology that helps understand the molecular mechanism of the mode of action of small molecules. The Capture Compounds are trifunctional probes: A selectivity function (the drug) interacts with the proteins in a biological sample, a reactivity function (phenylazide) irreversibly forms a covalent bond, and a sorting function (biotin) allows the captured protein(s) to be isolated for mass spectrometric analysis. Tolcapone and entacapone are potent inhibitors of catechol-O-methyltransferase (COMT) for the treatment of Parkinson's disease. We aimed to understand the molecular basis of the difference of both drugs with respect to side effects. Using Capture Compounds with these drugs as selectivity functions, we were able to unambiguously and reproducibly isolate and identify their known target COMT. Tolcapone Capture Compounds captured five times more proteins than entacapone Capture Compounds. Moreover, tolcapone Capture Compounds isolated mitochondrial and peroxisomal proteins. The major tolcapone-protein interactions occurred with components of the respiratory chain and of the fatty acid beta-oxidation. Previously reported symptoms in tolcapone-treated rats suggested that tolcapone might act as decoupling reagent of the respiratory chain (Haasio et al., 2002b). Our results demonstrate that CCMS is an effective tool for the identification of a drug's potential off targets. It fills a gap in currently used in vitro screens for drug profiling that do not contain all the toxicologically relevant proteins. Thereby, CCMS has the potential to fill a technological need in drug safety assessment and helps reengineer or to reject drugs at an early preclinical stage.

Identification of Hepatitis C Virus Inhibitors Targeting Different Aspects of Infection Using a Cell-Based Assay

PubMed Central

Yu, Xuemei; Sainz, Bruno; Petukhov, Pavel A.

2012-01-01

With 2 to 3% of the worldwide population chronically infected, hepatitis C virus (HCV) infection continues to be a major health care burden. Unfortunately, current interferon-based treatment options are not effective in all patients and are associated with significant side effects. Consequently, there is an ongoing need to identify and develop new anti-HCV therapies. Toward this goal, we previously developed a cell-based HCV infection assay for antiviral compound screening based on a low-multiplicity-of-infection approach that uniquely allows for the identification of antiviral compounds that target cell culture-derived HCV (HCVcc) at any step of the viral infection cycle. Using this assay, here we report the screening of the NCI Diversity Set II library, containing 1,974 synthesized chemical compounds, and the identification of compounds with specific anti-HCV activity. In combination with toxicity counterscreening, we identified 30 hits from the compound library, 13 of which showed reproducible and dose-dependent inhibition of HCV with mean therapeutic indices (50% cytotoxic concentration [CC50]/50% effective concentration [EC50]) of greater than 6. Using HCV pseudotype and replicon systems of multiple HCV genotypes, as well as infectious HCVcc-based assembly and secretion analysis, we determined that different compounds within this group of candidate inhibitors target different steps of viral infection. The compounds identified not only will serve as biological probes to study and further dissect the biology of viral infection but also should facilitate the development of new anti-HCV therapeutic treatments. PMID:22948883

Phytochemical screening and in-vitro antioxidant activity isolated bioactive compounds from Tridax procumbens Linn.

PubMed

Saxena, Manjusha; Mir, Abrar Hussain; Sharma, Manik; Malla, Mohd Yousu; Qureshi, Sumeerah; Mir, Mohd Iqbal; Chaturvedi, Yogesh

2013-12-15

Tridax procumbens L., Asteraceae, has been extensively used for various ailments in the Ayurvedic system of medicine. Previous studies have revealed remarkable phytoconstituents from Tridax procumbens L. with significant antioxidant activity. The aim of the present study is to measure the anti-DPPH activity of the purified isolated compounds from n butanol soluble part and ethyl acetate soluble part of successive methanolic extract of Tridax procumbens L. We thus quantified the total phenolic and total flavonoids in different purified isolated compounds, the whole of the tests were evaluated with a sample cone. of 100 microg mL(-1) and were determined spectrophotometrically using Folin-ciocaltue and AlCl3 reagents, respectively. DPPH (1,1-diphenyl, 2-picryl hydrazyl) assay was used to determine the in vitro antioxidant activity of different isolated compounds. Isolated compounds, one from ethyl acetate soluble part (EF-I) and one from n butanol soluble part (BF-II) were reported to possess a significant anti DPPH activity with lowest IC50 values 67.26 and 80.90 microg mL(-1), respectively while comparable to standard ascorbic acid with IC50 value of 59.62 microg mL(-1), due to the high concentration of phenols 146.4 microg mL(-1) from EF-I and 142.2 microg mL(-1) from BF-II and flavonoids 48 and 42.5 microg mL(-1) found in EF-I and BF-II isolated compounds, respectively.

Inhibition of aflatoxin biosynthesis in Aspergillus flavus by phenolic compounds extracted of Piper betle L.

PubMed

Yazdani, Darab; Mior Ahmad, Zainal Abidin; Yee How, Tan; Jaganath, Indu Bala; Shahnazi, Sahar

2013-12-01

Food contamination by aflatoxins is an important food safety concern for agricultural products. In order to identify and develop novel antifungal agents, several plant extracts and isolated compounds have been evaluated for their bioactivities. Anti-infectious activity of Piper betle used in traditional medicine of Malaysia has been reported previously. Crude methanol extract from P. betel powdered leaves was partitioned between chloroform and water. The fractions were tested against A. flavus UPMC 89, a strong aflatoxin producing strain. Inhibition of mycelial growth and aflatoxin biosynthesis were tested by disk diffusion and macrodillution techniques, respectively. The presence of aflatoxin was determined by thin-layer chromatography (TLC) and fluorescence spectroscopy techniques using AFB1 standard. The chloroform soluble compounds were identified using HPLC-Tandem mass spectrometry technique. The results, evaluated by measuring the mycelial growth and quantification of aflatoxin B1(AFLB1) production in broth medium revealed that chloroform soluble compounds extract from P. betle dried leaves was able to block the aflatoxin biosynthesis pathway at concentration of 500μg/ml without a significant effect on mycelium growth. In analyzing of this effective fractions using HPLC-MS(2) with ESI ionization technique, 11 phenolic compounds were identified. The results showed that the certain phenolic compounds are able to decline the aflatoxin production in A. flavus with no significant effect on the fungus mycelia growth. The result also suggested P. betle could be used as potential antitoxin product.

Antidiabetic compounds from Sarracenia purpurea used traditionally by the Eeyou Istchee Cree First Nation.

PubMed

Muhammad, Asim; Guerrero-Analco, Jose A; Martineau, Louis C; Musallam, Lina; Madiraju, Padma; Nachar, Abir; Saleem, Ammar; Haddad, Pierre S; Arnason, John T

2012-07-27

Through ethnobotanical surveys, the CIHR Team in Aboriginal Antidiabetic Medicines identified 17 boreal forest plants stemming from the pharmacopeia of the Cree First Nations of Eeyou Istchee (James Bay region of Northern Quebec) that were used traditionally against diabetes symptoms. The leaves of Sarracenia purpurea (pitcher plant), one of the identified Cree plants, exhibited marked antidiabetic activity in vitro by stimulating glucose uptake in C2C12 mouse muscle cells and by reducing glucose production in H4IIE rat liver cells. Fractionation guided by glucose uptake in C2C12 cells resulted in the isolation of 11 compounds from this plant extract, including a new phenolic glycoside, flavonoid glycosides, and iridoids. Compounds 6 (isorhamnetin-3-O-glucoside), 8 [kaempferol-3-O-(6″-caffeoylglucoside], and 11 (quercetin-3-O-galactoside) potentiated glucose uptake in vitro, which suggests they represent active principles of S. purpurea (EC(50) values of 18.5, 13.8, and 60.5 μM, respectively). This is the first report of potentiation of glucose uptake by compounds 6 and 8, while compound 11 (isolated from Vaccinium vitis) was previously shown to enhance glucose uptake. Treatment of H4IIE liver cells with the new compound 1, 6'-O-caffeoylgoodyeroside, decreased hepatic glucose production by reducing glucose-6-phosphatase enzymatic activity (IC(50) = 13.6 μM), which would contribute to lowering glycemia and to the antidiabetic potential of S. purpurea.

Algicidal activity of thiazolidinedione derivatives against harmful algal blooming species.

PubMed

Kim, Yeon-Mi; Wu, Ying; Duong, Thi Uyen; Jung, Seul-Gi; Kim, Si Wouk; Cho, Hoon; Jin, Eonseon

2012-06-01

Thiazolidinedione (TD) derivatives exhibit algicidal activity against harmful algal blooming species such as Chattonella marina, Heterosigma akashiwo, and Cochlodinium polykrikoides, as reported previously. In this study, the efficacies and selectivities of TD derivatives were tested by analyzing the structure-activity relationships of various TD derivatives. To investigate structure-activity relationships for growth inhibition of harmful algae, we added a methylene group between the cyclohexyl ring and oxygen of 5-(3-chloro-4-hydroxybenzylidene)-TD, which decreased the inhibitory potency of compound 17. Interestingly, another addition of a methylene group significantly increased the inhibitory potency against C. polykrikoides. The addition of 1 μM compound 17 resulted in the cell rupture of harmful algae after less than 10 h incubation at 20 °C. Compound 17 was applied to both harmful and non-harmful algae and showed a drastic reduction in the efficiency of photosystem II, resulting in reduced photosynthetic oxygen evolution. Compound 17 at a 5 μM concentration destroyed all of the harmful algae, while algicidal activity against non-harmful algae did not exceed 30% of the control within the concentration range tested. In contrast, a herbicide, 3-(3,4-dichlorophenyl)-1,1-dimethylurea, tested at a 5 μM concentration, exhibited 40-70% algicidal activity relative to that of the control against both harmful and non-harmful algae. Compound 17 is a promising lead compound for the development of algicides to control harmful algal blooming species.

73Ge, 119Sn and 207Pb: general cooperative effects of single atom ligands on the NMR signals observed in tetrahedral [MXnY4-n] (M = Ge, Sn, Pb; 1 ≤ n ≤ 4; X, Y = Cl, Br, I) coordination compounds of heavier XIV group elements.

PubMed

Benedetti, M; De Castro, F; Fanizzi, F P

2017-02-28

An inverse linear relationship between 73 Ge, 119 Sn and 207 Pb NMR chemical shifts and the overall sum of ionic radii of coordinated halido ligands has been discovered in tetrahedral [MX n Y 4-n ] (M = Ge, Sn, Pb; 1 ≤ n ≤ 4; X, Y = Cl, Br, I) coordination compounds. This finding is consistent with a previously reported correlation found in octahedral, pentacoordinate and square planar platinum complexes. The effect of the coordinated halido ligands acting on the metal as shielding conducting rings is therefore confirmed also by 73 Ge, 119 Sn and 207 Pb NMR spectroscopy.

A novel dimeric flavonol glycoside from Cynanchum acutum subsp. sibiricum.

PubMed

Yuan, Si-Wen; Dai, Wei; Pan, Xin-Hui; Lu, Yan; Chen, Dao-Feng; Wang, Qi

2018-06-11

A novel dimeric flavonol glycoside, Cynanflavoside A (1), together with six analogues, kaempferol-3-O-α-L-rhamnopyranosyl-(1→2)-β-D-glucopyranoside (2), quercetin-3-O-α-L-rhamnopyranosyl-(1→2)-β-D-glucopyranoside (3), kaempferol-3-O-α-L-rhamnopyranosyl-(1→2)-β-D-xylopyranoside (4), quercetin-3-O-α-L-rhamnopyranosyl-(1→2)-β-D-xylopyranoside (5), kaempferol-3-O-β-D-glucopyranosyl-7-O-α-L-rhamnopyranoside (6), and quercetin-3-O-galactoside (7) were isolated from the n-butyl alcohol extract of Cynanchum acutum subsp. sibiricum. Their structures were determined spectroscopically and compared with previously reported spectral data. All compounds were evaluated for their anti-complementary activity in vitro, and only compound 5 exhibited anti-complement effects with CH 50 value of 0.33 mM.

Analysis of differential secondary effects of novel rexinoids: select rexinoid X receptor ligands demonstrate differentiated side effect profiles

PubMed Central

Marshall, Pamela A; Jurutka, Peter W; Wagner, Carl E; van der Vaart, Arjan; Kaneko, Ichiro; Chavez, Pedro I; Ma, Ning; Bhogal, Jaskaran S; Shahani, Pritika; Swierski, Johnathon C; MacNeill, Mairi

2015-01-01

In order to determine the feasibility of utilizing novel rexinoids for chemotherapeutics and as potential treatments for neurological conditions, we undertook an assessment of the side effect profile of select rexinoid X receptor (RXR) analogs that we reported previously. We assessed pharmacokinetic profiles, lipid and thyroid-stimulating hormone (TSH) levels in rats, and cell culture activity of rexinoids in sterol regulatory element-binding protein (SREBP) induction and thyroid hormone inhibition assays. We also performed RNA sequencing of the brain tissues of rats that had been dosed with the compounds. We show here for the first time that potent rexinoid activity can be uncoupled from drastic lipid changes and thyroid axis variations, and we propose that rexinoids can be developed with improved side effect profiles than the parent compound, bexarotene (1). PMID:26038698

Recessive variants of MuSK are associated with late onset CMS and predominant limb girdle weakness.

PubMed

Owen, David; Töpf, Ana; Preethish-Kumar, Veeramani; Lorenzoni, Paulo José; Vroling, Bas; Scola, Rosana Herminia; Dias-Tosta, Elza; Geraldo, Argemiro; Polavarapu, Kiran; Nashi, Saraswati; Cox, Daniel; Evangelista, Teresinha; Dawson, John; Thompson, Rachel; Senderek, Jan; Laurie, Steven; Beltran, Sergi; Gut, Marta; Gut, Ivo; Nalini, Atchayaram; Lochmüller, Hanns

2018-04-28

Congenital myasthenic syndrome (CMS) is a heterogeneous disorder that causes fatigable muscle weakness. CMS has been associated with variants in the MuSK gene and, to date, 16 patients have been reported. MuSK-CMS patients present a different phenotypic pattern of limb girdle weakness. Here, we describe four additional patients and discuss the phenotypic and clinical relationship with those previously reported. Two novel damaging missense variants are described: c.1742T > A; p.I581N found in homozygosis, and c.1634T > C; p.L545P found in compound heterozygosis with p.R166*. The reported patients had predominant limb girdle weakness with symptom onset at 12, 17, 18, and 30 years of age, and the majority exhibited a good clinical response to Salbutamol therapy, but not to esterase inhibitors. Meta-analysis including previously reported variants revealed an increased likelihood of a severe, respiratory phenotype with null alleles. Missense variants exclusively affecting the kinase domain, but not the catalytic site, are associated with late onset. These data refine the phenotype associated with MuSK-related CMS. © 2018 Wiley Periodicals, Inc.

Tracing fresh assimilates through Larix decidua exposed to elevated CO₂ and soil warming at the alpine treeline using compound-specific stable isotope analysis.

PubMed

Streit, Kathrin; Rinne, Katja T; Hagedorn, Frank; Dawes, Melissa A; Saurer, Matthias; Hoch, Günter; Werner, Roland A; Buchmann, Nina; Siegwolf, Rolf T W

2013-02-01

How will carbon source-sink relations of 35-yr-old larch trees (Larix decidua) at the alpine treeline respond to changes in atmospheric CO(2) and climate? We evaluated the effects of previously elevated CO(2) concentrations (9 yr, 580 ppm, ended the previous season) and ongoing soil warming (4 yr, + 4°C). Larch branches were pulse labeled (50 at% (13)CO(2)) in July 2010 to trace fresh assimilates through tissues (buds, needles, bark and wood) and non-structural carbon compounds (NCC; starch, lipids, individual sugars) using compound-specific isotope analysis. Nine years of elevated CO(2) did not lead to increased NCC concentrations, nor did soil warming increase NCC transfer velocities. By contrast, we found slower transfer velocities and higher NCC concentrations than reported in the literature for lowland larch. As a result of low dilution with older carbon, sucrose and glucose showed the highest maximum (13)C labels, whereas labels were lower for starch, lipids and pinitol. Label residence times in needles were shorter for sucrose and starch (c. 2 d) than for glucose (c. 6 d). Although our treatments showed no persistent effect on larch carbon relations, low temperature at high altitudes clearly induced a limitation of sink activities (growth, respiration, root exudation), expressed in slower carbon transfer and higher NCC concentrations. © 2012 The Authors. New Phytologist © 2012 New Phytologist Trust.

5-Bromo-2-aryl benzimidazole derivatives as non-cytotoxic potential dual inhibitors of α-glucosidase and urease enzymes.

PubMed

Arshad, Tanzila; Khan, Khalid Mohammed; Rasool, Najma; Salar, Uzma; Hussain, Shafqat; Asghar, Humna; Ashraf, Mohammed; Wadood, Abdul; Riaz, Muhammad; Perveen, Shahnaz; Taha, Muhammad; Ismail, Nor Hadiani

2017-06-01

On the basis of previous report on promising α-glucosidase inhibitory activity of 5-bromo-2-aryl benzimidazole derivatives, these derivatives were further screened for urease inhibitory and cytotoxicity activity in order to get more potent and non-cytotoxic potential dual inhibitor for the patients suffering from diabetes as well as peptic ulcer. In this study, all compounds showed varying degree of potency in the range of (IC 50 =8.15±0.03-354.67±0.19μM) as compared to standard thiourea (IC 50 =21.25±0.15μM). It is worth mentioning that derivatives 7 (IC 50 =12.07±0.05μM), 8 (IC 50 =10.57±0.12μM), 11 (IC 50 =13.76±0.02μM), 14 (IC 50 =15.70±0.12μM) and 22 (IC 50 =8.15±0.03μM) were found to be more potent inhibitors than standard. All compounds were also evaluated for cytotoxicity towards 3T3 mouse fibroblast cell line and found to be completely non-toxic. Previously benzimidazole 1-25 were also showed α-glucosidase inhibitory potential. In silico studies were performed on the lead molecules i.e.2, 7, 8, 11, 14, and 22, in order to rationalize the binding interaction of compounds with the active site of urease enzyme. Copyright © 2017 Elsevier Inc. All rights reserved.

Derivatives of furanditerpenes from Pterodon genus: Pharmacological studies disclose their potential as chronic pain relief in mice.

PubMed

Spindola, Humberto M; Grando, Rogério; Figueiredo, Mariana C; Basting, Rosana; Queiroz, N C A; de Fátima, Ângelo; de Carvalho, João E; Wang, Zaijie J; Foglio, M A

2017-06-05

Pterodon genus fruits are commercially available at the Brazilian medicinal market used in folk medicine due to their anti-inflammatory, analgesic, and anti-rheumatic effects. Previous studies demonstrated that furanditerpenes possessing vouacapan skeleton, isolated from Pterodon genus, possess expressive antinociceptive activities, with promising moiety for the development of new analgesic products. The antinociceptive properties of compounds 6α,7β-6α-hidroxivouacapan-7β-17β-lactone (HVL) and 6α-oxovouacapan-7β-17β-lactone (OVL), semi-synthetic analogues of furanditerpenes previously reported as analgesic agents were evaluated on animal experimental models (Spindola et al., 2010, 2011). The chemical-induced pain methods used in the present work, demonstrated for the first time that both compounds HVL and OVL have potential as important templates for the development of chronic pain control drugs. The main findings of this work were that both compounds were: effective in the writhing test; reduced paw edema in the carrageenan test; effective in the inflammatory phase of the formalin test corroborating their activity against inflammatory pain conditions; effective on reducing pain through the stimulation of vanilloid receptors sensible to capsaicin (an important pathway for chronic pain maintenance); reduced the pain stimulus caused by PGE 2 injection (a pathway involved in chronic pain hypersensitivity); effective on decreasing mechanical allodynia in the CFA-model, demonstrating their potential use against chronic pain disorders. Copyright © 2017 Elsevier B.V. All rights reserved.

Genetic diversity-independent neutralization of pandemic viruses (e.g. HIV), potentially pandemic (e.g. H5N1 strain of influenza) and carcinogenic (e.g. HBV and HCV) viruses and possible agents of bioterrorism (variola) by enveloped virus neutralizing compounds (EVNCs).

PubMed

Kotwal, Girish J

2008-06-06

Genetic diversity and hypermutation contribute to difficulties in developing a vaccine against viruses like HIV and influenza. There are currently no known immune correlates of protection against HIV. This has made the development of a vaccine against HIV that would provide sterilizing immunity in the near future an impossible task. The abandonment of a recent AIDS vaccine human trial due to a failure to elicit a protective sterilising immune response confirms that empirical attempts to develop a vaccine may result in failures. Also the difficulty in predicting the next pandemic strain of influenza may make it difficult to respond rapidly should there be an outbreak. Therefore, it is time to explore broad spectrum agents that can target either the lipid portion of the envelope or the sugar moieties of the glycoproteins or the rafts (regions within viral and cell envelopes where a higher concentration of the glycoproteins exist). Broad spectrum agents that can serve as disrafters or neutralize the viral infectivity by binding to the envelope lipid or sugar moieties will not be affected by the vagaries of hypermutation of surface antigens. This is because the post-translation modification is a host function. Presented here is a review of recently reported agents present in pomegranate juice (polyphenols, beta-sitosterol, sugars and ellagic acid) and fulvic acid, described here as the envelope virus neutralising compounds (EVNCs) and complex molecules like lectins and mucins. Pomegranate juice was previously reported to inactivate HIV and further shown by our group to inactivate influenza, herpes viruses and poxviruses. A formulation consisting of fulvic acid, a complex mixture of compounds was previously reported to render vaccinia virus, HIV and SARS virus non-infectious. Recently, both fulvic acid and pomegranate juice have been shown to inactivate genetically diverse strains of influenza including H5N1, further confirming the broad spectrum nature of these agents. How EVNCs will be used in developing a vaccine achieving sterilizing immunity or prophylaxis needs to be researched.

Compounds from the Fruits of the Popular European Medicinal Plant Vitex agnus-castus in Chemoprevention via NADP(H):Quinone Oxidoreductase Type 1 Induction.

PubMed

Li, Shenghong; Qiu, Shengxiang; Yao, Ping; Sun, Handong; Fong, Harry H S; Zhang, Hongjie

2013-01-01

As part of our continuing efforts in the search for potential biologically active compounds from medicinal plants, we have isolated 18 compounds including two novel nitrogen containing diterpenes from extracts of the fruits of Vitex agnus-castus. These isolates, along with our previously obtained novel compound vitexlactam A (1), were evaluated for potential biological effects, including cancer chemoprevention. Chemically, the nitrogenous isolates were found to be two labdane diterpene alkaloids, each containing an α , β -unsaturated γ -lactam moiety. Structurally, they were elucidated to be 9 α -hydroxy-13(14)-labden-16,15-amide (2) and 6 β -acetoxy-9 α -hydroxy-13(14)-labden-15,16-amide (3), which were named vitexlactams B and C, respectively. The 15 known isolates were identified as vitexilactone (4), rotundifuran (5), 8-epi-manoyl oxide (6), vitetrifolin D (7), spathulenol (8), cis-dihydro-dehydro-diconiferylalcohol-9-O- β -D-glucoside (9), luteolin-7-O-glucoside (10), 5-hydroxy-3,6,7,4'-tetramethoxyflavone (11), casticin (12), artemetin (13), aucubin (14), agnuside (15), β -sitosterol (16), p-hydroxybenzoic acid (17), and p-hydroxybenzoic acid glucose ester (18). All compound structures were determined/identified on the basis of 1D and/or 2D NMR and mass spectrometry techniques. Compounds 6, 8, 9, and 18 were reported from a Vitex spieces for the first time. The cancer chemopreventive potentials of these isolates were evaluated for NADP(H):quinone oxidoreductase type 1 (QR1) induction activity. Compound 7 demonstrated promising QR1 induction effect, while the new compound vitexlactam (3) was only slightly active.

Compounds from the Fruits of the Popular European Medicinal Plant Vitex agnus-castus in Chemoprevention via NADP(H):Quinone Oxidoreductase Type 1 Induction

PubMed Central

Li, Shenghong; Qiu, Shengxiang; Yao, Ping; Sun, Handong; Fong, Harry H. S.; Zhang, Hongjie

2013-01-01

As part of our continuing efforts in the search for potential biologically active compounds from medicinal plants, we have isolated 18 compounds including two novel nitrogen containing diterpenes from extracts of the fruits of Vitex agnus-castus. These isolates, along with our previously obtained novel compound vitexlactam A (1), were evaluated for potential biological effects, including cancer chemoprevention. Chemically, the nitrogenous isolates were found to be two labdane diterpene alkaloids, each containing an α, β-unsaturated γ-lactam moiety. Structurally, they were elucidated to be 9α-hydroxy-13(14)-labden-16,15-amide (2) and 6β-acetoxy-9α-hydroxy-13(14)-labden-15,16-amide (3), which were named vitexlactams B and C, respectively. The 15 known isolates were identified as vitexilactone (4), rotundifuran (5), 8-epi-manoyl oxide (6), vitetrifolin D (7), spathulenol (8), cis-dihydro-dehydro-diconiferylalcohol-9-O-β-D-glucoside (9), luteolin-7-O-glucoside (10), 5-hydroxy-3,6,7,4′-tetramethoxyflavone (11), casticin (12), artemetin (13), aucubin (14), agnuside (15), β-sitosterol (16), p-hydroxybenzoic acid (17), and p-hydroxybenzoic acid glucose ester (18). All compound structures were determined/identified on the basis of 1D and/or 2D NMR and mass spectrometry techniques. Compounds 6, 8, 9, and 18 were reported from a Vitex spieces for the first time. The cancer chemopreventive potentials of these isolates were evaluated for NADP(H):quinone oxidoreductase type 1 (QR1) induction activity. Compound 7 demonstrated promising QR1 induction effect, while the new compound vitexlactam (3) was only slightly active. PMID:23662135

Occurrence of sarmentosin and other hydroxynitrile glucosides in Parnassius (papilionidae) butterflies and their food plants.

PubMed

Bjarnholt, Nanna; Nakonieczny, Mirosław; Kędziorski, Andrzej; Debinski, Diane M; Matter, Stephen F; Olsen, Carl Erik; Zagrobelny, Mika

2012-05-01

Sequestration of plant secondary metabolites is a widespread phenomenon among aposematic insects. Sarmentosin is an unsaturated γ-hydroxynitrile glucoside known from plants and some Lepidoptera. It is structurally and biosynthetically closely related to cyanogenic glucosides, which are commonly sequestered from food plants and/or de novo synthesized by lepidopteran species. Sarmentosin was found previously in Parnassius (Papilionidae) butterflies, but it was not known how the occurrence was related to food plants or whether Parnassius species could biosynthesize the compound. Here, we report on the occurrence of sarmentosin and related compounds in four different Parnassius species belonging to two different clades, as well as their known and suspected food plants. There were dramatic differences between the two clades, with P. apollo and P. smintheus from the Apollo group containing high amounts of sarmentosin, and P. clodius and P. mnemosyne from the Mnemosyne group containing low or no detectable amounts. This was reflected in the larval food plants; P. apollo and P. smintheus larvae feed on Sedum species (Crassulaceae), which all contained considerable amounts of sarmentosin, while the known food plants of the two other species, Dicentra and Corydalis (Fumariaceae), had no detectable levels of sarmentosin. All insects and plants containing sarmentosin also contained other biosynthetically related hydroxynitrile glucosides in patterns previously reported for plants, but not for insects. Not all findings could be explained by sequestration alone and we therefore hypothesize that Parnassius species are able to de novo synthesize sarmentosin.

Rate constants for the reactions of OH with CH3Cl, CH2Cl2, CHCl3, and CH3Br

NASA Technical Reports Server (NTRS)

Hsu, K.-J.; Demore, W. B.

1994-01-01

Rate constants for the reactions of OH with CH3Cl, CH2Cl2, CHCl3, and CH3Br have been measured by a relative rate technique in which the reaction rate of each compound was compared to that of HFC-152a (CH3CHF2) and (for CH2Cl2) HFC-161 (CH3CH2F). Using absolute rate constants for HFC-152a and HFC-161, which we have determined relative to those for CH4, CH3CCl3, and C2H6, temperature dependent rate constants of both compounds were derived. The derived rate constant for CH3Br is in good agreement with recent absolute measurements. However, for the chloromethanes all the rate constants are lower at atmospheric temperatures than previously reported, especially for CH2Cl2 where the present rate constant is about a factor of 1.6 below the JPL 92-20 value. The new rate constant appears to resolve a discrepancy between the observed atmospheric concentrations and those calculated from the previous rate constant and estimated release rates.

Strongly Enhanced Photovoltaic Performance and Defect Physics of Air-Stable Bismuth Oxyiodide (BiOI)

DOE PAGES

Hoye, Robert L. Z.; Lee, Lana C.; Kurchin, Rachel C.; ...

2017-07-17

Bismuth-based compounds have recently gained increasing attention as potentially nontoxic and defect-tolerant solar absorbers. However, many of the new materials recently investigated show limited photovoltaic performance. Herein, one such compound is explored in detail through theory and experiment: bismuth oxyiodide (BiOI). BiOI thin films are grown by chemical vapor transport and found to maintain the same tetragonal phase in ambient air for at least 197 d. The computations suggest BiOI to be tolerant to antisite and vacancy defects. All-inorganic solar cells (ITO|NiO x|BiOI|ZnO|Al) with negligible hysteresis and up to 80% external quantum efficiency under select monochromatic excitation are demonstrated. Themore » short-circuit current densities and power conversion efficiencies under AM 1.5G illumination are nearly double those of previously reported BiOI solar cells, as well as other bismuth halide and chalcohalide photovoltaics recently explored by many groups. Through a detailed loss analysis using optical characterization, photoemission spectroscopy, and device modeling, direction for future improvements in efficiency is provided. In conclusion, this work demonstrates that BiOI, previously considered to be a poor photocatalyst, is promising for photovoltaics.« less

Unique Bond Breaking in Crystalline Phase Change Materials and the Quest for Metavalent Bonding.

PubMed

Zhu, Min; Cojocaru-Mirédin, Oana; Mio, Antonio M; Keutgen, Jens; Küpers, Michael; Yu, Yuan; Cho, Ju-Young; Dronskowski, Richard; Wuttig, Matthias

2018-05-01

Laser-assisted field evaporation is studied in a large number of compounds, including amorphous and crystalline phase change materials employing atom probe tomography. This study reveals significant differences in field evaporation between amorphous and crystalline phase change materials. High probabilities for multiple events with more than a single ion detected per laser pulse are only found for crystalline phase change materials. The specifics of this unusual field evaporation are unlike any other mechanism shown previously to lead to high probabilities of multiple events. On the contrary, amorphous phase change materials as well as other covalently bonded compounds and metals possess much lower probabilities for multiple events. Hence, laser-assisted field evaporation in amorphous and crystalline phase change materials reveals striking differences in bond rupture. This is indicative for pronounced differences in bonding. These findings imply that the bonding mechanism in crystalline phase change materials differs substantially from conventional bonding mechanisms such as metallic, ionic, and covalent bonding. Instead, the data reported here confirm a recently developed conjecture, namely that metavalent bonding is a novel bonding mechanism besides those mentioned previously. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Synthesis and Evaluation of Orexin-1 Receptor Antagonists with Improved Solubility and CNS Permeability.

PubMed

Perrey, David A; Decker, Ann M; Zhang, Yanan

2018-03-21

Orexins are hypothalamic neuropeptides playing important roles in many functions including the motivation of addictive behaviors. Blockade of the orexin-1 receptor has been suggested as a potential strategy for the treatment of drug addiction. We have previously reported OX 1 receptor antagonists based on the tetrahydroisoquinoline scaffold with excellent OX 1 potency and selectivity; however, these compounds had high lipophilicity (clogP > 5) and low to moderate solubility. In an effort to improve their properties, we have designed and synthesized a series of analogues where the 7-position substituents known to favor OX 1 potency and selectivity were retained, and groups of different nature were introduced at the 1-position where substitution was generally tolerated as demonstrated in previous studies. Compound 44 with lower lipophilicity (clogP = 3.07) displayed excellent OX 1 potency ( K e = 5.7 nM) and selectivity (>1,760-fold over OX 2 ) in calcium mobilization assays. In preliminary ADME studies, 44 showed excellent kinetic solubility (>200 μM), good CNS permeability ( P app = 14.7 × 10 -6 cm/sec in MDCK assay), and low drug efflux (efflux ratio = 3.3).

A critical review of both the synthesis approach and the receptor profile of the 8-chloro-1-(2',4'-dichlorophenyl)-N-piperidin-1-yl-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-c]pyrazole-3-carboxamide and analogue derivatives.

PubMed

Lazzari, Paolo; Distinto, Rita; Manca, Ilaria; Baillie, Gemma; Murineddu, Gabriele; Pira, Marilena; Falzoi, Matteo; Sani, Monica; Morales, Paula; Ross, Ruth; Zanda, Matteo; Jagerovic, Nadine; Pinna, Gérard Aimè

2016-10-04

8-Chloro-1-(2',4'-dichlorophenyl)-N-piperidin-1-yl-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-c]pyrazole-3-carboxamide 9a was discovered as potent and selective CB1 antagonist by part of our group few years ago. In particular it was reported to have an affinity towards the CB1 cannabinoid receptor (CB1R), expressed as Ki, of 0.00035 nM. Nevertheless significantly divergent data were reported for the same compound from other laboratories. To unequivocally define the receptor profile of 9a, we have critically reviewed both its synthesis approach and binding data. Here we report that, in contrast to our previously reported data, 9a showed a Ki value for CB1R in the order of nanomolar rather than of fentomolar range. The new determined receptor profile of 9a was also ascertained for analogue derivatives 9b-i, as well as for 12. Moreover, the structural features of the synthesized compounds necessary for CB1R were investigated. Amongst the novel series, effects on CB1R intrinsic activity was highlighted due to the substituents at the position 3 of the pyrazole ring of the 1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-c]pyrazole scaffold. Although the cannabinoid receptor profile of 9a was reviewed in this work, the relevance of this compound in CB1R antagonist based drug discovery is confirmed. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

DADS Analogues Ameliorated the Cognitive Impairments of Alzheimer-Like Rat Model Induced by Scopolamine.

PubMed

Manral, Apra; Meena, Poonam; Saini, Vikas; Siraj, Fouzia; Shalini, Shruti; Tiwari, Manisha

2016-10-01

The development of agents that affect two or more relevant targets has drawn considerable attention in treatment of AD. Diallyl disulfide (DADS), an active principle of garlic, has been reported to prevent APP processing by amyloidogenic pathway. Recently, we have reported a new series of DADS derivatives and our findings revealed that compound 7k and 7l could provide good templates for developing new multifunctional agents for AD treatment. Thus, the present study was constructed to investigate the neuroprotective effect of DADS analogues (7k and 7l) against Aβ-induced neurotoxicity in SH-SY5Y human neuroblastoma cells and in ameliorating the cognition deficit induced by scopolamine in rat model. The results indicated that compound 7k and 7l significantly inhibited Aβ1-42-induced neuronal cell death by inhibiting ROS generation. Moreover, they prevented apoptosis, in response to ROS, by restoring normal Bax/Bcl-2 ratio. Furthermore, it was observed that scopolamine-induced memory impairment was coupled by alterations in neurotransmitters, acetylcholinesterase activity and oxidative stress markers. Histological analysis revealed severe damaging effects of scopolamine on the structure of cerebral cortex and hippocampus. Administration of compounds 7k and 7l at 5 mg/kg significantly reversed scopolamine-induced behavioural, biochemical, neurochemical and histological changes in a manner comparable to standard donepezil. Together the present findings and previous studies indicate that compounds 7k and 7l have neuroprotective and cognition-enhancing effects, which makes them a promising multi-target candidate for addressing the complex nature of AD.

The effect of structure and a secondary carbon source on the microbial degradation of chlorophenoxy acids.

PubMed

Evangelista, S; Cooper, D G; Yargeau, V

2010-05-01

Pseudomonas putida, Aspergillus niger, Bacillus subtilis, Pseudomonas fluorescens, Sphingomonas herbicidovorans and Rhodococcus rhodochrous growing on glucose in a medium containing one of three chlorophenoxy acids at a concentration of 0.1 g L(-1) (clofibric acid, (R)-2-(4-chloro-2-methylphenoxy)propionic acid (mecoprop or MCPP) and 4-chloro-2-methylphenoxyacetic acid (MCPA)) degraded these compounds to varying degrees; from nonmeasurable to almost complete removal. These results with the addition of glucose (2.5 g L(-1)) as an easy to use carbon source indicated the formation of metabolites different from results reported in the literature for growth studies in which the chlorophenoxy acid was the sole carbon source. The metabolite, 4-chloro-2-methylphenol, which had been reported previously, was only observed in trace amounts for MCPP and MCPA in the presence of S. herbicidovorans and glucose. In addition, three other compounds (M1, M3 and M4) were observed. It is suggested that these unidentified metabolites resulted from ring opening of the metabolite 4-chloro-2-methylphenol (M2). The rate of biodegradation of the chlorophenoxy acids was influenced by the degree of steric hindrance adjacent to the internal oxygen bond common to all three compounds. The most hindered compound, clofibric acid, was converted to ethyl clofibrate by R. rhodochrous but was not degraded by any microorganisms studied. The more accessible internal oxygen bonds of the other two chlorophenoxy acids, MCPP and MCPA, were readily broken by S. herbicidovorans. Copyright (c) 2010 Elsevier Ltd. All rights reserved.

[Juvenile form of Sandhoff disease: first case reported in Argentina].

PubMed

Mugnaini, Julia; Pereyra, Marcela; Dodelson de Kremer, Raquel; Gamboni, Beatriz; Argaraña, Carlos E; Oller Ramírez, Ana M

2017-10-01

Sandhoff disease is a neurodegenerative, lysosomal and autosomal recessive disease caused by mutations in the HEXB gene. Three forms are recognized: infantile, juvenile and adult. Previously, an endogamous population in Córdoba, Argentina, was identified with a high incidence of Sandhoff disease, all reported cases were of the infantile type. In this work, we describe a child with the juvenile form of Sandhoff disease, the first case reported in Argentina. The patient is a 7-year-old boy presenting with ataxia, speech disturbances and global developmental delay, symptoms starting at the age of 2 years. Diagnosis was based on the hexosaminidase deficiency. Sequencing of genomic DNA revealed compound heterozygosity for two HEXB gene mutations: c.796T>G (p.Y266D) and c.1615C>T (p.R539C), both already reported. Sociedad Argentina de Pediatría.

Natural Product Libraries to Accelerate the High Throughput Discovery of Therapeutic Leads±

PubMed Central

Johnson, Tyler A.; Sohn, Johann; Inman, Wayne D.; Estee, Samarkand A.; Loveridge, Steven T.; Vervoort, Helene C.; Tenney, Karen; Liu, Junke; Ang, Kenny Kean-Hooi; Ratnam, Joseline; Bray, Walter M.; Gassner, Nadine C.; Shen, Young Y.; Lokey, R. Scott; McKerrow, James H.; Boundy-Mills, Kyria; Nukanto, Arif; Kanti, Atit; Julistiono, Heddy; Kardono, Leonardus B. S.; Bjeldanes, Leonard F.; Crews, Phillip

2011-01-01

A high throughput (HT) paradigm generating LC-MS-UV-ELSD based natural product libraries to discover compounds with new bioactivities and or molecular structures is presented. To validate this methodology an extract of the Indo Pacific marine sponge Cacospongia mycofijiensis was evaluated using assays involving cytoskeletal profiling, tumor cell lines, and parasites. Twelve known compounds were identified including the latrunculins (1–4, 10), fijianolides (5, 8–9), mycothiazole (11), the aignopsanes (6–7) and sacrotride A (13). Compounds 1–4, 5, 8–11 exhibited bioactivity not previously reported against the parasite T. brucei, while 11 showed selectivity for lymphoma (U937) tumor cell lines. Four new compounds were also discovered including: aignopsanoic acid B (13), apo latrunculin T (14), 20-methoxy-fijianolide A (15) and aignopsane ketal (16). Compounds 13 and 16 represent important derivatives of the aignopsane class, 14 exhibited inhibition of T. brucei without disrupting microfilament assembly and 15 demonstrated modest microtubule stabilizing effects. The use of removable well plate libraries to avoid false positives from extracts enriched with only 1–2 major metabolites is also discussed. Overall, these results highlight the advantages of applying modern methods in natural products-based research to accelerate the HT discovery of therapeutic leads and or new molecular structures using LC-MS-UV-ELSD based libraries. PMID:22129061

Structure-based design, synthesis, and biological evaluation of novel pyrrolyl aryl sulfones: HIV-1 non-nucleoside reverse transcriptase inhibitors active at nanomolar concentrations.

PubMed

Artico, M; Silvestri, R; Pagnozzi, E; Bruno, B; Novellino, E; Greco, G; Massa, S; Ettorre, A; Loi, A G; Scintu, F; La Colla, P

2000-05-04

Pyrrolyl aryl sulfones (PASs) have been recently reported as a new class of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) inhibitors acting at the non-nucleoside binding site of this enzyme (Artico, M.; et al. J. Med. Chem. 1996, 39, 522-530). Compound 3, the most potent inhibitor within the series (EC(50) = 0.14 microM, IC(50) = 0.4 microM, and SI > 1429), was then selected as a lead compound for a synthetic project based on molecular modeling studies. Using the three-dimensional structure of RT cocrystallized with the alpha-APA derivative R95845, we derived a model of the RT/3 complex by taking into account previously developed structure-activity relationships. Inspection of this model and docking calculations on virtual compounds prompted the design of novel PAS derivatives and related analogues. Our computational approach proved to be effective in making qualitative predictions, that is in discriminating active versus inactive compounds. Among the compounds synthesized and tested, 20 was the most active one, with EC(50) = 0.045 microM, IC(50) = 0.05 microM, and SI = 5333. Compared with the lead 3, these values represent a 3- and 8-fold improvement in the cell-based and enzyme assays, respectively, together with the highest selectivity achieved so far in the PAS series.

Novel primary amine diazeniumdiolates-Chemical and biological characterization.

PubMed

Puglisi, Melany P; Bradaric, Michael J; Pontikis, John; Cabai, Jonathan; Weyna, Theodore; Tednes, Patrick; Schretzman, Robert; Rickert, Karl; Cao, Zhao; Andrei, Daniela

2018-05-02

Hit, Lead & Candidate Discovery Diazeniumdiolates, also known as NONOates, are extensively used in biochemical, physiological, and pharmacological studies due to their ability to release nitric oxide (NO . ) and/or their congeneric nitroxyl (HNO). The purpose of this work was to synthesize a series of primary amine-based diazeniumdiolates as HNO/NO donors and to determine their efficacy as anticancer and antifungal agents in vivo. The seven compounds (3a-3g) were successfully synthesized and characterized, one of which had been previously reported in the literature (3g). Two compounds showed anti-proliferative effects against ovarian (ES2 and SKOV3) and AML monocyte-derived cancer cells (THP-1) when tested with standard MTT assays. Compounds 3a and 3g demonstrated reduced ovarian cancer cell proliferation when treated at doses from 0.033 to 1.0 mg/mL at the 24 hr time point. These compounds also exhibited moderate and selective antifungal activity against Fusarium oxysporum f.sp. lycopersici, one cause of opportunistic infections of immunocompromised patients, inhibiting the growth of the fungi at LD 50 at 10 mg/mL. A third compound (3e) did not exhibit similar activities, possibly due to the alkyl chain. Our results suggest that the primary amine diazeniumdiolates may offer a versatile platform for the development of HNO/NO donors for biomedical applications. © 2018 Wiley Periodicals, Inc.

Frog volatile compounds: application of in vivo SPME for the characterization of the odorous secretions from two species of Hypsiboas treefrogs.

PubMed

Brunetti, Andrés E; Merib, Josias; Carasek, Eduardo; Caramão, Elina B; Barbará, Janaina; Zini, Claudia A; Faivovich, Julián

2015-04-01

A novel in vivo design was used in combination with solid-phase microextraction (SPME) and gas chromatography/mass spectrometry (GC/MS) to characterize the volatile compounds from the skin secretion of two species of tree frogs. Conventional SPME-GC/MS also was used for the analysis of volatiles present in skin samples and for the analysis of volatiles present in the diet and terraria. In total, 40 and 37 compounds were identified in the secretion of Hypsiboas pulchellus and H. riojanus, respectively, of which, 35 were common to both species. Aliphatic aldehydes, a low molecular weight alkadiene, an aromatic alcohol, and other aromatics, ketones, a methoxy pyrazine, sulfur containing compounds, and hemiterpenes are reported here for the first time in anurans. Most of the aliphatic compounds seem to be biosynthesized by the frogs following different metabolic pathways, whereas aromatics and monoterpenes are most likely sequestered from environmental sources. The characteristic smell of the secretion of H. pulchellus described by herpetologists as skunk-like or herbaceous is explained by a complex blend of different odoriferous components. The possible role of the volatiles found in H. pulchellus and H. riojanus is discussed in the context of previous hypotheses about the biological function of volatile secretions in frogs (e.g., sex pheromones, defense secretions against predators, mosquito repellents).

Identification of Potential Pharmacoperones Capable of Rescuing the Functionality of Misfolded Vasopressin 2 Receptor Involved in Nephrogenic Diabetes Insipidus.

PubMed

Smith, Emery; Janovick, Jo Ann; Bannister, Thomas D; Shumate, Justin; Scampavia, Louis; Conn, P Michael; Spicer, Timothy P

2016-09-01

Pharmacoperones correct the folding of otherwise misfolded protein mutants, restoring function (i.e., providing "rescue") by correcting their trafficking. Currently, most pharmacoperones possess intrinsic antagonist activity because they were identified using methods initially aimed at discovering such functions. Here, we describe an ultra-high-throughput homogeneous cell-based assay with a cAMP detection system, a method specifically designed to identify pharmacoperones of the vasopressin type 2 receptor (V2R), a GPCR that, when mutated, is associated with nephrogenic diabetes insipidus. Previously developed methods to identify compounds capable of altering cellular trafficking of V2R were modified and used to screen a 645,000 compound collection by measuring the ability of library compounds to rescue a mutant hV2R [L83Q], using a cell-based luminescent detection system. The campaign initially identified 3734 positive modulators of cAMP. The confirmation and counterscreen identified only 147 of the active compounds with an EC50 of ≤5 µM. Of these, 83 were reconfirmed as active through independently obtained pure samples and were also inactive in a relevant counterscreen. Active and tractable compounds within this set can be categorized into three predominant structural clusters, described here, in the first report detailing the results of a large-scale pharmacoperone high-throughput screening campaign. © 2016 Society for Laboratory Automation and Screening.

Aminosugar derivatives as potential anti-human immunodeficiency virus agents.

PubMed Central

Karpas, A; Fleet, G W; Dwek, R A; Petursson, S; Namgoong, S K; Ramsden, N G; Jacob, G S; Rademacher, T W

1988-01-01

Recent data suggest that aminosugar derivatives which inhibit glycoprotein processing have potential anti-human immunodeficiency virus (HIV) activity. These inhibitory effects may be due to disruption of cell fusion and subsequent cell-cell transmission of the acquired immunodeficiency syndrome (AIDS) virus. Free virus particles able to bind CD4-positive cells are still produced in the presence of these compounds with only partial reduction of infectivity. We now report a method to score in parallel both the degree of antiviral activity and the effect on cell division of aminosugar derivatives. We find that (i) the compounds 1,4-dideoxy-1,4-imino-L-arabinitol and N-(5-carboxymethyl-1-pentyl)-1,5-imino-L-fucitol partially inhibit the cytopathic effect (giant cell formation, etc.) of HIV and yield of infectious virus; (ii) the compounds N-methyldeoxynojirimycin and N-ethyldeoxynojirimycin reduce the yield of infectious HIV by an order of four and three logarithms, respectively; and (iii) one compound, N-butyldeoxynojirimycin, of the 47 compounds previously screened reduces infectious viral particles by a logarithmic order greater than five at noncytotoxic concentrations. In addition, long-term growth of infected cells in the presence of N-butyldeoxynojirimycin gradually decreases the proportion of infected cells, leading to eventual elimination of HIV from culture. This result suggests that replication is associated with cytolysis. The ability to break the cycle of replication and reinfection has important implications in the chemotherapy of AIDS. PMID:3264071

Analysis and improved characterization of minor antioxidants from leaves of Malus doumeri using a combination of major constituents' knockout with high-performance liquid chromatography-diode array detector-quadrupole time-of-flight tandem mass spectrometry.

PubMed

Zhao, Huading; Hu, Xin; Chen, Xiaoqin; Shi, Shuyun; Jiang, Xinyu; Liang, Xuejuan; Chen, Wei; Zhang, Shuihan

2015-06-12

Due to the complexity of natural products, efficient identification of bioactive compounds, especially for minor compounds, would require a huge effort. Here, we developed an effective strategy based on combining major constituents' knockout with high-performance liquid chromatography-diode array detector-quadrupole time-of-flight tandem mass spectrometry (HPLC-DAD-QTOF-MS/MS) to comprehensively identify minor antioxidants in Malus doumeri, one of the longest known and most used tonic plant in Taiwan. First, five major compounds (I-V) in M. doumeri were knocked out by two-step stepwise high-speed countercurrent chromatography (HSCCC). Second, minor antioxidants were screened by 1,1-diphenyl-2-picrylhydrazyl radical-HPLC (DPPH-HPLC) assay. Third, structures of thirty minor antioxidants, including 11 dihydrochalcones, 4 flavanones, 3 flavonols, 2 flavones, 3 aurones and 7 phenolic acids, were unambiguously or tentatively identified by matching their characteristic UV spectra, accurate mass signals and key diagnostic fragment ions with standards or previously reported compounds. Twenty-six of them, as far as was known, were discovered from M. doumeri for the first time. The results indicated that the proposed method was a useful approach to explore minor bioactive compounds from complex natural products. Copyright © 2015 Elsevier B.V. All rights reserved.

Stability studies of endocrine disrupting tributyltin and triphenyltin compounds in an artificial sea water model.

PubMed

Novotny, Ladislav; Sharaf, Leyla; Abdel-Hamid, Mohammed E; Brtko, Julius

2018-01-01

Triorganotins belong to toxic components present predominantly in antifouling paints for marine vessels. Tributyltin/triphenyltin at pico- or nanomolar concentrations in sea water are known to induce an irreversible sexual abnormality in females of over 190 marine species, an "imposex" phenomenon - the superimposition of male genitalia on a female. Moreover, trialkyltins and triaryltins function as potent nuclear retinoid X receptors (RXR) agonists. In mammals, triorganotin compounds induce immunosuppressive, metabolic, reproductive or developmental effects. Toxic effects of triorganotins warrant the need for monitoring of their long-lasting presence in the environment. This study brings novel data on the stability of two triorganotin compounds in artificial sea water model obtained by applying ultra-pressure liquid chromatography (UPLC) and gas chromatography-mass spectrometry (GC-MS) methods. Stability of tributyltin and triphenyltin chlorides was studied for 180 days and the degradation kinetic parameters were obtained. Tributyltin chloride was the less stable with the degradation kinetic parameters Kdeg = 0.00014 day-1 and t1/2 = 4950 days (13.6 years). Kdeg of the more stable triphenyltin chloride was determined to be Kdeg = 0.00006 day-1 with t1/2 = 11550 days (31.6 years). Since similar stability data of triorganotin compounds were not published previously, we report high stability for both tested compounds, which indicates a significant environmental problem when these substances enter sea water and later coastal sediments.

Characterization of a Melamino Nitroheterocycle as a Potential Lead for the Treatment of Human African Trypanosomiasis

PubMed Central

Giordani, Federica; Buschini, Annamaria; Baliani, Alessandro; Kaiser, Marcel; Brun, Reto; Barrett, Michael P.; Pellacani, Claudia; Poli, Paola

2014-01-01

This paper reports an evaluation of a melamino nitroheterocycle, a potential lead for further development as an agent against human African trypanosomiasis (HAT). Studies on its efficacy, physicochemical and biopharmaceutical properties, and potential for toxicity are described. The compound previously had been shown to possess exceptional activity against Trypanosoma brucei in in vitro assays comparable to that of melarsoprol. Here, we demonstrate that the compound also was curative in the stringent acute mouse model T. brucei rhodesiense STIB 900 when given intraperitoneally at 40 mg/kg of body weight. Nevertheless, activity was only moderate when the oral route was used, and no cure was obtained when the compound was tested in a stage 2 rodent model of infection. Genotoxic profiling revealed that the compound induces DNA damage by a mechanism apparently independent from nitroreduction and involving the introduction of base pair substitutions (Ames test), possibly caused by oxidative damage of the DNA (comet test). No significant genotoxicity was observed at the chromosome level (micronucleus assay). The lack of suitable properties for oral and central nervous system uptake and the genotoxic liabilities prevent the progression of this melamine nitroheterocycle as a drug candidate for HAT. Further modification of the compound is required to improve the pharmacokinetic properties of the molecule and to separate the trypanocidal activity from the toxic potential. PMID:25022590

Molecular descriptors calculation as a tool in the analysis of the antileishmanial activity achieved by two series of diselenide derivatives. An insight into its potential action mechanism.

PubMed

Font, María; Baquedano, Ylenia; Plano, Daniel; Moreno, Esther; Espuelas, Socorro; Sanmartín, Carmen; Palop, Juan Antonio

2015-07-01

A molecular modeling study has been carried out on two previously reported series of symmetric diselenide derivatives that show remarkable antileishmanial in vitro activity against Leishmania infantum intracellular amastigotes and in infected macrophages (THP-1 cells), in addition to showing favorable selectivity indices. Series 1 consists of compounds that can be considered as central scaffold constructed with a diaryl/dialkylaryl diselenide central nucleus, decorated with different substituents located on the aryl rings. Series 2 consists of compounds constructed over a diaryl diselenide central nucleus, decorated in 4 and 4' positions with an aryl or heteroaryl sulfonamide fragment, thus forming the diselenosulfonamide derivatives. With regard to the diselenosulfonamide derivatives (2 series), the activity can be related, as a first approximation, with (a) the ability to release bis(4-aminophenyl) diselenide, the common fragment which can be ultimately responsible for the activity of the compounds. (b) the anti-parasitic activity achieved by the sulfonamide pharmacophore present in the analyzed derivatives. The data that support this connection include the topography of the molecules, the conformational behavior of the compounds, which influences the bond order, as well as the accessibility of the hydrolysis point, and possibly the hydrophobicity and polarizability of the compounds. Copyright © 2015 Elsevier Inc. All rights reserved.

X-ray diffraction and Raman spectroscopy study of white decorations on tricolored ceramics from Northwestern Argentina

NASA Astrophysics Data System (ADS)

Freire, E.; Acevedo, V.; Halac, E. B.; Polla, G.; López, M.; Reinoso, M.

2016-03-01

White virgules, commas, and dot designs on tricolored ceramics are sporadically found in different archaeological sites located in Northwestern Argentina area, as Puna and Quebrada de Humahuaca. This decorating style has been reported in several articles, but few previous archaeometric studies have been carried out on the pigment composition. Fragments from Puna and Quebrada archaeological sites, belonging to Regional Development Period (900-1430 AD), were analyzed by X-ray diffraction and Raman spectroscopy in order to characterize the pigments employed. Red and black pigments are based on iron and manganese oxides, as it has been extensively reported for the NW Argentina area. White pigments from white virgules, comma, and dot designs have shown different composition. Hydroxyapatite was found in samples from Doncellas site (North Puna region), and calcium and calcium-magnesium containing compounds, as vaterite and dolomite, along with titanium containing compounds were detected on samples from Abralaite (Central Puna region) and Gasoducto (Quebrada de Humahuaca region). It has been concluded that pigment composition is not characteristic of a unique region.

X-ray diffraction and Raman spectroscopy study of white decorations on tricolored ceramics from Northwestern Argentina.

PubMed

Freire, E; Acevedo, V; Halac, E B; Polla, G; López, M; Reinoso, M

2016-03-15

White virgules, commas, and dot designs on tricolored ceramics are sporadically found in different archaeological sites located in Northwestern Argentina area, as Puna and Quebrada de Humahuaca. This decorating style has been reported in several articles, but few previous archaeometric studies have been carried out on the pigment composition. Fragments from Puna and Quebrada archaeological sites, belonging to Regional Development Period (900-1430 AD), were analyzed by X-ray diffraction and Raman spectroscopy in order to characterize the pigments employed. Red and black pigments are based on iron and manganese oxides, as it has been extensively reported for the NW Argentina area. White pigments from white virgules, comma, and dot designs have shown different composition. Hydroxyapatite was found in samples from Doncellas site (North Puna region), and calcium and calcium-magnesium containing compounds, as vaterite and dolomite, along with titanium containing compounds were detected on samples from Abralaite (Central Puna region) and Gasoducto (Quebrada de Humahuaca region). It has been concluded that pigment composition is not characteristic of a unique region. Copyright © 2015 Elsevier B.V. All rights reserved.

Theoretical investigations of the role played by quercetinase enzymes upon the flavonoids oxygenolysis mechanism.

PubMed

Antonczak, Serge; Fiorucci, Sébastien; Golebiowski, Jérôme; Cabrol-Bass, Daniel

2009-03-14

Quercetinase enzymatic activity consists in the addition of dioxygen onto flavonoids, some natural polyphenol compounds, leading to the production of both molecular carbon monoxide and to the structurally related depside compound. Experimental studies have reported degradation rates of various flavonoids by such enzymes that can not be directly correlated neither to the number nor to the place of the hydroxyl groups. In order to decipher the role of these functions, we have theoretically characterised the stationary points of various flavonoids oxygenolysis mechanisms by density functional quantum methods. Thus in the present study are reported the main energetic, structural and electronic features that drive this degradation. Together with previous analysis from MD simulations taking into account the dynamic behaviour of the substrate embedded in the enzyme cavity, the present results show that the role of the enzyme, in terms of structural and electronic effects, can not be neglected. Thus, we propose here that deformations of the substrate induced by the enzyme could originate the differences in the degradation rates experimentally observed.

Pentahydroxyscirpene—Producing Strains, Formation In Planta, and Natural Occurrence

PubMed Central

Varga, Elisabeth; Wiesenberger, Gerlinde; Fruhmann, Philipp; Malachová, Alexandra; Svoboda, Thomas; Lemmens, Marc; Adam, Gerhard; Berthiller, Franz

2016-01-01

Trichothecenes are a class of structurally diverse mycotoxins with more than 200 naturally occurring compounds. Previously, a new compound, pentahydroxyscirpene (PHS), was reported as a byproduct of a nivalenol producing Fusarium strain, IFA189. PHS contains a hydroxy group at C-8 instead of the keto group of type B trichothecenes. In this work, we demonstrate that IFA189 belongs to the species Fusarium kyushuense using molecular tools. Production of PHS in vitro was also observed for several isolates of other Fusarium species producing nivalenol. Furthermore, we report the formation of 4-acetyl-PHS by F. kyushuense on inoculated rice. Wheat ears of the variety Remus were infected with IFA189 and the in planta production of PHS was confirmed. Natural occurrence of PHS was verified in barley samples from the Czech Republic using a liquid chromatographic-tandem mass spectrometric method validated for this purpose. Toxicity of PHS to wheat ribosomes was evaluated with a coupled in vitro transcription and translation assay, which showed that PHS inhibits protein biosynthesis slightly less than nivalenol and deoxynivalenol. PMID:27754401

On-site GC/MS analysis of Chapman gasification separator liquor. Final report Jul 80-Mar 81

DOE Office of Scientific and Technical Information (OSTI.GOV)

Thielen, C.J.; Magee, R.A.; Collins, R.V.

1981-08-01

The report gives results of a characterization of a wastewater stream from a coal gasification plant, using on-site extraction and GC/MS analysis. Extractable material in the wastewater was primarily phenols and alkylphenols, accounting for about 99% of the total mass identified. Several polynuclear aromatic compounds were also identified. The composition of the sample deteriorated even though the water was held in amber bottles at 4C: this was most evident in the concentration of dimethylphenols which dropped about 75% during 2 weeks of refrigerated storage. Ambient sample storage produced a greater decrease in the concentration of phenol, but did not appearmore » to affect the alkylphenols or the base/neutral compounds as much. The observed changes in composition should hamper any off-site wastewater treatbility studies with waters of this type. Diisopropyl ether (DIPE) extraction confirmed the 99-plus % removal efficiency of phenol which had been demonstrated in previous studies. Wet oxidation removed organics almost as efficiently as DIPE extraction, but may have limited use because of its high operating cost.« less

Effects of structure on the interactions between five natural antimicrobial compounds and phospholipids of bacterial cell membrane on model monolayers

USDA-ARS?s Scientific Manuscript database

Monolayers composed of bacterial phospholipids were used as model membranes to study interactions of naturally occurring phenolic compounds 2,5-dihydroxybenzaldehyde, 2-hydroxy-5-methoxybenzaldehyde and the plant essential oil compounds carvacrol, cinnamaldehyde, and geraniol, previously found to be...

Botany, ethnomedicines, phytochemistry and pharmacology of Himalayan paeony (Paeonia emodi Royle.).

PubMed

Ahmad, Mushtaq; Malik, Khafsa; Tariq, Akash; Zhang, Guolin; Yaseen, Ghulam; Rashid, Neelam; Sultana, Shazia; Zafar, Muhammad; Ullah, Kifayat; Khan, Muhammad Pukhtoon Zada

2018-06-28

Himalayan paeony (Paeonia emodi Royle.) is an important species used to treat various diseases. This study aimed to compile the detailed traditional medicinal uses, phytochemistry, pharmacology and toxicological investigations on P. emodi. This study also highlights taxonomic validity, quality of experimental designs and shortcomings in previously reported information on Himalayan paeony. The data was extracted from unpublished theses (Pakistan, China, India and Nepal), and different published research articles confined to pharmacology, phytochemistry and antimicrobial activities using different databases through specific keywords. The relevant information regarding medicinal uses, taxonomic/common names, part used, collection and identification source, authentication, voucher specimen number, plant extracts and their characterization, isolation and identification of phytochemicals, methods of study in silico, in vivo or in vitro, model organism used, dose and duration, minimal active concentration, zone of inhibition (antimicrobial study), bioactive compound(s), mechanism of action on single or multiple targets, and toxicological information. P. emodi is reported for diverse medicinal uses with pharmacological properties like antioxidant, nephroprotective, lipoxygenase inhibitory, cognition and oxidative stress release, cytotoxic, anti-inflammatory, antiepileptic, anticonvulsant, haemaglutination, alpha-chymotrypsin inhibitory, hepatoprotective, hepatic chromes and pharmacokinetics of carbamazepine expression, β-glucuronidase inhibitory, spasmolytic and spasmogenic, and airway relaxant. Data confined to its taxonomic validity, shows 10% studies with correct taxonomic name while 90% studies with incorrect taxonomic, pharmacopeial and common names. The literature reviewed, shows lack of collection source (11 reports), without proper source of identification (15 reports), 33 studies without voucher specimen number, 26 reports lack information on authentic herbarium submission and most of the studies (90%) without validation of taxonomic names using recognized databases. In reported methods, 67% studies without characterization of extracts, 25% lack proper dose, 40% without duration and 31% reports lack information on proper controls. Similarly, only 18% studies reports active compound(s) responsible for pharmacological activities, 14% studies show minimal active concentration, only 2.5% studies report mechanism of action on target while none of the reports mentioned in silico approach. P. emodi is endemic to Himalayan region (Pakistan, China, India and Nepal) with diverse traditional therapeutic uses. Majority of reviewed studies showed confusion in its taxonomic validity, incomplete methodologies and ambiguous findings. Keeping in view the immense uses of P. emodi in various traditional medicinal systems, holistic pharmacological approaches in combination with reverse pharmacology, system biology, and "omics" technologies are recommended to improve the quality of research which leads to natural drug discovery development at global perspectives. Copyright © 2018 Elsevier B.V. All rights reserved.

Cooked carrot volatiles. AEDA and odor activity comparisons. Identification of linden ether as an important aroma component.

PubMed

Buttery, Ron G; Takeoka, Gary R

2013-09-25

MS with GC-RI evidence was found for the presence of linden ether in cooked carrot (Daucus carota). Evaluation of the GC effluent from cooked carrot volatiles using aroma extract dilution analysis (AEDA) found linden ether with the highest flavor dilution (FD) factor. Others with 10-fold lower FD factors were β-ionone, eugenol, the previously unidentified β-damascenone, (E)-2-nonenal, octanal (+ myrcene), and heptanal. All other previously identified volatiles showed lower FD factors. Odor thresholds, concentrations, and odor activity values of previously identified compounds are reviewed. This indicated that at least 20 compounds occur in cooked carrots above their odor thresholds (in water). Compounds showing the highest odor activity values included β-damascenone, (E)-2-nonenal, (E,E)-2,4-decadienal, β-ionone, octanal, (E)-2-decenal, eugenol, and p-vinylguaiacol.

Anti-cancer activity of compounds from Bauhinia strychnifolia stem.

PubMed

Yuenyongsawad, Supreeya; Bunluepuech, Kingkan; Wattanapiromsakul, Chatchai; Tewtrakul, Supinya

2013-11-25

The stem and root of Bauhinia strychnifolia Craib (Fabaceae family) have been traditionally used in Thailand to treat fever, alcoholic toxication, allergy and cancer. An EtOH extract of Bauhinia strychnifolia showed good inhibitory activity against several cancer cell lines including HT-29, HeLa, MCF-7 and KB. As there has been no previous reports on chemical constituents of Bauhinia strychnifolia, this study is aimed to isolate the pure compounds with anti-cancer activity. Five pure compounds were isolated from EtOH extract of Bauhinia strychnifolia stem using silica gel, dianion HP-20 and sephadex LH-20 column chromatography and were tested for their cytotoxic effects against HT-29, HeLa, MCF-7 and KB cell lines using the Sulforhodamine B (SRB) assay. Among five compounds, 3,5,7,3',5'-pentahydroxyflavanonol-3-O-α-l-rhamnopyranoside (2) possessed very potent activity against KB (IC₅₀=0.00054μg/mL), HT-29 (IC₅₀=0.00217 μg/mL), MCF-7 (IC₅₀=0.0585 μg/mL) and HeLa cells (IC₅₀=0.0692 μg/mL). 3,5,7-Trihydroxychromone-3-O-α-l-rhamnopyranoside (3) also showed good activity against HT-29 (IC₅₀=0.02366 μg/mL), KB (IC₅₀=0.0412 μg/mL) and MCF-7 (IC₅₀=0.297 μg/mL), respectively. The activity of 2 (IC₅₀=0.00054 μg/mL) against KB cell was ten times higher than that of the positive control, Camptothecin (anti-cancer drug, IC₅₀=0.0057 μg/mL). All compounds did not show any cytotoxicity with normal cells at the concentration of 1 μg/mL. This is the first report of compounds 2 and 3 on anti-cancer activity and based on the anti-cancer activity of extracts and pure compounds isolated from Bauhinia strychnifolia stem, it might be suggested that this plant could be useful for treatment of cancer. © 2013 Elsevier Ireland Ltd. All rights reserved.

4′,5-Dihy­droxy-7-meth­oxy­flavanone dihydrate

PubMed Central

Brito, Iván; Bórquez, Jorge; Simirgiotis, Mario; Cárdenas, Alejandro; López-Rodríguez, Matías

2012-01-01

The title compound, C16H14O5·2H2O [systematic name: 5-hy­droxy-2-(4-hy­droxy­phen­yl)-7-meth­oxy­chroman-4-one dihydrate], is a natural phytoalexin flavone isolated from the native chilean species Heliotropium taltalense and crystallizes with an organic mol­ecule and two water mol­ecules in the asymmetric unit. The 5-hy­droxy group forms a strong intra­molecular hydrogen bond with the carbonyl group, resulting in a six-membered ring. In the crystal, the components are linked by O—H⋯O hydrogen bonds, forming a three-dimensional network. The 4-hy­droxy­phenyl benzene ring is bonded equatorially to the pyrone ring, which adopts a slightly distorted sofa conformation. The title compound is the hydrated form of a previously reported structure [Shoja (1990 ▶). Acta Cryst. C46, 1969–1971]. There are only slight variations in the mol­ecular geometry between the two compounds. PMID:22259537

Novel conduction behavior in nanopores coated with hydrophobic molecules

NASA Astrophysics Data System (ADS)

Balagurusamy, Venkat; Stolovitzky, Gustavo; Afzali-Ardakani, Ali

2015-03-01

We obtain (Bi0.7Pb0.3)Sr2Ca2Cu3O10 nano-crystals by sol-gel improved with acrylamide and microwaves, not reported in the literature. TGA gives an idea of the reaction temperatures (200-550 ° C) for the formation of binary, ternary and unknown materials. SEM and TEM shows morphology and crystal size 30-33 nm. We studied the thermodynamic and kinetic stability of the gel quenching, by varying the temperature and time according to a previous thermal analysis. Starting compounds (bismuth oxide, strontium carbonate, copper acetate, lead nitrate and calcium sulfate) were analyzed by XRD. By AFM we observed the dehydrated gel surface absorbed water from the environment. From the micrographs we measured the size of the fibers, grains and nano-crystals. We found at 560 ° C Bi1.6Pb0.4Sr2Ca2Cu3Ox compound with tetragonal crystal structure, corresponding to the 2:2:2:3 compound, with Tc 110 K. At 860 ° C seen a shift of some reflections corresponding to two phases. Xerogel magnetic measurement shows antiferromagnetic behavior at 63 K.

The essential roles of chemistry in high-throughput screening triage

PubMed Central

Dahlin, Jayme L; Walters, Michael A

2015-01-01

It is increasingly clear that academic high-throughput screening (HTS) and virtual HTS triage suffers from a lack of scientists trained in the art and science of early drug discovery chemistry. Many recent publications report the discovery of compounds by screening that are most likely artifacts or promiscuous bioactive compounds, and these results are not placed into the context of previous studies. For HTS to be most successful, it is our contention that there must exist an early partnership between biologists and medicinal chemists. Their combined skill sets are necessary to design robust assays and efficient workflows that will weed out assay artifacts, false positives, promiscuous bioactive compounds and intractable screening hits, efforts that ultimately give projects a better chance at identifying truly useful chemical matter. Expertise in medicinal chemistry, cheminformatics and purification sciences (analytical chemistry) can enhance the post-HTS triage process by quickly removing these problematic chemotypes from consideration, while simultaneously prioritizing the more promising chemical matter for follow-up testing. It is only when biologists and chemists collaborate effectively that HTS can manifest its full promise. PMID:25163000

A Drosophila Gustatory Receptor Required for Strychnine Sensation.

PubMed

Lee, Youngseok; Moon, Seok Jun; Wang, Yijin; Montell, Craig

2015-09-01

Strychnine is a potent, naturally occurring neurotoxin that effectively protects plants from animal pests by deterring feeding behavior. In insects, such as the fruit fly, Drosophila melanogaster, bitter-tasting aversive compounds are detected primarily through a family of gustatory receptors (GRs), which are expressed in gustatory receptor neurons. We previously described multiple GRs that eliminate the behavioral avoidance to all bitter compounds tested, with the exception of strychnine. Here, we report the identity of a strychnine receptor, referred to as GR47a. We generated a mutation in Gr47a and found that it eliminated strychnine repulsion and strychnine-induced action potentials. GR47a was narrowly tuned, as the responses to other avoidance compounds were unaffected in the mutant animals. This analysis supports an emerging model that Drosophila GRs fall broadly into two specificity classes-one class is comprised of core receptors that are broadly required, whereas the other class, which includes GR47a, consists of narrowly tuned receptors that define chemical specificity. © The Author 2015. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Magnetism in S = 1 / 2 Double Perovskites with Strong Spin-Orbit Interactions

NASA Astrophysics Data System (ADS)

Ishizuka, Hiroaki; Balents, Leon

2015-03-01

Motivated by recent studies on heavy-element double-perovskite (DP) compounds, we theoretically studied spin models on a FCC lattice with anisotropic interactions. In these systems, competition/cooperation of spin, orbital, and the lattice degrees of freedoms in the presence of the strong-spin orbit coupling is of particular interest. In a previous theoretical study, the magnetic phase diagrams of DP compounds with 5d1 electron configuration was studied using a model with four-fold degenerated single-ion state. On the other hand, a recent experiment on a DP material, Ba2Na2OsO6, reported that the compound is likely to be an effective S = 1 / 2 magnet. Inspired by the experimental observation, we considered spin models with symmetry-allowed anisotropic nearest-neighbor interactions. By a combination of various analytical and numerical techniques, we present the magnetic phase diagram of the model and the effect of thermal and quantum fluctuations. In particular, we show that fluctuations induce < 110 > anisotropy of magnetic moments. We also discuss a possible ``nematic'' phase driven by spin-phonon couplings.