Synthesis and Structure-Activity Relationships of a Series of Aporphine Derivatives with Antiarrhythmic Activities and Acute Toxicity

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Hui Wang

2016-11-01

Full Text Available Some aporphine alkaloids, such as crebanine, were found to present arrhythmic activity and also higher toxicity. A series of derivatives were synthesized by using three kinds of aporphine alkaloids (crebanine, isocorydine, and stephanine as lead compounds. Chemical methods, including ring-opening reaction, bromination, methylation, acetylation, quaternization, and dehydrogenation, were adopted. Nineteen target derivatives were evaluated for their antiarrhythmic potential in the mouse model of ventricular fibrillation (VF, induced by CHCl3, and five of the derivatives were investigated further in the rat model of arrhythmia, induced by BaCl2. Meanwhile, preliminary structure-activity/toxicity relationship analyses were carried out. Significantly, N-acetamidesecocrebanine (1d, three bromo-substituted products of crebanine (2a, 2b, 2c, N-methylcrebanine (2d, and dehydrostephanine (4a displayed antiarrhythmic effects in the CHCl3-induced model. Among them, 7.5 mg/kg of 2b was able to significantly reduce the incidence of VF induced by CHCl3 (p < 0.05, increase the number of rats that resumed sinus rhythm from arrhythmia, induced by BaCl2 (p < 0.01, and the number of rats that maintained sinus rhythm for more than 20 min (p < 0.01. Therefore, 2b showed remarkably higher antiarrhythmic activity and a lower toxicity (LD50 = 59.62 mg/kg, mice, simultaneously, indicating that 2b could be considered as a promising candidate in the treatment of arrhythmia. Structural-activity analysis suggested that variationsin antiarrhythmic efficacy and toxicity of aporphines were related to the C-1,C-2-methylenedioxy group on ring A, restricted ring B structural conformation, N-quaternization of ring B, levoduction of 6a in ring C, and the 8-, 9-, 10-methoxy groups on ring D on the skeleton.

Calculation of Quantitative Structure-Activity Relationship Descriptors of Artemisinin Derivatives

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Jambalsuren Bayarmaa

2008-06-01

Full Text Available Quantitative structure-activity relationships are based on the construction of predictive models using a set of known molecules and associated activity value. This accurate methodology, developed with adequate mathematical and computational tools, leads to a faster, cheaper and more comprehensive design of new products, reducing the experimental synthesis and testing on animals. Preparation of the QSAR models of artemisinin derivatives was carried out by the genetic function algorithm (GFA method for 91 molecules. The results show some relationships to the observed antimalarial activities of the artemisinin derivatives. The most statistically signi fi cant regression equation obtained from the fi nal GFA relates to two molecular descriptors.

Structure-activity relationship of surfactant for preparing DMFC anodic catalyst

International Nuclear Information System (INIS)

Su Yi; Xue Xinzhong; Xu Weilin; Liu Changpeng; Xing Wei; Zhou Xiaochun; Tian Tian; Lu Tianhong

2006-01-01

Three kinds of surfactants as stabilizer were applied to the preparation of electrocatalysts for direct methanol fuel cell (DMFC). The catalysts have been characterized by examining their catalytic activities, morphologies and particle sizes by means of cyclic voltammetry, chronoamperometry, X-ray diffraction and transmission electron microscopy (TEM). It is found that the surfactants with different structures have a significantly influence on the catalyst shape and activity. The catalysts prepared with non-ionic surfactants as the stabilizer show higher activity for direct oxidation of methanol. The structure-activity relationship (SAR) analysis has been explored and the effect of hydrophile-lipophile balance (HLB value) has also been discussed

Biosynthesis and structure-activity relationships of the lipid a family of glycolipids.

Science.gov (United States)

Xiao, Xirui; Sankaranarayanan, Karthik; Khosla, Chaitan

2017-10-01

Lipopolysaccharide (LPS), a glycolipid found in the outer membrane of Gram-negative bacteria, is a potent elicitor of innate immune responses in mammals. A typical LPS molecule is composed of three different structural domains: a polysaccharide called the O-antigen, a core oligosaccharide, and Lipid A. Lipid A is the amphipathic glycolipid moiety of LPS. It stimulates the immune system by tightly binding to Toll-like receptor 4. More recently, Lipid A has also been shown to activate intracellular caspase-4 and caspase-5. An impressive diversity is observed in Lipid A structures from different Gram-negative bacteria, and it is well established that subtle changes in chemical structure can result in dramatically different immune activities. For example, Lipid A from Escherichia coli is highly toxic to humans, whereas a biosynthetic precursor called Lipid IV A blocks this toxic activity, and monophosphoryl Lipid A from Salmonella minnesota is a vaccine adjuvant. Thus, an understanding of structure-activity relationships in this glycolipid family could be used to design useful immunomodulatory agents. Here we review the biosynthesis, modification, and structure-activity relationships of Lipid A. Copyright © 2017 Elsevier Ltd. All rights reserved.

Investigating the Structure-Activity Relationship of the Insecticidal Natural Product Rocaglamide.

Science.gov (United States)

Hall, Roger G; Bruce, Ian; Cooke, Nigel G; Diorazio, Louis J; Cederbaum, Fredrik; Dobler, Markus R; Irving, Ed

2017-12-01

The natural product Rocaglamide (1), isolated from the tree Aglaia elliptifolia, is a compelling but also challenging lead structure for crop protection. In laboratory assays, the natural product shows highly interesting insecticidal activity against chewing pests and beetles, but also phytotoxicity on some crop plants. Multi-step syntheses with control of stereochemistry were required to probe the structure-activity relationship (SAR), and seek simplified analogues. After a significant research effort, just two areas of the molecule were identified which allow modification whilst maintaining activity, as will be highlighted in this paper.

Structure-activity relationships of rosiglitazone for peroxisome proliferator-activated receptor gamma transrepression.

Science.gov (United States)

Toyota, Yosuke; Nomura, Sayaka; Makishima, Makoto; Hashimoto, Yuichi; Ishikawa, Minoru

2017-06-15

Anti-inflammatory effects of peroxisome proliferator-activated receptor gamma (PPRAγ) ligands are thought to be largely due to PPARγ-mediated transrepression. Thus, transrepression-selective PPARγ ligands without agonistic activity or with only partial agonistic activity should exhibit anti-inflammatory properties with reduced side effects. Here, we investigated the structure-activity relationships (SARs) of PPARγ agonist rosiglitazone, focusing on transrepression activity. Alkenic analogs showed slightly more potent transrepression with reduced efficacy of transactivating agonistic activity. Removal of the alkyl group on the nitrogen atom improved selectivity for transrepression over transactivation. Among the synthesized compounds, 3l exhibited stronger transrepressional activity (IC 50 : 14μM) and weaker agonistic efficacy (11%) than rosiglitazone or pioglitazone. Copyright © 2017 Elsevier Ltd. All rights reserved.

Relationship between electronic structure and radioprotective activity of some indazoles

International Nuclear Information System (INIS)

Sokolov, Yu.A.

2000-01-01

The quantum-chemical study of electronic structure of 29 indasoles with complete optimization of geometry and search of quantitative link between the established characteristics and radioprotective activity (RPA) was carried out through the MNDO method with application of multiple linear and nonlinear regression analysis and the basic component method. The equations of correlation relationship between the RPA and electronic characteristics are presented. 10 indasole structures, the forecasted RPA values whereof (survival rate, %) equal 50% and above, are selected. The statistic significance of the obtained correlation equations and their regression coefficients make it possible to conclude, that the established relationships are not accidental and are prospective for forecasting RPA of other close compounds of the indasole series [ru

Quantitative structure-activation barrier relationship modeling for Diels-Alder ligations utilizing quantum chemical structural descriptors.

Science.gov (United States)

Nandi, Sisir; Monesi, Alessandro; Drgan, Viktor; Merzel, Franci; Novič, Marjana

2013-10-30

In the present study, we show the correlation of quantum chemical structural descriptors with the activation barriers of the Diels-Alder ligations. A set of 72 non-catalysed Diels-Alder reactions were subjected to quantitative structure-activation barrier relationship (QSABR) under the framework of theoretical quantum chemical descriptors calculated solely from the structures of diene and dienophile reactants. Experimental activation barrier data were obtained from literature. Descriptors were computed using Hartree-Fock theory using 6-31G(d) basis set as implemented in Gaussian 09 software. Variable selection and model development were carried out by stepwise multiple linear regression methodology. Predictive performance of the quantitative structure-activation barrier relationship (QSABR) model was assessed by training and test set concept and by calculating leave-one-out cross-validated Q2 and predictive R2 values. The QSABR model can explain and predict 86.5% and 80% of the variances, respectively, in the activation energy barrier training data. Alternatively, a neural network model based on back propagation of errors was developed to assess the nonlinearity of the sought correlations between theoretical descriptors and experimental reaction barriers. A reasonable predictability for the activation barrier of the test set reactions was obtained, which enabled an exploration and interpretation of the significant variables responsible for Diels-Alder interaction between dienes and dienophiles. Thus, studies in the direction of QSABR modelling that provide efficient and fast prediction of activation barriers of the Diels-Alder reactions turn out to be a meaningful alternative to transition state theory based computation.

Structure-activity relationship studies of the aromatic positions in cyclopentapeptide CXCR4 antagonists

DEFF Research Database (Denmark)

Mungalpara, Jignesh; Zachariassen, Zack G; Thiele, Stefanie

2013-01-01

, and autoimmune diseases. While the structure-activity relationships for Arg(1), Arg(2), and Gly(4) are well established, less is understood about the roles of the aromatic residues 2-Nal(3) and D-Tyr(5). Here we report further structure-activity relationship studies of these two positions, which showed that (i......) the distal aromatic ring of the 2-Nal(3) side chain is required in order to maintain high potency and (ii) replacement of D-Tyr(5) with conformationally constrained analogues results in significantly reduced activity. However, a simplified analogue that contained Gly instead of D-Tyr(5) was only 13-fold less...

Quantitative structure-activity relationships for green algae growth inhibition by polymer particles.

NARCIS (Netherlands)

Nolte, Tom M; Peijnenburg, Willie J G M; Hendriks, A Jan; van de Meent, Dik

After use and disposal of chemical products, many types of polymer particles end up in the aquatic environment with potential toxic effects to primary producers like green algae. In this study, we have developed Quantitative Structure-Activity Relationships (QSARs) for a set of highly structural

Structure-Activity Relationships on the Molecular Descriptors Family Project at the End

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Lorentz JÄNTSCHI

2007-12-01

Full Text Available Molecular Descriptors Family (MDF on the Structure-Activity Relationships (SAR, a promising approach in investigation and quantification of the link between 2D and 3D structural information and the activity, and its potential in the analysis of the biological active compounds is summarized. The approach, attempts to correlate molecular descriptors family generated and calculated on a set of biological active compounds with their observed activity. The estimation as well as prediction abilities of the approach are presented. The obtained MDF SAR models can be used to predict the biological activity of unknown substrates in a series of compounds.

Molecular design and structure--activity relationships leading to the potent, selective, and orally active thrombin active site inhibitor BMS-189664.

Science.gov (United States)

Das, Jagabandhu; Kimball, S David; Hall, Steven E; Han, Wen Ching; Iwanowicz, Edwin; Lin, James; Moquin, Robert V; Reid, Joyce A; Sack, John S; Malley, Mary F; Chang, Chiehying Y; Chong, Saeho; Wang-Iverson, David B; Roberts, Daniel G M; Seiler, Steven M; Schumacher, William A; Ogletree, Martin L

2002-01-07

A series of structurally novel small molecule inhibitors of human alpha-thrombin was prepared to elucidate their structure-activity relationships (SARs), selectivity and activity in vivo. BMS-189664 (3) is identified as a potent, selective, and orally active reversible inhibitor of human alpha-thrombin which is efficacious in vivo in a mouse lethality model, and at inhibiting both arterial and venous thrombosis in cynomolgus monkey models.

Resumption Of Sexual Relationship After Childbirth: Preliminary ...

African Journals Online (AJOL)

Resumption Of Sexual Relationship After Childbirth: Preliminary Observations On Husband\\'s Attitude. ... An open-ended questionnaire developed by the authors was used to elicit information on relevant aspects of husbands' reproductive behaviour. We found that husbands' preferred time of resumption of sexual ...

Quantitative structure-activity relationship of some 1-benzylbenzimidazole derivatives as antifungal agents

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Podunavac-Kuzmanović Sanja O.

2007-01-01

Full Text Available In the present study, the antifungal activity of some 1-benzylbenzimidazole derivatives against yeast Saccharomyces cerevisiae was investigated. The tested benzimidazoles displayed in vitro antifungal activity and minimum inhibitory concentration (MIC was determined for all the compounds. Quantitative structure-activity relationship (QSAR has been used to study the relationships between the antifungal activity and lipophilicity parameter, logP, calculated by using CS Chem-Office Software version 7.0. The results are discussed on the basis of statistical data. The best QSAR model for prediction of antifungal activity of the investigated series of benzimidazoles was developed. High agreement between experimental and predicted inhibitory values was obtained. The results of this study indicate that the lipophilicity parameter has a significant effect on antifungal activity of this class of compounds, which simplify design of new biologically active molecules.

Brief Report: The Relationship of Parental Support and Conflict to Physical Activity in Preadolescents with Type 1 Diabetes

OpenAIRE

Mackey, Eleanor Race; Streisand, Randi

2008-01-01

Objective To use structural equation modeling to provide a preliminary examination of the relationship between parental support and conflict regarding physical activity behaviors in preadolescents with type 1 diabetes. Method Parent–child dyads (n = 85, M child age = 10.8) completed physical activity items from the Diabetes Family Behavior Scale, Diabetes Related Conflict Scale, and Self-Care Inventory. Children completed physical activity items from the Center for Disease Control's Youth Ris...

In vitro anticancer activity, toxicity and structure-activity relationships of phyllostictine A, a natural oxazatricycloalkenone produced by the fungus Phyllosticta cirsii

International Nuclear Information System (INIS)

Le Calve, Benjamin; Lallemand, Benjamin; Perrone, Carmen; Lenglet, Gaelle; Depauw, Sabine; Van Goietsenoven, Gwendoline; Bury, Marina; Vurro, Maurizio; Herphelin, Francoise; Andolfi, Anna; Zonno, Maria Chiara; Mathieu, Veronique; Dufrasne, Francois; Van Antwerpen, Pierre; Poumay, Yves

2011-01-01

The in vitro anticancer activity and toxicity of phyllostictine A, a novel oxazatricycloalkenone recently isolated from a plant-pathogenic fungus (Phyllosticta cirsii) was characterized in six normal and five cancer cell lines. Phyllostictine A displays in vitro growth-inhibitory activity both in normal and cancer cells without actual bioselectivity, while proliferating cells appear significantly more sensitive to phyllostictine A than non-proliferating ones. The main mechanism of action by which phyllostictine displays cytotoxic effects in cancer cells does not seem to relate to a direct activation of apoptosis. In the same manner, phyllostictine A seems not to bind or bond with DNA as part of its mechanism of action. In contrast, phyllostictine A strongly reacts with GSH, which is a bionucleophile. The experimental data from the present study are in favor of a bonding process between GSH and phyllostictine A to form a complex though Michael attack at C=C bond at the acrylamide-like system. Considering the data obtained, two new hemisynthesized phyllostictine A derivatives together with three other natural phyllostictines (B, C and D) were also tested in vitro in five cancer cell lines. Compared to phyllostictine A, the two derivatives displayed a higher, phyllostictines B and D a lower, and phyllostictine C an almost equal, growth-inhibitory activity, respectively. These results led us to propose preliminary conclusions in terms of the structure-activity relationship (SAR) analyses for the anticancer activity of phyllostictine A and its related compounds, at least in vitro.

Quantitative Structure – Antioxidant Activity Relationships of Flavonoid Compounds

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Károly Héberger

2004-12-01

Full Text Available A quantitative structure – antioxidant activity relationship (QSAR study of 36 flavonoids was performed using the partial least squares projection of latent structures (PLS method. The chemical structures of the flavonoids have been characterized by constitutional descriptors, two-dimensional topological and connectivity indices. Our PLS model gave a proper description and a suitable prediction of the antioxidant activities of a diverse set of flavonoids having clustering tendency.

Structure-activity relationships between sterols and their thermal stability in oil matrix.

Science.gov (United States)

Hu, Yinzhou; Xu, Junli; Huang, Weisu; Zhao, Yajing; Li, Maiquan; Wang, Mengmeng; Zheng, Lufei; Lu, Baiyi

2018-08-30

Structure-activity relationships between 20 sterols and their thermal stabilities were studied in a model oil system. All sterol degradations were found to be consistent with a first-order kinetic model with determination of coefficient (R 2 ) higher than 0.9444. The number of double bonds in the sterol structure was negatively correlated with the thermal stability of sterol, whereas the length of the branch chain was positively correlated with the thermal stability of sterol. A quantitative structure-activity relationship (QSAR) model to predict thermal stability of sterol was developed by using partial least squares regression (PLSR) combined with genetic algorithm (GA). A regression model was built with R 2 of 0.806. Almost all sterol degradation constants can be predicted accurately with R 2 of cross-validation equals to 0.680. Four important variables were selected in optimal QSAR model and the selected variables were observed to be related with information indices, RDF descriptors, and 3D-MoRSE descriptors. Copyright © 2018 Elsevier Ltd. All rights reserved.

A biology-based approach for quantitative structure-activity relationships (QSARs) in ecotoxicity.

NARCIS (Netherlands)

Jager, T.; Kooijman, S.A.L.M.

2009-01-01

Quantitative structure-activity relationships (QSARs) for ecotoxicity can be used to fill data gaps and limit toxicity testing on animals. QSAR development may additionally reveal mechanistic information based on observed patterns in the data. However, the use of descriptive summary statistics for

Structure-thermodynamics-antioxidant activity relationships of selected natural phenolic acids and derivatives: an experimental and theoretical evaluation.

Science.gov (United States)

Chen, Yuzhen; Xiao, Huizhi; Zheng, Jie; Liang, Guizhao

2015-01-01

Phenolic acids and derivatives have potential biological functions, however, little is known about the structure-activity relationships and the underlying action mechanisms of these phenolic acids to date. Herein we investigate the structure-thermodynamics-antioxidant relationships of 20 natural phenolic acids and derivatives using DPPH• scavenging assay, density functional theory calculations at the B3LYP/6-311++G(d,p) levels of theory, and quantitative structure-activity relationship (QSAR) modeling. Three main working mechanisms (HAT, SETPT and SPLET) are explored in four micro-environments (gas-phase, benzene, water and ethanol). Computed thermodynamics parameters (BDE, IP, PDE, PA and ETE) are compared with the experimental radical scavenging activities against DPPH•. Available theoretical and experimental investigations have demonstrated that the extended delocalization and intra-molecular hydrogen bonds are the two main contributions to the stability of the radicals. The C = O or C = C in COOH, COOR, C = CCOOH and C = CCOOR groups, and orthodiphenolic functionalities are shown to favorably stabilize the specific radical species to enhance the radical scavenging activities, while the presence of the single OH in the ortho position of the COOH group disfavors the activities. HAT is the thermodynamically preferred mechanism in the gas phase and benzene, whereas SPLET in water and ethanol. Furthermore, our QSAR models robustly represent the structure-activity relationships of these explored compounds in polar media.

The Structure-Activity Relationship between Marine Algae Polysaccharides and Anti-Complement Activity

Science.gov (United States)

Jin, Weihua; Zhang, Wenjing; Liang, Hongze; Zhang, Quanbin

2015-01-01

In this study, 33 different polysaccharides were prepared to investigate the structure-activity relationships between the polysaccharides, mainly from marine algae, and anti-complement activity in the classical pathway. Factors considered included extraction methods, fractionations, molecular weight, molar ratio of galactose to fucose, sulfate, uronic acid (UA) content, linkage, branching, and the type of monosaccharide. It was shown that the larger the molecular weights, the better the activities. The molar ratio of galactose (Gal) to fucose (Fuc) was a positive factor at a concentration lower than 10 µg/mL, while it had no effect at a concentration more than 10 µg/mL. In addition, sulfate was necessary; however, the sulfate content, the sulfate pattern, linkage and branching had no effect at a concentration of more than 10 µg/mL. Moreover, the type of monosaccharide had no effect. Laminaran and UA fractions had no activity; however, they could reduce the activity by decreasing the effective concentration of the active composition when they were mixed with the active compositions. The effect of the extraction methods could not be determined. Finally, it was observed that sulfated galactofucan showed good anti-complement activity after separation. PMID:26712768

Electron-topological investigation of the structure-antitumor activity relationship of thiosemicarbazone derivatives.

Science.gov (United States)

Dimoglo, A S; Chumakov, Y M; Dobrova, B N; Saracoglu, M

1997-04-01

In the frameworks of the electron-topological method (ETM) the structure-antitumor activity relationship was investigated for a series of thiosemicarbazone derivatives. The series included 70 compounds. Conformational analysis and quantum-chemical calculations were carried out for each compound. The revealed activity feature showed a satisfactory description of the class of active compounds according to two different parameters P and alpha estimating the probabilities of the feature realization in the class of active compounds (they are equal to 0.94 and 0.86, correspondingly). The results of testing demonstrated the high ability of ETM in predicting the activity investigated.

Quantitative structure-activity relationship (QSAR) models for polycyclic aromatic hydrocarbons (PAHs) dissipation in rhizosphere based on molecular structure and effect size

International Nuclear Information System (INIS)

Ma Bin; Chen Huaihai; Xu Minmin; Hayat, Tahir; He Yan; Xu Jianming

2010-01-01

Rhizoremediation is a significant form of bioremediation for polycyclic aromatic hydrocarbons (PAHs). This study examined the role of molecular structure in determining the rhizosphere effect on PAHs dissipation. Effect size in meta-analysis was employed as activity dataset for building quantitative structure-activity relationship (QSAR) models and accumulative effect sizes of 16 PAHs were used for validation of these models. Based on the genetic algorithm combined with partial least square regression, models for comprehensive dataset, Poaceae dataset, and Fabaceae dataset were built. The results showed that information indices, calculated as information content of molecules based on the calculation of equivalence classes from the molecular graph, were the most important molecular structural indices for QSAR models of rhizosphere effect on PAHs dissipation. The QSAR model, based on the molecular structure indices and effect size, has potential to be used in studying and predicting the rhizosphere effect of PAHs dissipation. - Effect size based on meta-analysis was used for building PAHs dissipation quantitative structure-activity relationship (QSAR) models.

Quantitative structure-activity relationship (QSAR) models for polycyclic aromatic hydrocarbons (PAHs) dissipation in rhizosphere based on molecular structure and effect size

Energy Technology Data Exchange (ETDEWEB)

Ma Bin; Chen Huaihai; Xu Minmin; Hayat, Tahir [Zhejiang Provincial Key Laboratory of Subtropical Soil and Plant Nutrition, College of Environmental and Natural Resource Sciences, Zhejiang University, Hangzhou 310029 (China); He Yan, E-mail: yhe2006@zju.edu.c [Zhejiang Provincial Key Laboratory of Subtropical Soil and Plant Nutrition, College of Environmental and Natural Resource Sciences, Zhejiang University, Hangzhou 310029 (China); Xu Jianming, E-mail: jmxu@zju.edu.c [Zhejiang Provincial Key Laboratory of Subtropical Soil and Plant Nutrition, College of Environmental and Natural Resource Sciences, Zhejiang University, Hangzhou 310029 (China)

2010-08-15

Rhizoremediation is a significant form of bioremediation for polycyclic aromatic hydrocarbons (PAHs). This study examined the role of molecular structure in determining the rhizosphere effect on PAHs dissipation. Effect size in meta-analysis was employed as activity dataset for building quantitative structure-activity relationship (QSAR) models and accumulative effect sizes of 16 PAHs were used for validation of these models. Based on the genetic algorithm combined with partial least square regression, models for comprehensive dataset, Poaceae dataset, and Fabaceae dataset were built. The results showed that information indices, calculated as information content of molecules based on the calculation of equivalence classes from the molecular graph, were the most important molecular structural indices for QSAR models of rhizosphere effect on PAHs dissipation. The QSAR model, based on the molecular structure indices and effect size, has potential to be used in studying and predicting the rhizosphere effect of PAHs dissipation. - Effect size based on meta-analysis was used for building PAHs dissipation quantitative structure-activity relationship (QSAR) models.

Structure-activity relationship of new antimalarial 1-aryl-3-susbtituted propanol derivatives: Synthesis, preliminary toxicity profiling, parasite life cycle stage studies, target exploration, and targeted delivery.

Science.gov (United States)

Quiliano, Miguel; Pabón, Adriana; Moles, Ernest; Bonilla-Ramirez, Leonardo; Fabing, Isabelle; Fong, Kim Y; Nieto-Aco, Diego A; Wright, David W; Pizarro, Juan C; Vettorazzi, Ariane; López de Cerain, Adela; Deharo, Eric; Fernández-Busquets, Xavier; Garavito, Giovanny; Aldana, Ignacio; Galiano, Silvia

2018-05-25

Design, synthesis, structure-activity relationship, cytotoxicity studies, in silico drug-likeness, genotoxicity screening, and in vivo studies of new 1-aryl-3-substituted propanol derivatives led to the identification of nine compounds with promising in vitro (55, 56, 61, 64, 66, and 70-73) and in vivo (66 and 72) antimalarial profiles against Plasmodium falciparum and Plasmodium berghei. Compounds 55, 56, 61, 64, 66 and 70-73 exhibited potent antiplasmodial activity against chloroquine-resistant strain FCR-3 (IC 50 s activity in chloroquine-sensitive and multidrug-resistant strains (IC 50 s antimalarial compounds. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Red Wine Tannin Structure-Activity Relationships during Fermentation and Maceration.

Science.gov (United States)

Yacco, Ralph S; Watrelot, Aude A; Kennedy, James A

2016-02-03

The correlation between tannin structure and corresponding activity was investigated by measuring the thermodynamics of interaction between tannins isolated from commercial red wine fermentations and a polystyrene divinylbenzene HPLC column. Must and/or wine samples were collected throughout fermentation/maceration from five Napa Valley wineries. By varying winery, fruit source, maceration time, and cap management practice, it was considered that a reasonably large variation in commercially relevant tannin structure would result. Tannins were isolated from samples collected using low pressure chromatography and were then characterized by gel permeation chromatography and acid-catalyzed cleavage in the presence of excess phloroglucinol (phloroglucinolysis). Corresponding tannin activity was determined using HPLC by measuring the thermodynamics of interaction between isolated tannin and a polystyrene divinylbenzene HPLC column. This measurement approach was designed to determine the ability of tannins to hydrophobically interact with a hydrophobic surface. The results of this study indicate that tannin activity is primarily driven by molecular size. Compositionally, tannin activity was positively associated with seed tannins and negatively associated with skin and pigmented tannins. Although measured indirectly, the extent of tannin oxidation as determined by phloroglucinolysis conversion yield suggests that tannin oxidation at this stage of production reduces tannin activity. Based upon maceration time, this study indicates that observed increases in perceived astringency quality, if related to tannin chemistry, are driven by tannin molecular mass as opposed to pigmented tannin formation or oxidation. Overall, the results of this study give new insight into tannin structure-activity relationships which dominate during extraction.

Synthesis and anticancer structure activity relationship investigation of cationic anthraquinone analogs.

Science.gov (United States)

Shrestha, Jaya P; Fosso, Marina Y; Bearss, Jeremiah; Chang, Cheng-Wei Tom

2014-04-22

We have synthesized a series of novel 4,9-dioxo-4,9-dihydro-1H-naphtho[2,3-d][1,2,3]triazol-3-ium salts, which can be viewed as analogs of cationic anthraquinones. Unlike the similar analogs that we have reported previously, these compounds show relatively weak antibacterial activities but exert strong anticancer activities (low μM to nM GI50), in particular, against melanoma, colon cancer, non-small cell lung cancer and central nervous system (CNS) cancer. These compounds are structurally different from their predecessors by having the aromatic group, instead of alkyl chains, directly attached to the cationic anthraquinone scaffold. Further investigation in the structure-activity relationship (SAR) reveals the significant role of electron donating substituents on the aromatic ring in enhancing the anticancer activities via resonance effect. Steric hindrance of these groups is disadvantageous but is less influential than the resonance effect. The difference in the attached groups at N-1 position of the cationic anthraquinone analog is the main structural factor for the switching of biological activity from antibacterial to anticancer. The discovery of these compounds may lead to the development of novel cancer chemotherapeutics. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Structure-activity relationships of nucleoside analogues for inhibition of tick-borne encephalitis virus

Czech Academy of Sciences Publication Activity Database

Eyer, L.; Šmídková, Markéta; Nencka, Radim; Neča, J.; Kastl, T.; Palus, Martin; De Clercq, E.; Růžek, Daniel

2016-01-01

Roč. 133, Sep (2016), s. 119-129 ISSN 0166-3542 R&D Projects: GA MZd(CZ) NV16-34238A; GA ČR(CZ) GA16-20054S Institutional support: RVO:61388963 ; RVO:60077344 Keywords : structure-activity relationship * tick-borne encephalitis * nucleoside inhibitor * antiviral activity * cytotoxicity Subject RIV: CC - Organic Chemistry; EE - Microbiology, Virology (BC-A) Impact factor: 4.271, year: 2016

Cationic lipids: molecular structure/ transfection activity relationships and interactions with biomembranes.

Science.gov (United States)

Koynova, Rumiana; Tenchov, Boris

2010-01-01

Abstract Synthetic cationic lipids, which form complexes (lipoplexes) with polyanionic DNA, are presently the most widely used constituents of nonviral gene carriers. A large number of cationic amphiphiles have been synthesized and tested in transfection studies. However, due to the complexity of the transfection pathway, no general schemes have emerged for correlating the cationic lipid chemistry with their transfection efficacy and the approaches for optimizing their molecular structures are still largely empirical. Here we summarize data on the relationships between transfection activity and cationic lipid molecular structure and demonstrate that the transfection activity depends in a systematic way on the lipid hydrocarbon chain structure. A number of examples, including a large series of cationic phosphatidylcholine derivatives, show that optimum transfection is displayed by lipids with chain length of approximately 14 carbon atoms and that the transfection efficiency strongly increases with increase of chain unsaturation, specifically upon replacement of saturated with monounsaturated chains.

Quantitative structure-activity relationship (QSAR) for insecticides: development of predictive in vivo insecticide activity models.

Science.gov (United States)

Naik, P K; Singh, T; Singh, H

2009-07-01

Quantitative structure-activity relationship (QSAR) analyses were performed independently on data sets belonging to two groups of insecticides, namely the organophosphates and carbamates. Several types of descriptors including topological, spatial, thermodynamic, information content, lead likeness and E-state indices were used to derive quantitative relationships between insecticide activities and structural properties of chemicals. A systematic search approach based on missing value, zero value, simple correlation and multi-collinearity tests as well as the use of a genetic algorithm allowed the optimal selection of the descriptors used to generate the models. The QSAR models developed for both organophosphate and carbamate groups revealed good predictability with r(2) values of 0.949 and 0.838 as well as [image omitted] values of 0.890 and 0.765, respectively. In addition, a linear correlation was observed between the predicted and experimental LD(50) values for the test set data with r(2) of 0.871 and 0.788 for both the organophosphate and carbamate groups, indicating that the prediction accuracy of the QSAR models was acceptable. The models were also tested successfully from external validation criteria. QSAR models developed in this study should help further design of novel potent insecticides.

STRUCTURE-ACTIVITY RELATIONSHIP STUDY OF DITERPENES FOR TREATMENT OF ALZHEIMER'S DISEASE

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Gabriel F. dos Santos

Full Text Available Alzheimer's disease is an irreversible, degenerative and age-related disease which is growing more and more with the increase in life expectancy. Kaurane diterpenes are a class of natural products available in large amounts in nature and isolated from plants grown worldwide. In the present work¸ twenty-seven kaurane diterpenes of natural origin and some readily available derivatives were assayed for acetylcholinesterase inhibition and the structure-activity relationship was analyzed. The kaurenoic acid derivatives screened showed to be promising inhibitors of AChE, which could provide new leads for drugs to fight Alzheimer's disease symptoms. Among them, eleven compounds showed activities comparable or higher than the positive control galantamine. Existence of an allylic hydroxyl group showed to be an important structural feature for AChE inhibition. In addition, presence of free hydroxyl groups at C-17 and C-19, furnished a diol especially active, able to completely inhibit AChE.

The effect of leverage and/or influential on structure-activity relationships.

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Bolboacă, Sorana D; Jäntschi, Lorentz

2013-05-01

In the spirit of reporting valid and reliable Quantitative Structure-Activity Relationship (QSAR) models, the aim of our research was to assess how the leverage (analysis with Hat matrix, h(i)) and the influential (analysis with Cook's distance, D(i)) of QSAR models may reflect the models reliability and their characteristics. The datasets included in this research were collected from previously published papers. Seven datasets which accomplished the imposed inclusion criteria were analyzed. Three models were obtained for each dataset (full-model, h(i)-model and D(i)-model) and several statistical validation criteria were applied to the models. In 5 out of 7 sets the correlation coefficient increased when compounds with either h(i) or D(i) higher than the threshold were removed. Withdrawn compounds varied from 2 to 4 for h(i)-models and from 1 to 13 for D(i)-models. Validation statistics showed that D(i)-models possess systematically better agreement than both full-models and h(i)-models. Removal of influential compounds from training set significantly improves the model and is recommended to be conducted in the process of quantitative structure-activity relationships developing. Cook's distance approach should be combined with hat matrix analysis in order to identify the compounds candidates for removal.

Study of the structure-activity relationships of parabens: a practical class

Energy Technology Data Exchange (ETDEWEB)

Fernandes, Joao Paulo dos Santos; Savino, Giovanna; Amarante, Andre Cortinas Goncalves, E-mail: joao.fernandes@mackenzie.br [Centro de Ciencias Biologicas e da Saude, Universidade Presbiteriana Mackenzie, Sao Paulo, SP (Brazil); Sousa, Milena Rodrigues de; Silva, Geane Ramos da [Universidade Camilo Castelo Branco, Sao Paulo, SP (Brazil); Cianciulli, Maria Eliza [Universidade do Grande ABC, Santo Andre, SP (Brazil); Correa, Michelle Fidelis; Ferrarini, Marcio [Centro Universitario Sao Camilo, Sao Paulo, SP (Brazil)

2013-09-01

Parabens are p-hydroxybenzoic acid esters widely used as preservatives. With the aim of teaching the structure-activity relationships (SAR) knowledge in a practical form, this paper proposed a practical class to view the SAR of parabens as antimicrobial agents. Methyl, ethyl, n-propyl, isopropyl and isopentyl paraben compounds were synthesized and their respective antimicrobial activities were assessed through determination of minimum inhibitory concentrations (MIC) against Staphylococcus aureus ATCC 25923 and Escherichia coli ATCC 25922 stains. With the MIC values, it was possible to verify their correlation with calculated lipophilicity (ClogP). This method can be applied in practical Medicinal Chemistry classes. (author)

Study of the structure-activity relationships of parabens: a practical class

International Nuclear Information System (INIS)

Fernandes, João Paulo dos Santos; Savino, Giovanna; Amarante, André Cortinas Gonçalves; Sousa, Milena Rodrigues de; Silva, Geane Ramos da; Cianciulli, Maria Eliza; Corrêa, Michelle Fidelis; Ferrarini, Márcio

2013-01-01

Parabens are p-hydroxybenzoic acid esters widely used as preservatives. With the aim of teaching the structure-activity relationships (SAR) knowledge in a practical form, this paper proposed a practical class to view the SAR of parabens as antimicrobial agents. Methyl, ethyl, n-propyl, isopropyl and isopentyl paraben compounds were synthesized and their respective antimicrobial activities were assessed through determination of minimum inhibitory concentrations (MIC) against Staphylococcus aureus ATCC 25923 and Escherichia coli ATCC 25922 stains. With the MIC values, it was possible to verify their correlation with calculated lipophilicity (ClogP). This method can be applied in practical Medicinal Chemistry classes. (author)

Molecular Descriptors Family on Structure Activity Relationships 3. Antituberculotic Activity of some Polyhydroxyxanthones

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Sorana BOLBOACĂ

2005-06-01

Full Text Available The antituberculotic activity of some polyhydroxyxanthones was estimated using the Molecular Descriptors Family on Structure Activity Relationships methodology. From a total number of 298110 real and distinct calculated descriptors, 94843 were significantly different and entered into multiple linear regression analysis. The best performing bi-varied model was obtained by use of all polyhydroxyxanthones. The MDF SAR model was validated splitting the molecules into training and test sets. A correlated correlations analysis was applied in other to compare the MDF SAR models with the previous SAR model. The prediction ability of antituberculotic activity of polyhydroxyxanthones with MDF SAR methodology is sustained by three arguments: leave-one-out procedure, training vs. test procedure, and the correlated correlations analysis. Looking at the bi-varied MDF SAR model, we can conclude that the antituberculotic activity of polyhydroxyxanthones is almost of geometrical nature (99% and is strongly dependent on partial atomic charge and group electronegativity.

Structure modification and functionality of whey proteins: quantitative structure-activity relationship approach.

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Nakai, S; Li-Chan, E

1985-10-01

According to the original idea of quantitative structure-activity relationship, electric, hydrophobic, and structural parameters should be taken into consideration for elucidating functionality. Changes in these parameters are reflected in the property of protein solubility upon modification of whey proteins by heating. Although solubility is itself a functional property, it has been utilized to explain other functionalities of proteins. However, better correlations were obtained when hydrophobic parameters of the proteins were used in conjunction with solubility. Various treatments reported in the literature were applied to whey protein concentrate in an attempt to obtain whipping and gelling properties similar to those of egg white. Mapping simplex optimization was used to search for the best results. Improvement in whipping properties by pepsin hydrolysis may have been due to higher protein solubility, and good gelling properties resulting from polyphosphate treatment may have been due to an increase in exposable hydrophobicity. However, the results of angel food cake making were still unsatisfactory.

Environmental properties of long-chain alcohols. Structure-activity Relationship for Chronic Aquatic Toxicity

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Schaefers, Christoph; Sanderson, Hans; Boshof, Udo

2009-01-01

Daphnia magna reproduction tests were performed with C10, C12, C14 and C15 alcohols to establish a structure-activity relationship of chronic effects of long-chain alcohols. The data generation involved substantial methodological efforts due to the exceptionally rapid biodegradability of the test...

Structure-Activity Relationships of the Human Immunodeficiency Virus Type 1 Maturation Inhibitor PF-46396.

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Murgatroyd, Christopher; Pirrie, Lisa; Tran, Fanny; Smith, Terry K; Westwood, Nicholas J; Adamson, Catherine S

2016-09-15

HIV-1 maturation inhibitors are a novel class of antiretroviral compounds that consist of two structurally distinct chemical classes: betulinic acid derivatives and the pyridone-based compound PF-46396. It is currently believed that both classes act by similar modes of action to generate aberrant noninfectious particles via inhibition of CA-SP1 cleavage during Gag proteolytic processing. In this study, we utilized a series of novel analogues with decreasing similarity to PF-46396 to determine the chemical groups within PF-46396 that contribute to antiviral activity, Gag binding, and the relationship between these essential properties. A spectrum of antiviral activity (active, intermediate, and inactive) was observed across the analogue series with respect to CA-SP1 cleavage and HIV-1 (NL4-3) replication kinetics in Jurkat T cells. We demonstrate that selected inactive analogues are incorporated into wild-type (WT) immature particles and that one inactive analogue is capable of interfering with PF-46396 inhibition of CA-SP1 cleavage. Mutations that confer PF-46396 resistance can impose a defective phenotype on HIV-1 that can be rescued in a compound-dependent manner. Some inactive analogues retained the capacity to rescue PF-46396-dependent mutants (SP1-A3V, SP1-A3T, and CA-P157S), implying that they can also interact with mutant Gag. The structure-activity relationships observed in this study demonstrate that (i) the tert-butyl group is essential for antiviral activity but is not an absolute requirement for Gag binding, (ii) the trifluoromethyl group is optimal but not essential for antiviral activity, and (iii) the 2-aminoindan group is important for antiviral activity and Gag binding but is not essential, as its replacement is tolerated. Combinations of antiretroviral drugs successfully treat HIV/AIDS patients; however, drug resistance problems make the development of new mechanistic drug classes an ongoing priority. HIV-1 maturation inhibitors are novel as they

Relationship between structure and antiproliferative activity of polymethoxyflavones towards HL60 cells.

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Kawaii, Satoru; Ikuina, Tomoyasu; Hikima, Takeshi; Tokiwano, Tetsuo; Yoshizawa, Yuko

2012-12-01

As part of our continuing investigation of polymethoxyflavone (PMF) derivatives as potential anticancer substances, a series of PMF derivatives was synthesized. The synthesized compounds were evaluated for cytotoxicity against the promyelocytic leukemic HL60 cell line, and structure-activity relationship correlations were investigated along with previously isolated PMFs from the peel of king orange (Citrus nobilis). 7,3'-Dimethoxyflavone demonstrated the most potent activity among the synthetic PMFs. Consideration of correlation between the methoxylation pattern and antiproliferative activity revealed the importance of the 3'-methoxyl group and the higher degree of methoxylation on the A-ring moiety of PMFs.

Structure-activity relationships of heterogeneous catalysts from time-resolved X-ray absorption spectroscopy

International Nuclear Information System (INIS)

Ressler, T.; Jentoft, R.E.; Wienold, J.; Girgsdies, F.; Neisius, T.; Timpe, O.

2003-01-01

Knowing the composition and the evolution of the bulk structure of a heterogeneous catalyst under working conditions (in situ) is a pre-requisite for understanding structure-activity relationships. X-ray absorption spectroscopy can be employed to study a catalytically active material in situ. In addition to steady-state investigations, the technique permits experiments with a time-resolution in the sub-second range to elucidate the solid-state kinetics of the reactions involved. Combined with mass spectrometry, the evolution of the short-range order structure of a heterogeneous catalyst, the average valence of the constituent metals, and the phase composition can be obtained. Here we present results obtained from time-resolved studies on the reduction of MoO 3 in propene and in propene and oxygen

Effect of conditioners upon the thermodynamics and kinetics of methane hydrate formation. A preliminary structure-properties relationship study

Energy Technology Data Exchange (ETDEWEB)

Di Profio, Pietro; Arca, Simone; Germani, Raimondo; Savelli, Gianfranco

2005-07-01

The synthesis and stability of gas hydrates was found to be heavily affected by the presence of small quantities of additives, or conditioners, particularly surfactants. In a recent work, we showed that the enhancement of hydrate formation, both from previously described and newly synthesized surfactants, is probably due to surfactant monomers, rather than micelles, and that the features of hydrate induction time should not be used as a measure of critical micelle concentration. In the present paper, we discuss the results of a structure-properties relationship study in which a preliminary attempt to relate the structural features of several amphiphilic additives to some kinetic and thermodynamic parameters of methane hydrate formation - e.g., induction times, rate of formation, occupancy, etc. - is conducted. According to the present study, it is found that, for a particular conditioner, a reduction of induction time does not correlate to an increase of the formation rate and occupancy, and vice versa. This may be related to the nature of chemical moieties forming a particular amphiphile (e.g., the hydrophobic tail, head group, counterion, etc.). The understanding of the mechanisms by which those moieties play their differential role may be the key tool to the design and synthesis of tailored conditioners. (Author)

Modifiers in rhodium catalysts for carbon monoxide hydrogenation: Structure-activity relationships

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Bhore, N. A.

1989-05-01

This report is aimed at identifying interesting modified rhodium systems and elucidating structure-activity relationships in these systems with the overall goal of understanding the scientific issues in the catalytic conversion of syngas to oxygenates. Specific additives (sodium and molybdenum) are selected based on the scoping experiments. The effect of the additives on supported rhodium catalysts is then investigated. Throughout the investigation, experiments and analysis were performed on real systems instead of ideal systems. 374 refs., 82 figs., 57 tabs.

Dillapiole as antileishmanial agent: discovery, cytotoxic activity and preliminary SAR studies of dillapiole analogues.

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Parise-Filho, Roberto; Pasqualoto, Kerly Fernanda Mesquita; Magri, Fátima Maria Motter; Ferreira, Adilson Kleber; da Silva, Bárbara Athayde Vaz Galvão; Damião, Mariana Celestina Frojuello Costa Bernstorff; Tavares, Maurício Temotheo; Azevedo, Ricardo Alexandre; Auada, Aline Vivian Vatti; Polli, Michelle Carneiro; Brandt, Carlos Alberto

2012-12-01

In this paper, the isolation of dillapiole (1) from Piper aduncum was reported as well as the semi-synthesis of two phenylpropanoid derivatives [di-hydrodillapiole (2), isodillapiole (3)], via reduction and isomerization reactions. Also, the compounds' molecular properties (structural, electronic, hydrophobic, and steric) were calculated and investigated to establish some preliminary structure-activity relationships (SAR). Compounds were evaluated for in vitro antileishmanial activity and cytotoxic effects on fibroblast cells. Compound 1 presented inhibitory activity against Leishmania amazonensis (IC(50)  = 69.3 µM) and Leishmania brasiliensis (IC(50)  = 59.4 µM) and induced cytotoxic effects on fibroblast cells mainly in high concentrations. Compounds 2 (IC(50)  = 99.9 µM for L. amazonensis and IC(50)  = 90.5 µM for L. braziliensis) and 3 (IC(50)  = 122.9 µM for L. amazonensis and IC(50)  = 109.8 µM for L. brasiliensis) were less active than dillapiole (1). Regarding the molecular properties, the conformational arrangement of the side chain, electronic features, and the hydrophilic/hydrophobic balance seem to be relevant for explaining the antileishmanial activity of dillapiole and its analogues. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Fragment-based quantitative structure-activity relationship (FB-QSAR) for fragment-based drug design.

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Du, Qi-Shi; Huang, Ri-Bo; Wei, Yu-Tuo; Pang, Zong-Wen; Du, Li-Qin; Chou, Kuo-Chen

2009-01-30

In cooperation with the fragment-based design a new drug design method, the so-called "fragment-based quantitative structure-activity relationship" (FB-QSAR) is proposed. The essence of the new method is that the molecular framework in a family of drug candidates are divided into several fragments according to their substitutes being investigated. The bioactivities of molecules are correlated with the physicochemical properties of the molecular fragments through two sets of coefficients in the linear free energy equations. One coefficient set is for the physicochemical properties and the other for the weight factors of the molecular fragments. Meanwhile, an iterative double least square (IDLS) technique is developed to solve the two sets of coefficients in a training data set alternately and iteratively. The IDLS technique is a feedback procedure with machine learning ability. The standard Two-dimensional quantitative structure-activity relationship (2D-QSAR) is a special case, in the FB-QSAR, when the whole molecule is treated as one entity. The FB-QSAR approach can remarkably enhance the predictive power and provide more structural insights into rational drug design. As an example, the FB-QSAR is applied to build a predictive model of neuraminidase inhibitors for drug development against H5N1 influenza virus. (c) 2008 Wiley Periodicals, Inc.

Quantitative Structure Activity Relationship of Cinnamaldehyde Compounds against Wood-Decaying Fungi

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Dongmei Yang

2016-11-01

Full Text Available Cinnamaldehyde, of the genius Cinnamomum, is a major constituent of the bark of the cinnamon tree and possesses broad-spectrum antimicrobial activity. In this study, we used best multiple linear regression (BMLR to develop quantitative structure activity relationship (QSAR models for cinnamaldehyde derivatives against wood-decaying fungi Trametes versicolor and Gloeophyllun trabeum. Based on the two optimal QSAR models, we then designed and synthesized two novel cinnamaldehyde compounds. The QSAR models exhibited good correlation coefficients: R2Tv = 0.910 for Trametes versicolor and R2Gt = 0.926 for Gloeophyllun trabeum. Small errors between the experimental and calculated values of two designed compounds indicated that these two QSAR models have strong predictability and stability.

Structure-activity relationships of lanostane-type triterpenoids from Ganoderma lingzhi as α-glucosidase inhibitors.

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Fatmawati, Sri; Kondo, Ryuichiro; Shimizu, Kuniyoshi

2013-11-01

A series of lanostane-type triterpenoids, identified as ganoderma alcohols and ganoderma acids, were isolated from the fruiting body of Ganoderma lingzhi. Some of these compounds were confirmed as active inhibitors of the in vitro human recombinant aldose reductase. This paper aims to explain the structural requirement for α-glucosidase inhibition. Our structure-activity studies of ganoderma alcohols showed that the OH substituent at C-3 and the double-bond moiety at C-24 and C-25 are necessary to increase α-glucosidase inhibitory activity. The structure-activity relationships of ganoderma acids revealed that the OH substituent at C-11 is an important feature and that the carboxylic group in the side chain is essential for the recognition of α-glucosidase inhibitory activity. Moreover, the double-bond moiety at C-20 and C-22 in the side chain and the OH substituent at C-3 of ganoderma acids improve α-glucosidase inhibitory activity. These results provide an approach with which to consider the structural requirements of lanostane-type triterpenoids from G. lingzhi. An understanding of these requirements is considered necessary in order to improve a new type of α-glucosidase inhibitor. Copyright © 2013 Elsevier Ltd. All rights reserved.

A Review of Recent Advances towards the Development of (Quantitative Structure-Activity Relationships for Metallic Nanomaterials

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Guangchao Chen

2017-08-01

Full Text Available Gathering required information in a fast and inexpensive way is essential for assessing the risks of engineered nanomaterials (ENMs. The extension of conventional (quantitative structure-activity relationships ((QSARs approach to nanotoxicology, i.e., nano-(QSARs, is a possible solution. The preliminary attempts of correlating ENMs’ characteristics to the biological effects elicited by ENMs highlighted the potential applicability of (QSARs in the nanotoxicity field. This review discusses the current knowledge on the development of nano-(QSARs for metallic ENMs, on the aspects of data sources, reported nano-(QSARs, and mechanistic interpretation. An outlook is given on the further development of this frontier. As concluded, the used experimental data mainly concern the uptake of ENMs by different cell lines and the toxicity of ENMs to cells lines and Escherichia coli. The widely applied techniques of deriving models are linear and non-linear regressions, support vector machine, artificial neural network, k-nearest neighbors, etc. Concluded from the descriptors, surface properties of ENMs are seen as vital for the cellular uptake of ENMs; the capability of releasing ions and surface redox properties of ENMs are of importance for evaluating nanotoxicity. This review aims to present key advances in relevant nano-modeling studies and stimulate future research efforts in this quickly developing field of research.

Structural Characterization and Evaluation of the Antioxidant Activity of Phenolic Compounds from Astragalus taipaishanensis and Their Structure-Activity Relationship

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Pu, Wenjun; Wang, Dongmei; Zhou, Dan

2015-09-01

Eight phenolic compounds were isolated using bio-guided isolation and purified from the roots of Astragalus taipaishanensis Y. C. Ho et S. B. Ho (A. taipaishanensis) for the first time. Their structures were elucidated by ESI-MS, HR-ESI-MS, 1D-NMR and 2D-NMR as 7,2‧-dihydroxy-3‧,4‧-dimethoxy isoflavan (1), formononetin (2), isoliquiritigenin (3), quercetin (4), kaempferol (5), ononin (6), p-hydroxybenzoic acid (7) and vanillic acid (8). Six flavonoids (compounds 1-6) exhibited stronger antioxidant activities (determined by DPPH, ABTS, FRAP and lipid peroxidation inhibition assays) than those of BHA and TBHQ and also demonstrated noticeable protective effects (particularly quercetin and kaempferol) on Escherichia coli under oxidative stress. Additionally, the chemical constituents compared with those of Astragalus membranaceus and the structure-activity relationship of the isolated compounds were both analyzed. The results clearly demonstrated that A. taipaishanensis has the potential to be selected as an alternative medicinal and food plant that can be utilized in health food products, functional tea and pharmaceutical products.

Structure-activity relationship (SAR) study and design strategies of nitrogen-containing heterocyclic moieties for their anticancer activities.

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Akhtar, Jawaid; Khan, Ahsan Ahmed; Ali, Zulphikar; Haider, Rafi; Shahar Yar, M

2017-01-05

The present review article offers a detailed account of the design strategies employed for the synthesis of nitrogen-containing anticancer agents. The results of different studies describe the N-heterocyclic ring system is a core structure in many synthetic compounds exhibiting a broad range of biological activities. Benzimidazole, benzothiazole, indole, acridine, oxadiazole, imidazole, isoxazole, pyrazole, triazoles, quinolines and quinazolines including others drugs containing pyridazine, pyridine and pyrimidines are covered. The following studies of these compounds suggested that these compounds showed their antitumor activities through multiple mechanisms including inhibiting protein kinase (CDK, MK-2, PLK1, kinesin-like protein Eg5 and IKK), topoisomerase I and II, microtubule inhibition, and many others. Our concise representation exploits the design and anticancer potency of these compounds. The direct comparison of anticancer activities with the standard enables a systematic analysis of the structure-activity relationship among the series. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Structure activity relationship study of curcumin analogues toward the amyloid-beta aggregation inhibitor.

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Endo, Hitoshi; Nikaido, Yuri; Nakadate, Mamiko; Ise, Satomi; Konno, Hiroyuki

2014-12-15

Inhibition of the amyloid β aggregation process could possibly prevent the onset of Alzheimer's disease. In this article, we report a structure-activity relationship study of curcumin analogues for anti amyloid β aggregation activity. Compound 7, the ideal amyloid β aggregation inhibitor in vitro among synthesized curcumin analogues, has not only potent anti amyloid β aggregation effects, but also water solubility more than 160 times that of curcumin. In addition, new approaches to improve water solubility of curcumin-type compounds are proposed. Copyright © 2014 Elsevier Ltd. All rights reserved.

An overview of structure-activity relationship studies of curcumin analogs as antioxidant and anti-inflammatory agents.

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Arshad, Laiba; Haque, Md Areeful; Abbas Bukhari, Syed Nasir; Jantan, Ibrahim

2017-04-01

Curcumin, extracted mainly from Curcuma longa rhizomes, has been reported to possess potent anti-inflammatory and anti-oxidant activities. Although safe at higher doses and exhibiting multiple biological activities, curcumin still has the problem of poor bioavailability which has been an attractive area of research over the last few years. A number of efforts have been made by modifying structural features of curcumin. This review highlights the structurally modified and more stable newly synthesized curcumin analogs that have been screened against antioxidant and anti-inflammatory activities. Also the structure-activity relationship to gain insight into future guidelines for scheming new compounds has been discussed, and further these analogs being more stable may serve as promising agents for use in different pathological conditions.

A Quantitative Structure-Activity Relationships (QSAR Study of Piperine Based Derivatives with Leishmanicidal Activity

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Edilson Beserra Alencar Filho

2017-04-01

Full Text Available Leishmaniasis is a parasitic disease which represents a serious public health problem in developing countries. It is considered a neglected tropical disease, for which there is little initiative in the search for therapeutic alternatives by pharmaceutical industry. Natural products remain a great source of inspiration for obtaining bioactive molecules. In 2010, Singh and co-workers published the synthesis and in vitro biological activity of piperoyl-aminoacid conjugates, as well as of piperine, against cellular cultures of Leishmania donovani. The piperine is an alkaloid isolated from Piper nigrum that has many activities described in the literature. In this work, we present a Quantitative Structure-Activity Study of piperine derivatives tested by Singh and co-workers, aiming to highlight important molecular features for leishmanicidal activity, obtaining a mathematical model to predict the activity of new analogs. Compounds were submitted to a geometry optimization computational procedure at semiempirical level of quantum theory. Molecular descriptors for the set of compounds were calculated by E-Dragon online plataform, followed by a variable selection procedure using Ordered Predictors Selection algorithm. Validation parameters obtained showed that a good QSAR model, based on multiple linear regression, was obtained (R2 = 0.85; Q2 = 0.69, and the following conclusions regarding the structure-activity relationship were elucidated: Compounds with electronegative atoms on different substituent groups of analogs, absence of unsaturation on lateral chain, presence of ester instead of carboxyl, and large volumes (due the presence of additional aromatic rings trends to increase the activity against promastigote forms of leishmania. DOI: http://dx.doi.org/10.17807/orbital.v9i1.893

Quantitative structure activity relationship for the computational prediction of nitrocompounds carcinogenicity

International Nuclear Information System (INIS)

Morales, Aliuska Helguera; Perez, Miguel Angel Cabrera; Combes, Robert D.; Gonzalez, Maykel Perez

2006-01-01

Several nitrocompounds have been screened for carcinogenicity in rodents, but this is a lengthy and expensive process, taking two years and typically costing 2.5 million dollars, and uses large numbers of animals. There is, therefore, much impetus to develop suitable alternative methods. One possible way of predicting carcinogenicity is to use quantitative structure-activity relationships (QSARs). QSARs have been widely utilized for toxicity testing, thereby contributing to a reduction in the need for experimental animals. This paper describes the results of applying a TOPological substructural molecular design (TOPS-MODE) approach for predicting the rodent carcinogenicity of nitrocompounds. The model described 79.10% of the experimental variance, with a standard deviation of 0.424. The predictive power of the model was validated by leave-one-out validation, with a determination coefficient of 0.666. In addition, this approach enabled the contribution of different fragments to carcinogenic potency to be assessed, thereby making the relationships between structure and carcinogenicity to be transparent. It was found that the carcinogenic activity of the chemicals analysed was increased by the presence of a primary amine group bonded to the aromatic ring, a manner that was proportional to the ring aromaticity. The nitro group bonded to an aromatic carbon atom is a more important determinant of carcinogenicity than the nitro group bonded to an aliphatic carbon. Finally, the TOPS-MODE approach was compared with four other predictive models, but none of these could explain more than 66% of the variance in the carcinogenic potency with the same number of variables

Structure-activity relationships of bumetanide derivatives

DEFF Research Database (Denmark)

Pedersen, Kasper Lykke; Töllner, Kathrin; Römermann, Kerstin

2015-01-01

of diuretics such as bumetanide. Bumetanide was discovered by screening ∼5000 3-amino-5-sulfamoylbenzoic acid derivatives, long before NKCC2 was identified in the kidney. Therefore, structure-activity studies on effects of bumetanide derivatives on NKCC2 are not available. EXPERIMENTAL APPROACH: In this study......, the effect of a series of diuretically active bumetanide derivatives was investigated on human NKCC2 variant A (hNKCC2A) expressed in Xenopus laevis oocytes. KEY RESULTS: Bumetanide blocked hNKCC2A transport with an IC50 of 4 μM. There was good correlation between the diuretic potency of bumetanide and its...... of the structural requirements that determine relative potency of loop diuretics on human NKCC2 splice variants, and may lead to the discovery of novel high-ceiling diuretics....

Structure-antioxidant activity relationships of flavonoids isolated from the resinous exudate of Heliotropium sinuatum.

Science.gov (United States)

Modak, Brenda; Contreras, M Leonor; González-Nilo, Fernando; Torres, René

2005-01-17

Relationships between the structural characteristics of flavonoids isolated from the resinous exudate of Heliotropium sinuatum and their antioxidant activity were studied. Radical formation energies, DeltaH of dehydrogenation and spin densities were calculated using DFT methods (B3LYP/6-31G*). Results show that studied flavonoids can be divided into two sets according to their activity. It has been found that antioxidant activity depends both on substitution pattern of hydroxyl groups of the flavonoid skeleton and the presence of an unsaturation at the C2-C3 bond. A good tendency between DeltaH of dehydrogenation and antioxidant activity was established.

Relationship between Chemical Structure and Antimicrobial Activities of Isothiocyanates from Cruciferous Vegetables against Oral Pathogens.

Science.gov (United States)

Ko, Mi-Ok; Kim, Mi-Bo; Lim, Sang-Bin

2016-12-28

We evaluated the potentials of 10 isothiocyanates (ITCs) from cruciferous vegetables and radish root hydrolysate for inhibiting the growth of oral pathogens, with an emphasis on assessing any structure-function relationship. Structural differences in ITCs impacted their antimicrobial activities against oral pathogens differently. The indolyl ITC (indol-3-carbinol) was the most potent inhibitor of the growth of oral pathogens, followed by aromatic ITCs (benzyl ITC (BITC) and phenylethyl ITC (PEITC)) and aliphatic ITCs (erucin, iberin, and sulforaphene). Sulforaphene, which is similar in structure, but has one double bond, showed higher antimicrobial activity than sulforaphane. Erucin, which has a thiol group, showed higher antimicrobial activity than sulforaphane, which has a sulfinyl group. BITC and iberin with a short chain exhibited higher antimicrobial potential than PEITC and sulforaphane with a longer chain, respectively. ITCs have strong antimicrobial activities and may be useful in the prevention and management of dental caries.

Preliminary conceptual design and analysis on KALIMER reactor structures

International Nuclear Information System (INIS)

Kim, Jong Bum

1996-10-01

The objectives of this study are to perform preliminary conceptual design and structural analyses for KALIMER (Korea Advanced Liquid Metal Reactor) reactor structures to assess the design feasibility and to identify detailed analysis requirements. KALIMER thermal hydraulic system analysis results and neutronic analysis results are not available at present, only-limited preliminary structural analyses have been performed with the assumptions on the thermal loads. The responses of reactor vessel and reactor internal structures were based on the temperature difference of core inlet and outlet and on engineering judgments. Thermal stresses from the assumed temperatures were calculated using ANSYS code through parametric finite element heat transfer and elastic stress analyses. While, based on the results of preliminary conceptual design and structural analyses, the ASME Code limits for the reactor structures were satisfied for the pressure boundary, the needs for inelastic analyses were indicated for evaluation of design adequacy of the support barrel and the thermal liner. To reduce thermal striping effects in the bottom are of UIS due to up-flowing sodium form reactor core, installation of Inconel-718 liner to the bottom area was proposed, and to mitigate thermal shock loads, additional stainless steel liner was also suggested. The design feasibilities of these were validated through simplified preliminary analyses. In conceptual design phase, the implementation of these results will be made for the design of the reactor structures and the reactor internal structures in conjunction with the thermal hydraulic, neutronic, and seismic analyses results. 4 tabs., 24 figs., 4 refs. (Author)

SmallWorld Behavior of the Worldwide Active Volcanoes Network: Preliminary Results

Science.gov (United States)

Spata, A.; Bonforte, A.; Nunnari, G.; Puglisi, G.

2009-12-01

We propose a preliminary complex networks based approach in order to model and characterize volcanoes activity correlation observed on a planetary scale over the last two thousand years. Worldwide volcanic activity is in fact related to the general plate tectonics that locally drives the faults activity, that in turn controls the magma upraise beneath the volcanoes. To find correlations among different volcanoes could indicate a common underlying mechanism driving their activity and could help us interpreting the deeper common dynamics controlling their unrest. All the first evidences found testing the procedure, suggest the suitability of this analysis to investigate global volcanism related to plate tectonics. The first correlations found, in fact, indicate that an underlying common large-scale dynamics seems to drive volcanic activity at least around the Pacific plate, where it collides and subduces beneath American, Eurasian and Australian plates. From this still preliminary analysis, also more complex relationships among volcanoes lying on different tectonic margins have been found, suggesting some more complex interrelationships between different plates. The understanding of eventually detected correlations could be also used to further implement warning systems, relating the unrest probabilities of a specific volcano also to the ongoing activity to the correlated ones. Our preliminary results suggest that, as for other many physical and biological systems, an underlying organizing principle of planetary volcanoes activity might exist and it could be a small-world principle. In fact we found that, from a topological perspective, volcanoes correlations are characterized by the typical features of small-world network: a high clustering coefficient and a low characteristic path length. These features confirm that global volcanoes activity is characterized by both short and long-range correlations. We stress here the fact that numerical simulation carried out in

Improving quantitative structure-activity relationship models using Artificial Neural Networks trained with dropout.

Science.gov (United States)

Mendenhall, Jeffrey; Meiler, Jens

2016-02-01

Dropout is an Artificial Neural Network (ANN) training technique that has been shown to improve ANN performance across canonical machine learning (ML) datasets. Quantitative Structure Activity Relationship (QSAR) datasets used to relate chemical structure to biological activity in Ligand-Based Computer-Aided Drug Discovery pose unique challenges for ML techniques, such as heavily biased dataset composition, and relatively large number of descriptors relative to the number of actives. To test the hypothesis that dropout also improves QSAR ANNs, we conduct a benchmark on nine large QSAR datasets. Use of dropout improved both enrichment false positive rate and log-scaled area under the receiver-operating characteristic curve (logAUC) by 22-46 % over conventional ANN implementations. Optimal dropout rates are found to be a function of the signal-to-noise ratio of the descriptor set, and relatively independent of the dataset. Dropout ANNs with 2D and 3D autocorrelation descriptors outperform conventional ANNs as well as optimized fingerprint similarity search methods.

Preliminary study of mercury target structure

Energy Technology Data Exchange (ETDEWEB)

Kaminaga, Masanori; Haga, Katsuhiro; Hino, Ryutaro [Japan Atomic Energy Research Inst., Tokai, Ibaraki (Japan). Tokai Research Establishment; Kumasaka, Katsuyuki; Uchida, Shoji; Nakagawa, Toshi; Mori, Seiji; Nishikawa, Akira

1997-11-01

Development of a proton accelerator based neutron source (1.5 GeV, 5.3 mA (for neutron source 3.3 mA), thermal power 8 MW) is currently conducted by the Special Task Force for Neutron Science Initiative, JAERI. Preliminary design studies and related R and D of a solid metal target for the first stage (1.5 GeV, 1 mA) and a liquid metal target for both the first and second stages (1.5 GeV, 3.3 mA) are conducted by the Target Group to develop both solid and liquid metal target systems. A few kinds of target structures have been investigated in FY 1996 and the preliminary results for the target structures are described in this paper. Investigation results of alternative materials for the target container are also described in this paper. (author)

Structure-activity relationships of diverse xanthones against multidrug resistant human tumor cells.

Science.gov (United States)

Wang, Qiwen; Ma, Chenyao; Ma, Yun; Li, Xiang; Chen, Yong; Chen, Jianwei

2017-02-01

Thirteen xanthones were isolated naturally from the stem of Securidaca inappendiculata Hassk, and structure-activity relationships (SARs) of these compounds were comparatively predicted for their cytotoxic activity against three human multidrug resistant (MDR) cell lines MCF-7/ADR, SMMC-7721/Taxol, and A549/Taxol cells. The results showed that the selected xanthones exhibited different potent cytotoxic activity against the growth of different human tumor cell lines, and most of the xanthones exhibited selective cytotoxicity against SMMC-7721/Taxol cells. Furthermore, some tested xanthones showed stronger cytotoxicity than Cisplatin, which has been used in clinical application extensively. The SARs analysis revealed that the cytotoxic activities of diverse xanthones were affected mostly by the number and position of methoxyl and hydroxyl groups. Xanthones with more free hydroxyl and methoxyl groups increased the cytotoxic activity significantly, especially for those with the presence of C-3 hydroxyl and C-4 methoxyl groups. Copyright © 2016 Elsevier Ltd. All rights reserved.

3-cyanoindole-based inhibitors of inosine monophosphate dehydrogenase: synthesis and initial structure-activity relationships.

Science.gov (United States)

Dhar, T G Murali; Shen, Zhongqi; Gu, Henry H; Chen, Ping; Norris, Derek; Watterson, Scott H; Ballentine, Shelley K; Fleener, Catherine A; Rouleau, Katherine A; Barrish, Joel C; Townsend, Robert; Hollenbaugh, Diane L; Iwanowicz, Edwin J

2003-10-20

A series of novel small molecule inhibitors of inosine monophosphate dehydrogenase (IMPDH), based upon a 3-cyanoindole core, were explored. IMPDH catalyzes the rate determining step in guanine nucleotide biosynthesis and is a target for anticancer, immunosuppressive and antiviral therapy. The synthesis and the structure-activity relationships (SAR), derived from in vitro studies, for this new series of inhibitors is given.

The use of comprehensive two-dimensional gas chromatography and structure-activity modeling for screening and preliminary risk assessment of organic contaminants in soil, sediment, and surface water

Energy Technology Data Exchange (ETDEWEB)

Moreira Bastos, Patricia; Haglund, Peter [Umeaa Univ. (Sweden). Dept. of Chemistry

2012-08-15

Purpose: This article aims to investigate the use and benefits of using comprehensive two-dimensional gas chromatography (GC x GC) and structure-activity relationship modeling for screening and prioritization of organic contaminants in complex matrices. The benefit of applying comprehensive screening techniques to samples with high organic contaminant content is primarily that compounds with diverse physicochemical properties can be analyzed simultaneously. Here, a heavily contaminated industrial area was surveyed for organic pollutants by analyzing soil, sediment, and surface water samples. The hazard of the pollutants were ranked using SARs. Material and methods: The water samples were liquid-liquid extracted using dichloromethane and directly analyzed by GC x GC-time-of-flight mass spectrometry (GC x GC-TofMS). Soil and sediment samples were extracted with dichloromethane in an ultrasonic bath and subjected to gel permeation chromatography to eliminate lipids and humic matter. The low molecular weight fraction was then analyzed with GC x GC-TofMS. Results and discussion: More than 10,000 components were found in each sample, of which ca. 300 individual compounds were unambiguously identified using the National Institute of Standards and Technology mass spectra library and authentic reference standards. Alkanes, polycyclic aromatic hydrocarbons, and phthalates were generally the most abundant and were found in all matrices. In contrast, chlorinated compounds such as chlorophenols, biphenyls, and chlorinated pesticides were only detected in samples from a few hotspot regions. The toxicities of the most frequently detected compounds and of the compounds detected at the highest concentrations in samples from hotspot regions were estimated by ecological structure-activity relationships. The ratio of the measured concentration to the predicted toxicity level was then calculated for each compound and used for an initial risk assessment in order to prioritize compounds

STRUCTURE – ANTIOXIDANT ACTIVITIES RELATIONSHIP ANALYSIS OF ISOEUGENOL, EUGENOL, VANILIN AND THEIR DERIVATIVES

Directory of Open Access Journals (Sweden)

Nur Aini

2010-06-01

Full Text Available Structure Activity Relationship (SAR technique between the theoretical parameters and antioxidant activities of isoeugenol, eugenol, vanillin and their derivatives as Mannich reaction products, have been analyzed. Antioxidant activities were examined by oxidation reaction of oleic acid at 60 °C with b-carotene methods, whereas theoretical parameters of the activities were determined by calculating Bonding Dissociation Enthalpy (BDE and net charge of oxygen atom(-OH using AM1 semi empiric methods. The result from both test showed in the following orders: BHT > Mannich product of isoeugenol > isoeugenol > Mannich product of eugenol > eugenol > Mannich product of vanillin > vanillin. The antioxidant activities increase with small the BDE value and high the net charge. Electron donating groups will increase the antioxidants activity with lowering the BDE value and increasing the net charge, while electron-withdrawing groups will decrease antioxidants activity.   Keywords: SAR, antioxidants, Bonding Dissociation Entalphy, eugenol.

Stimulation of Orobanche ramosa seed germination by fusicoccin derivatives: a structure-activity relationship study.

Science.gov (United States)

Evidente, Antonio; Andolfi, Anna; Fiore, Michele; Boari, Angela; Vurro, Maurizio

2006-01-01

A structure-activity relationship study was conducted assaying 25 natural analogues and derivatives of fusicoccin (FC), and cotylenol, the aglycone of cotylenins, for their ability to stimulate the seed germination of the parasitic species Orobanche ramosa. Some of the compounds tested proved to be highly active, being 8,9-isopropylidene of the corresponding FC aglycone and the dideacetyl derivative the most active FC derivatives. In both groups of glucosides and aglycones (including cotylenol), the most important structural feature to impart activity appears to be the presence of the primary hydroxy group at C-19. Furthermore, the functionalities and the conformation of the carbotricyclic ring proved to play a significant role. The dideacetyl derivative of FC, being easily and rapidly obtainable in high yield starting by FC, could be of interest for its practical application as a stimulant of Orobanche ramosa seed germination, inducing the "suicidal germination", an interesting approach for parasitic plant management.

Relationship between chemical structure of soil organic matter and intra-aggregate pore structure: evidence from X-ray computed micro-tomography

Science.gov (United States)

Kravchenko, Alexandra; Grandy, Stuart A.

2014-05-01

between SOM chemical structure and pore characteristics differed in the aggregates of the two treatments. For example, in the agricultural treatment, the aggregate sections with prevalence of small pores had lower relative lignin abundance, while higher lignin abundances occurred in aggregate sections with more large pores. This relationship could be reflecting the low accessibility of the sections dominated by small pores to plant roots. It is interesting to note that no relationship between pores and lignin were observed in the aggregate from the native succession treatment. In the native succession aggregate we found that a larger presence of protein and N-bearing compounds was associated with sections with greater presence of 35-90 µm pores. This could be a result of fungal activities, as pores of this size constitute a primary fungal habitat and fungi are known for secreting proteins. Fewer fungi in the soil under agricultural management are likely the reason that no such relationship was observed in the aggregate from the agricultural treatment. Our preliminary results indicate that substantial spatial variability patterns in SOM chemical structure can exist even within a single macro-aggregate and that pores are likely a main driver of intra-aggregate SOM chemistry.

Modeling Chemical Interaction Profiles: I. Spectral Data-Activity Relationship and Structure-Activity Relationship Models for Inhibitors and Non-inhibitors of Cytochrome P450 CYP3A4 and CYP2D6 Isozymes

OpenAIRE

McPhail, Brooks; Tie, Yunfeng; Hong, Huixiao; Pearce, Bruce A.; Schnackenberg, Laura K.; Ge, Weigong; Valerio, Luis G.; Fuscoe, James C.; Tong, Weida; Buzatu, Dan A.; Wilkes, Jon G.; Fowler, Bruce A.; Demchuk, Eugene; Beger, Richard D.

2012-01-01

An interagency collaboration was established to model chemical interactions that may cause adverse health effects when an exposure to a mixture of chemicals occurs. Many of these chemicals—drugs, pesticides, and environmental pollutants—interact at the level of metabolic biotransformations mediated by cytochrome P450 (CYP) enzymes. In the present work, spectral data-activity relationship (SDAR) and structure-activity relationship (SAR) approaches were used to develop machine-learning classifi...

A Review of Recent Advances towards the Development of (Quantitative) Structure-Activity Relationships for Metallic Nanomaterials.

NARCIS (Netherlands)

Chen, Guangchao; Vijver, Martina G; Xiao, Yinlong; Peijnenburg, Willie J G M

2017-01-01

Gathering required information in a fast and inexpensive way is essential for assessing the risks of engineered nanomaterials (ENMs). The extension of conventional (quantitative) structure-activity relationships ((Q)SARs) approach to nanotoxicology, i.e., nano-(Q)SARs, is a possible solution. The

Review of Preliminary Analysis Techniques for Tension Structures.

Science.gov (United States)

1984-02-01

however,a linear dinamic analysis can be conducted for purposes of preliminary design, relative to the static configuration. It is noted that the amount of...16 Chapter 3. PRELIMINARY DESIGN OF TENSION STRUCTURES . . .. .. .. .... 22 S.3.1 Cable Systems . . . . . . . . . . . . .. .. .. .... 23...3.1.1 Singly-Connected Segments. .. .... ... 24 3.1.2 Multiply-Connected Segments . . .. .. .. .. 27 3.1.3 Linearized Dynamics of Cable Systems . . . . 29

Customer Relationship Management System in Occupational Safety & Health Companies: Research on Practice and Preliminary Design Solution

Directory of Open Access Journals (Sweden)

Robert Fabac

2011-10-01

Full Text Available One of the most prominent contemporary trends in formation of companies is the approach to development of a customer-oriented company. In this matter, various versions related to the intensity of this orientation are differentiated. Customer relationship management (CRM system is a well-known concept, and its practice is being studied and improved in connection to various sectors. Companies providing services of occupational safety and health (OHS mainly cooperate with a large number of customers and the quality of this cooperation largely affects the occupational safety and health of employees. Therefore, it is of both scientific and wider social interest to study and improve the relationship of these companies with their customers. This paper investigates the practice of applying CRM in Croatian OHS companies. It identifies the existing conditions and suggests possible improvements in the practice of CRM, based on experts’ assessments using analytic hierarchy process evaluation. Universal preliminary design was created as a framework concept for the formation of a typical customer-oriented OHS services company. Preliminary design includes a structural view, which provides more details through system diagrams, and an illustration of main cooperation processes of a company with its customer.

Validation of Quantitative Structure-Activity Relationship (QSAR Model for Photosensitizer Activity Prediction

Directory of Open Access Journals (Sweden)

Sharifuddin M. Zain

2011-11-01

Full Text Available Photodynamic therapy is a relatively new treatment method for cancer which utilizes a combination of oxygen, a photosensitizer and light to generate reactive singlet oxygen that eradicates tumors via direct cell-killing, vasculature damage and engagement of the immune system. Most of photosensitizers that are in clinical and pre-clinical assessments, or those that are already approved for clinical use, are mainly based on cyclic tetrapyrroles. In an attempt to discover new effective photosensitizers, we report the use of the quantitative structure-activity relationship (QSAR method to develop a model that could correlate the structural features of cyclic tetrapyrrole-based compounds with their photodynamic therapy (PDT activity. In this study, a set of 36 porphyrin derivatives was used in the model development where 24 of these compounds were in the training set and the remaining 12 compounds were in the test set. The development of the QSAR model involved the use of the multiple linear regression analysis (MLRA method. Based on the method, r2 value, r2 (CV value and r2 prediction value of 0.87, 0.71 and 0.70 were obtained. The QSAR model was also employed to predict the experimental compounds in an external test set. This external test set comprises 20 porphyrin-based compounds with experimental IC50 values ranging from 0.39 µM to 7.04 µM. Thus the model showed good correlative and predictive ability, with a predictive correlation coefficient (r2 prediction for external test set of 0.52. The developed QSAR model was used to discover some compounds as new lead photosensitizers from this external test set.

Finite-element model evaluation of barrier configurations to reduce infiltration into waste-disposal structures: preliminary results and design considerations

International Nuclear Information System (INIS)

Lu, A.H.; Phillips, S.J.; Adams, M.R.

1982-09-01

Barriers to reduce infiltration into waste burial disposal structures (trenches, pits, etc.) may be required to provide adequate waste confinement. The preliminary engineering design of these barriers should consider interrelated barrier performance factors. This paper summarizes preliminary computer simulation activities to further engineering barrier design efforts. Several barrier configurations were conceived and evaluated. Models were simulated for each barrier configuration using a finite element computer code. Results of this preliminary evaluation indicate that barrier configurations, depending on their morphology and materials, may significantly influence infiltration, flux, drainage, and storage of water through and within waste disposal structures. 9 figures

Structure-activity relationship of a u-type antimicrobial microemulsion system.

Directory of Open Access Journals (Sweden)

Hui Zhang

Full Text Available The structure-activity relationship of a U-type antimicrobial microemulsion system containing glycerol monolaurate and ethanol at a 1∶1 mass ratio as oil phase and Tween 20 as surfactant were investigated along a water dilution line at a ratio of 80∶20 mass% surfactant/oil phase, based on a pseudo-ternary phase diagram. The differential scanning calorimetry results showed that in the region of up to 33% water, all water molecules are confined to the hydrophilic core of the reverse micelles, leading to the formation of w/o microemulsion. As the water content increases, the water gains mobility, and transforms into bicontinuous in the region of 33-39% water, and finally the microemulsion become o/w in the region of above 39% water. The microstructure characterization was confirmed by the dynamic light scattering measurements and freeze-fracture transmission electron microscope observation. The antimicrobial activity assay using kinetics of killing analysis demonstrated that the microemulsions in w/o regions exhibited relatively high antimicrobial activity against Escherichia coli and Staphylococcus aureus due to the antimicrobial oil phase as the continuous phase, while the antimicrobial activity started to decrease when the microemulsions entered the bicontinuous region, and decreased rapidly as the water content increased in the o/w region, as a result of the dilution of antimicrobial oil droplets in the aqueous continuous phase.

Structure-Activity Relationship Studies of the Cyclic Depsipeptide Natural Product YM-254890, Targeting the Gq Protein

DEFF Research Database (Denmark)

Zhang, Hang; Xiong, Xiao-feng; Boesgaard, Michael W

2017-01-01

that specifically inhibit signaling mediated by the Gq subfamily. In this study we exploit a newly developed synthetic strategy for this compound class in the design, synthesis, and pharmacological evaluation of eight new analogues of YM-254890. These structure-activity relationship studies led to the discovery...

Applications of genetic algorithms on the structure-activity relationship analysis of some cinnamamides.

Science.gov (United States)

Hou, T J; Wang, J M; Liao, N; Xu, X J

1999-01-01

Quantitative structure-activity relationships (QSARs) for 35 cinnamamides were studied. By using a genetic algorithm (GA), a group of multiple regression models with high fitness scores was generated. From the statistical analyses of the descriptors used in the evolution procedure, the principal features affecting the anticonvulsant activity were found. The significant descriptors include the partition coefficient, the molar refraction, the Hammet sigma constant of the substituents on the benzene ring, and the formation energy of the molecules. It could be found that the steric complementarity and the hydrophobic interaction between the inhibitors and the receptor were very important to the biological activity, while the contribution of the electronic effect was not so obvious. Moreover, by construction of the spline models for these four principal descriptors, the effective range for each descriptor was identified.

Relationships between the structure of wheat gluten and ACE inhibitory activity of hydrolysate: stepwise multiple linear regression analysis.

Science.gov (United States)

Zhang, Yanyan; Ma, Haile; Wang, Bei; Qu, Wenjuan; Wali, Asif; Zhou, Cunshan

2016-08-01

Ultrasound pretreatment of wheat gluten (WG) before enzymolysis can improve the angiotensin converting enzyme (ACE) inhibitory activity of the hydrolysates by alerting the structure of substrate proteins. Establishment of a relationship between the structure of WG and ACE inhibitory activity of the hydrolysates to judge the end point of the ultrasonic pretreatment is vital. The results of stepwise multiple linear regression (MLR) showed that the contents of free sulfhydryl, α-helix, disulfide bond, surface hydrophobicity and random coil were significantly correlated to ACE Inhibitory activity of the hydrolysate, with the standard partial regression coefficients were 3.729, -0.676, -0.252, 0.022 and 0.156, respectively. The R(2) of this model was 0.970. External validation showed that the stepwise MLR model could well predict the ACE inhibitory activity of hydrolysate based on the content of free sulfhydryl, α-helix, disulfide bond, surface hydrophobicity and random coil of WG before hydrolysis. A stepwise multiple linear regression model describing the quantitative relationships between the structure of WG and the ACE Inhibitory activity of the hydrolysates was established. This model can be used to predict the endpoint of the ultrasonic pretreatment. © 2015 Society of Chemical Industry. © 2015 Society of Chemical Industry.

Non-linear quantitative structure-activity relationship for adenine derivatives as competitive inhibitors of adenosine deaminase

International Nuclear Information System (INIS)

Sadat Hayatshahi, Sayyed Hamed; Abdolmaleki, Parviz; Safarian, Shahrokh; Khajeh, Khosro

2005-01-01

Logistic regression and artificial neural networks have been developed as two non-linear models to establish quantitative structure-activity relationships between structural descriptors and biochemical activity of adenosine based competitive inhibitors, toward adenosine deaminase. The training set included 24 compounds with known k i values. The models were trained to solve two-class problems. Unlike the previous work in which multiple linear regression was used, the highest of positive charge on the molecules was recognized to be in close relation with their inhibition activity, while the electric charge on atom N1 of adenosine was found to be a poor descriptor. Consequently, the previously developed equation was improved and the newly formed one could predict the class of 91.66% of compounds correctly. Also optimized 2-3-1 and 3-4-1 neural networks could increase this rate to 95.83%

The relationship of resting cerebral blood flow and brain activation during a social cognition task in adolescents with chronic moderate to severe traumatic brain injury: a preliminary investigation.

Science.gov (United States)

Newsome, Mary R; Scheibel, Randall S; Chu, Zili; Hunter, Jill V; Li, Xiaoqi; Wilde, Elisabeth A; Lu, Hanzhang; Wang, Zhiyue J; Lin, Xiaodi; Steinberg, Joel L; Vasquez, Ana C; Cook, Lori; Levin, Harvey S

2012-05-01

Alterations in cerebrovascular function are evident acutely in moderate to severe traumatic brain injury (TBI), although less is known about their chronic effects. Adolescent and adult patients with moderate to severe TBI have been reported to demonstrate diffuse activation throughout the brain during functional magnetic resonance imaging (fMRI). Because fMRI is a measure related to blood flow, it is possible that any deficits in blood flow may alter activation. An arterial spin labeling (ASL) perfusion sequence was performed on seven adolescents with chronic moderate to severe TBI and seven typically developing (TD) adolescents during the same session in which they had performed a social cognition task during fMRI. In the TD group, prefrontal CBF was positively related to prefrontal activation and negatively related to non-prefrontal, posterior, brain activation. This relationship was not seen in the TBI group, who demonstrated a greater positive relationship between prefrontal CBF and non-prefrontal activation than the TD group. An analysis of CBF data independent of fMRI showed reduced CBF in the right non-prefrontal region (pflow throughout the right hemisphere in healthy brains. However, the TBI group demonstrated a positive association with activation constrained to the right non-prefrontal region. These data suggest a relationship between impaired non-prefrontal CBF and the presence of non-prefrontal extra-activation, where the region with more limited blood flow is associated with activation limited to that region. In a secondary analysis, pathology associated with hyperintensities on T2-weighted FLAIR imaging over the whole brain was related to whole brain activation, revealing a negative relationship between lesion volume and frontal activation, and a positive relationship between lesion volume and posterior activation. These preliminary data, albeit collected with small sample sizes, suggest that reduced non-prefrontal CBF, and possibly pathological

Quantitative structure-activity relationships of selective antagonists of glucagon receptor using QuaSAR descriptors.

Science.gov (United States)

Manoj Kumar, Palanivelu; Karthikeyan, Chandrabose; Hari Narayana Moorthy, Narayana Subbiah; Trivedi, Piyush

2006-11-01

In the present paper, quantitative structure activity relationship (QSAR) approach was applied to understand the affinity and selectivity of a novel series of triaryl imidazole derivatives towards glucagon receptor. Statistically significant and highly predictive QSARs were derived for glucagon receptor inhibition by triaryl imidazoles using QuaSAR descriptors of molecular operating environment (MOE) employing computer-assisted multiple regression procedure. The generated QSAR models revealed that factors related to hydrophobicity, molecular shape and geometry predominantly influences glucagon receptor binding affinity of the triaryl imidazoles indicating the relevance of shape specific steric interactions between the molecule and the receptor. Further, QSAR models formulated for selective inhibition of glucagon receptor over p38 mitogen activated protein (MAP) kinase of the compounds in the series highlights that the same structural features, which influence the glucagon receptor affinity, also contribute to their selective inhibition.

Relationships between structure and activity of carbon as a multifunctional support for electrocatalysts.

Science.gov (United States)

Stevanović, Sanja I; Panić, Vladimir V; Dekanski, Aleksandar B; Tripković, Amalija V; Jovanović, Vladislava M

2012-07-14

We report on new insights into the relationships between structure and activity of glassy carbon (GC), as a model material for electrocatalyst support, during its anodization in acid solution. Our investigation strongly confirms the role of CFGs in promotion of Pt activity by the "spill-over" effect related to CO(ads) for methanol electrooxidation (MEO) on a carbon-supported Pt catalyst. Combined analysis of voltammetric and impedance behaviour as well as changes in GC surface morphology induced by intensification of anodizing conditions reveal an intrinsic influence of the carbon functionalization and the structure of a graphene oxide (GO) layer on the electrical and electrocatalytic properties of activated GC. Although GO continuously grows during anodization, it structurally changes from being a graphite inter-layer within graphite ribbons toward a continuous GO surface layer that deteriorates the native structure of GC. As a consequence of the increased distance between GO-spaced graphite layers, the GC conductivity decreases until the case of profound GO exfoliation under drastic anodizing conditions. This exposes the native, yet abundantly functionalized, GC texture. While GC capacitance continuously increases with intensification of anodizing conditions, the surface nano-roughness and GO resistance reach the highest values at modest anodizing conditions, and then decrease upon drastic anodization due to the onset of GO exfoliation. We found for the first time that the activity of a GC-supported Pt catalyst in MEO, as one of the promising half-reactions in polymer electrolyte fuel cells, strictly follows the changes in GC nano-roughness and GO-induced GC resistance. The highest GC/Pt MEO activity is reached when optimal distance between graphite layers and optimal degree of GC functionalization bring the highest amount of CFGs into intimate contact with the Pt surface. This confirms the promoting role of CFGs in MEO catalysis.

Discovery and Structure-Activity Relationship of a Bioactive Fragment of ELABELA that Modulates Vascular and Cardiac Functions

NARCIS (Netherlands)

Murza, Alexandre; Sainsily, Xavier; Coquerel, David; Côté, Jérôme; Marx, Patricia; Besserer-Offroy, Élie; Longpré, Jean-Michel; Lainé, Jean; Reversade, Bruno; Salvail, Dany; Leduc, Richard; Dumaine, Robert; Lesur, Olivier; Auger-Messier, Mannix; Sarret, Philippe; Marsault, Éric

2016-01-01

ELABELA (ELA) was recently discovered as a novel endogenous ligand of the apelin receptor (APJ), a G protein-coupled receptor. ELA signaling was demonstrated to be crucial for normal heart and vasculature development during embryogenesis. We delineate here ELA's structure- activity relationships and

Designing a Quantitative Structure-Activity Relationship for the ...

Science.gov (United States)

Toxicokinetic models serve a vital role in risk assessment by bridging the gap between chemical exposure and potentially toxic endpoints. While intrinsic metabolic clearance rates have a strong impact on toxicokinetics, limited data is available for environmentally relevant chemicals including nearly 8000 chemicals tested for in vitro bioactivity in the Tox21 program. To address this gap, a quantitative structure-activity relationship (QSAR) for intrinsic metabolic clearance rate was developed to offer reliable in silico predictions for a diverse array of chemicals. Models were constructed with curated in vitro assay data for both pharmaceutical-like chemicals (ChEMBL database) and environmentally relevant chemicals (ToxCast screening) from human liver microsomes (2176 from ChEMBL) and human hepatocytes (757 from ChEMBL and 332 from ToxCast). Due to variability in the experimental data, a binned approach was utilized to classify metabolic rates. Machine learning algorithms, such as random forest and k-nearest neighbor, were coupled with open source molecular descriptors and fingerprints to provide reasonable estimates of intrinsic metabolic clearance rates. Applicability domains defined the optimal chemical space for predictions, which covered environmental chemicals well. A reduced set of informative descriptors (including relative charge and lipophilicity) and a mixed training set of pharmaceuticals and environmentally relevant chemicals provided the best intr

Effect of O-methylated and glucuronosylated flavonoids from Tamarix gallica on α-glucosidase inhibitory activity: structure-activity relationship and synergistic potential.

Science.gov (United States)

Ben Hmidene, Asma; Smaoui, Abderrazak; Abdelly, Chedly; Isoda, Hiroko; Shigemori, Hideyuki

2017-03-01

O-Methylated and glucuronosylated flavonoids were isolated from Tamarix gallica as α-glucosidase inhibitors. Structure-activity relationship of these flavonoids suggests that catechol moiety and glucuronic acid at C-3 are factors in the increase in α-glucosidase inhibitory activity. Furthermore, rhamnetin, tamarixetin, rhamnazin, KGlcA, KGlcA-Me, QGlcA, and QGlcA-Me exhibit synergistic potential when applied with a very low concentration of acarbose to α-glucosidase from rat intestine.

Biologically Inspired Visual Model With Preliminary Cognition and Active Attention Adjustment.

Science.gov (United States)

Qiao, Hong; Xi, Xuanyang; Li, Yinlin; Wu, Wei; Li, Fengfu

2015-11-01

Recently, many computational models have been proposed to simulate visual cognition process. For example, the hierarchical Max-Pooling (HMAX) model was proposed according to the hierarchical and bottom-up structure of V1 to V4 in the ventral pathway of primate visual cortex, which could achieve position- and scale-tolerant recognition. In our previous work, we have introduced memory and association into the HMAX model to simulate visual cognition process. In this paper, we improve our theoretical framework by mimicking a more elaborate structure and function of the primate visual cortex. We will mainly focus on the new formation of memory and association in visual processing under different circumstances as well as preliminary cognition and active adjustment in the inferior temporal cortex, which are absent in the HMAX model. The main contributions of this paper are: 1) in the memory and association part, we apply deep convolutional neural networks to extract various episodic features of the objects since people use different features for object recognition. Moreover, to achieve a fast and robust recognition in the retrieval and association process, different types of features are stored in separated clusters and the feature binding of the same object is stimulated in a loop discharge manner and 2) in the preliminary cognition and active adjustment part, we introduce preliminary cognition to classify different types of objects since distinct neural circuits in a human brain are used for identification of various types of objects. Furthermore, active cognition adjustment of occlusion and orientation is implemented to the model to mimic the top-down effect in human cognition process. Finally, our model is evaluated on two face databases CAS-PEAL-R1 and AR. The results demonstrate that our model exhibits its efficiency on visual recognition process with much lower memory storage requirement and a better performance compared with the traditional purely computational

6-Nitrobenzimidazole derivatives: potential phosphodiesterase inhibitors: synthesis and structure-activity relationship.

Science.gov (United States)

Khan, K M; Shah, Zarbad; Ahmad, V U; Ambreen, N; Khan, M; Taha, M; Rahim, F; Noreen, S; Perveen, S; Choudhary, M I; Voelter, W

2012-02-15

6-Nitrobenzimidazole derivatives (1-30) synthesized and their phosphodiesterase inhibitory activities determined. Out of thirty tested compounds, ten showed a varying degrees of phosphodiesterase inhibition with IC(50) values between 1.5±0.043 and 294.0±16.7 μM. Compounds 30 (IC(50)=1.5±0.043 μM), 1 (IC(50)=2.4±0.049 μM), 11 (IC(50)=5.7±0.113 μM), 13 (IC(50)=6.4±0.148 μM), 14 (IC(50)=10.5±0.51 μM), 9 (IC(50)=11.49±0.08 μM), 3 (IC(50)=63.1±1.48 μM), 10 (IC(50)=120.0±4.47 μM), and 6 (IC(50)=153.2±5.6 μM) showed excellent phosphodiesterase inhibitory activity, much superior to the standard EDTA (IC(50)=274±0.007 μM), and thus are potential molecules for the development of a new class of phosphodiesterase inhibitors. A structure-activity relationship is evaluated. All compounds are characterized by spectroscopic parameters. Copyright © 2011 Elsevier Ltd. All rights reserved.

Quantitative structure-activity relationship modeling of the toxicity of organothiophosphate pesticides to Daphnia magna and Cyprinus carpio

NARCIS (Netherlands)

Zvinavashe, E.; Du, T.; Griff, T.; Berg, van den J.H.J.; Soffers, A.E.M.F.; Vervoort, J.J.M.; Murk, A.J.; Rietjens, I.

2009-01-01

Within the REACH regulatory framework in the EU, quantitative structure-activity relationships (QSAR) models are expected to help reduce the number of animals used for experimental testing. The objective of this study was to develop QSAR models to describe the acute toxicity of organothiophosphate

Flavonoids as Vasorelaxant Agents: Synthesis, Biological Evaluation and Quantitative Structure Activities Relationship (QSAR Studies

Directory of Open Access Journals (Sweden)

Yongzhou Hu

2011-09-01

Full Text Available A series of 2-(2-diethylamino-ethoxychalcone and 6-prenyl(or its isomers-flavanones 10a,b and 11a–g were synthesized and evaluated for their vasorelaxant activities against rat aorta rings pretreated with 1 μM phenylephrine (PE. Several compounds showed potent vasorelaxant activities. Compound 10a (EC50 = 7.6 μM, Emax = 93.1%, the most potent one, would be a promising structural template for development of novel and more efficient vasodilators. Further, 2D-QSAR analysis of compounds 10a,b and 11c-e as well as thirty previously synthesized flavonoids 1-3 and 12-38 using Enhanced Replacement Method-Multiple Linear Regression (ERM-MLR was further performed based on an optimal set of molecular descriptors (H5m, SIC2, DISPe, Mor03u and L3m, leading to a reliable model with good predictive ability (Rtrain2 = 0.839, Qloo2 = 0.733 and Rtest2 = 0.804. The results provide good insights into the structure- activity relationships of the target compounds.

Representation of molecular structure using quantum topology with inductive logic programming in structure-activity relationships.

Science.gov (United States)

Buttingsrud, Bård; Ryeng, Einar; King, Ross D; Alsberg, Bjørn K

2006-06-01

The requirement of aligning each individual molecule in a data set severely limits the type of molecules which can be analysed with traditional structure activity relationship (SAR) methods. A method which solves this problem by using relations between objects is inductive logic programming (ILP). Another advantage of this methodology is its ability to include background knowledge as 1st-order logic. However, previous molecular ILP representations have not been effective in describing the electronic structure of molecules. We present a more unified and comprehensive representation based on Richard Bader's quantum topological atoms in molecules (AIM) theory where critical points in the electron density are connected through a network. AIM theory provides a wealth of chemical information about individual atoms and their bond connections enabling a more flexible and chemically relevant representation. To obtain even more relevant rules with higher coverage, we apply manual postprocessing and interpretation of ILP rules. We have tested the usefulness of the new representation in SAR modelling on classifying compounds of low/high mutagenicity and on a set of factor Xa inhibitors of high and low affinity.

Structure-activity relationships for novel drug precursor N-substituted-6-acylbenzothiazolon derivatives: A theoretical approach

Science.gov (United States)

Sıdır, Yadigar Gülseven; Sıdır, İsa

2013-08-01

In this study, the twelve new modeled N-substituted-6-acylbenzothiazolon derivatives having analgesic analog structure have been investigated by quantum chemical methods using a lot of electronic parameters and structure-activity properties; such as molecular polarizability (α), dipole moment (μ), EHOMO, ELUMO, q-, qH+, molecular volume (Vm), ionization potential (IP), electron affinity (EA), electronegativity (χ), molecular hardness (η), molecular softness (S), electrophilic index (ω), heat of formation (HOF), molar refractivity (MR), octanol-water partition coefficient (log P), thermochemical properties (entropy (S), capacity of heat (Cv)); as to investigate activity relationships with molecular structure. The correlations of log P with Vm, MR, ω, EA, EHOMO - ELUMO (ΔE), HOF in aqueous phase, χ, μ, S, η parameters, respectively are obtained, while the linear relation of log P with IP, Cv, HOF in gas phase are not observed. The log P parameter is obtained to be depending on different properties of compounds due to their complexity.

Application of cultured human mast cells (CHMC) for the design and structure-activity relationship of IgE-mediated mast cell activation inhibitors.

Science.gov (United States)

Argade, Ankush; Bhamidipati, Somasekhar; Li, Hui; Carroll, David; Clough, Jeffrey; Keim, Holger; Sylvain, Catherine; Rossi, Alexander B; Coquilla, Christina; Issakani, Sarkiz D; Masuda, Esteban S; Payan, Donald G; Singh, Rajinder

2015-01-01

Here we report the optimization of small molecule inhibitors of human mast cell degranulation via anti-IgE-mediated tryptase release following cross-linking and activation of IgE-loaded FcεR1 receptors. The compounds are selective upstream inhibitors of FcεR1-dependent human mast cell degranulation and proved to be devoid of activity in downstream ionomycin mediated degranulation. Structure-activity relationship (SAR) leading to compound 26 is outlined. Copyright © 2015 Elsevier Ltd. All rights reserved.

Structure-activity relationship of CART peptide fragments

Czech Academy of Sciences Publication Activity Database

Maletínská, Lenka; Maixnerová, Jana; Hlaváček, Jan; Blokešová, Darja; Elbert, Tomáš; Šanda, Miloslav; Slaninová, Jiřina; Železná, Blanka

2007-01-01

Roč. 88, č. 4 (2007), s. 565 ISSN 0006-3525. [American Peptide Society Symposium /20./. 26.06.2007-30.06.2007, Montreal] Institutional research plan: CEZ:AV0Z40550506 Keywords : cocaine and amphetamine regulated transcript peptide * structure * activity Subject RIV: CE - Biochemistry

Quantitative Structure ‒ Antiprotozoal Activity Relationships of Sesquiterpene Lactones

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Reto Brun

2009-06-01

Full Text Available Prompted by results of our previous studies where we found high activity of some sesquiterpene lactones (STLs against Trypanosoma brucei rhodesiense (which causes East African sleeping sickness, we have now conducted a structure-(in-vitro-activity study on a set of 40 STLs against T. brucei rhodesiense, T. cruzi, Leishmania donovani and Plasmodium falciparum. Furthermore, cytotoxic activity against L6 rat skeletal myoblast cells was assessed. Some of the compounds possess high activity, especially against T. brucei (e.g. helenalin and some of its esters with IC50-values of 0.05-0.1 µM, which is about 10 times lower than their cytotoxic activity. It was found that all investigated antiprotozoal activities are significantly correlated with cytotoxicity and the major determinants for activity are a,b-unsaturated structural elements, also known to be essential for other biological activities of STLs. It was observed, however, that certain compounds are considerably more toxic against protozoa than against mammalian cells while others are more cytotoxic than active against the protozoa. A comparative QSAR analysis was therefore undertaken, in order to discern the antiparasitic activity of STLs against T. brucei and cytotoxicity. Both activities were found to depend to a large extent on the same structural elements and molecular properties. The observed variance in the biological data can be explained in terms of subtle variations in the relative influences of various molecular descriptors.

Quantitative Structure activity relationship and risk analysis of some pesticides in the cattle milk

OpenAIRE

Faqir Muhammad*, Ijaz Javed, Masood Akhtar1, Zia-ur-Rahman, Mian Muhammad Awais1, Muhammad Kashif Saleemi2 and Muhammad Irfan Anwar3

2012-01-01

Milk of cattle was collected from various localities of Faisalabad, Pakistan. Pesticides concentration was determined by HPLC using solid phase microextraction. The residue analysis revealed that about 40% milk samples were contaminated with pesticides. The mean±SE levels (ppm) of cyhalothrin, endosulfan, chlorpyrifos and cypermethrin were 0.38±0.02, 0.26±0.02, 0.072±0.01 and 0.085±0.02, respectively. Quantitative structure activity relationship (QSAR) models were used to predict the residues...

Cytotoxic constituents of propolis from Myanmar and their structure-activity relationship.

Science.gov (United States)

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

2009-12-01

Thirteen cycloartane-type tritepenes (1-13) and four prenylated flavanones (14-17) isolated from propolis collected in Myanmar, were evaluated for their cytotoxic activity against a panel of six different cancer cell lines; three murine cancer cell lines (colon 26-L5 carcinoma, B16-BL6 melanoma, and Lewis lung carcinoma) and three human cancer cell lines (lung A549 adenocarcinoma, cervix HeLa adenocarcinoma and HT-1080 fibrosarcoma). Among them, a cycloartane-type triterpene, 3alpha,27-dihydroxycycloart-24E-en-26-oic acid (3), showed the most potent cytotoxicity against B16-BL6 cells with an IC(50) value of 5.91 microM, comparable to those of positive controls, doxorubicin (IC(50), 5.66 microM) and 5-fluorouracil (IC(50), 4.88 microM). In addition, (2S)-5,7-dihydroxy-4'-methoxy-8,3'-diprenylflavanone (14) exhibited strong cytotoxicity against all the tested cancer cell lines with the IC(50) values ranging from 14.0 to 26.4 microM. Based on the observed results, the structure-activity relationships are discussed.

Anosognosia in mild cognitive impairment: Relationship to activation of cortical midline structures involved in self-appraisal

Science.gov (United States)

Ries, Michele L.; Jabbar, Britta M.; Schmitz, Taylor W.; Trivedi, Mehul A.; Gleason, Carey E.; Carlsson, Cynthia M.; Rowley, Howard A.; Asthana, Sanjay; Johnson, Sterling C.

2009-01-01

Awareness of cognitive dysfunction shown by individuals with Mild Cognitive Impairment (MCI), a condition conferring risk for Alzheimer’s disease (AD), is variable. Anosognosia, or unawareness of loss of function, is beginning to be recognized as an important clinical symptom of MCI. However, little is known about the brain substrates underlying this symptom. We hypothesized that MCI participants’ activation of cortical midline structures (CMS) during self-appraisal would covary with level of insight into cognitive difficulties (indexed by a discrepancy score between patient and informant ratings of cognitive decline in each MCI participant). To address this hypothesis, we first compared 16 MCI participants and 16 age-matched controls, examining brain regions showing conjoint or differential BOLD response during self-appraisal. Second, we used regression to investigate the relationship between awareness of deficit in MCI and BOLD activity during self-appraisal, controlling for extent of memory impairment. Between-group comparisons indicated that MCI participants show subtly attenuated CMS activity during self-appraisal. Regression analysis revealed a highly-significant relationship between BOLD response during self-appraisal and self-awareness of deficit in MCI. This finding highlights the level of anosognosia in MCI as an important predictor of response to self-appraisal in cortical midline structures, brain regions vulnerable to changes in early AD. PMID:17445294

Anticancer and reversing multidrug resistance activities of natural isoquinoline alkaloids and their structure-activity relationship.

Science.gov (United States)

Qing, Zhi-Xing; Huang, Jia-Lu; Yang, Xue-Yi; Liu, Jing-Hong; Cao, Hua-Liang; Xiang, Feng; Cheng, Pi; Zeng, Jian-Guo

2017-09-20

The severe anticancer situation as well as the emergence of multidrug-resistant (MDR) cancer cells has created an urgent need for the development of novel anticancer drugs with different mechanisms of action. A large number of natural alkaloids, such as paclitaxel, vinblastine and camptothecin have already been successfully developed into chemotherapy agents. Following the success of these natural products, in this review, twenty-six types of isoquinoline alkaloid (a total of 379 alkaloids), including benzyltetrahydroisoquinoline, aporphine, oxoaporphine, isooxoaporphine, dimeric aporphine, bisbenzylisoquinoline, tetrahydroprotoberberine, protoberberine, protopine, dihydrobenzophenanthridine, benzophenanthridine, benzophenanthridine dimer, ipecac, simple isoquinoline, pavine, montanine, erythrina, chelidonine, tropoloisoquinoline, azafluoranthene, phthalideisoquinoline, naphthylisoquinoline, lycorine, crinane, narciclasine, and phenanthridone, were summarized based on their cytotoxic and MDR reversing activities against various cancer cells. Additionally, the structure-activity relationships of different types of isoquinoline alkaloid were also discussed. Interestingly, some aporphine, oxoaporphine, isooxoaporphine, bisbenzylisoquinoline, and protoberberine alkaloids display more potent anticancer activities or anti-MDR effects than positive control against the tested cancer cells and are regarded as attractive targets for discovery new anticancer drugs or lead compounds. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Cytotoxic constituents from Brazilian red propolis and their structure-activity relationship.

Science.gov (United States)

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

2008-05-15

Several classes of flavonoids [flavanoids (1-10), flavonol (11), isoflavones (12-18), isoflavanones (19-22), isoflavans (23-26), chalcones (27-30), auronol (31), pterocarpans (32-37), 2-arylbenzofuran (38), and neoflavonoid (39)] and lignans (40-42) isolated from the MeOH extract of Brazilian red propolis were investigated for their cytotoxic activity against a panel of six different cancer cell lines including murine colon 26-L5 carcinoma, murine B16-BL6 melanoma, murine Lewis lung carcinoma, human lung A549 adenocarcinoma, human cervix HeLa adenocarcinoma, and human HT-1080 fibrosarcoma cell lines. Based on the observed results, structure-activity relationships were discussed. Among the tested compounds, 7-hydroxy-6-methoxyflavanone (3) exhibited the most potent activity against B16-BL6 (IC(50), 6.66microM), LLC (IC(50), 9.29microM), A549 (IC(50), 8.63microM), and HT-1080 (IC(50), 7.94microM) cancer cell lines, and mucronulatol (26) against LLC (IC(50), 8.38microM) and A549 (IC(50), 9.9microM) cancer cell lines. These activity data were comparable to those of the clinically used anticancer drugs, 5-fluorouracil and doxorubicin, against the tested cell lines, suggesting that 3 and 26 are the good candidates for future anticancer drug development.

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

Science.gov (United States)

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

2014-05-05

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

Antiparasitic Activity of Natural and Semi-Synthetic Tirucallane Triterpenoids from Schinus terebinthifolius (Anacardiaceae: Structure/Activity Relationships

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Thiago R. Morais

2014-05-01

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

Synthesis, activity, and structure--activity relationship studies of novel cationic lipids for DNA transfer.

Science.gov (United States)

Byk, G; Dubertret, C; Escriou, V; Frederic, M; Jaslin, G; Rangara, R; Pitard, B; Crouzet, J; Wils, P; Schwartz, B; Scherman, D

1998-01-15

We have designed and synthesized original cationic lipids for gene delivery. A synthetic method on solid support allowed easy access to unsymmetrically monofunctionalized polyamine building blocks of variable geometries. These polyamine building blocks were introduced into cationic lipids. To optimize the transfection efficiency in the novel series, we have carried out structure-activity relationship studies by introduction of variable-length lipids, of variable-length linkers between lipid and cationic moiety, and of substituted linkers. We introduce the concept of using the linkers within cationic lipids molecules as carriers of side groups harboring various functionalities (side chain entity), as assessed by the introduction of a library composed of cationic entities, additional lipid chains, targeting groups, and finally the molecular probes rhodamine and biotin for cellular traffic studies. The transfection activity of the products was assayed in vitro on Hela carcinoma, on NIH3T3, and on CV1 fibroblasts and in vivo on the Lewis Lung carcinoma model. Products from the series displayed high transfection activities. Results indicated that the introduction of a targeting side chain moiety into the cationic lipid is permitted. A primary physicochemical characterization of the DNA/lipid complexes was demonstrated with this leading compound. Selected products from the series are currently being developed for preclinical studies, and the labeled lipopolyamines can be used to study the intracellular traffic of DNA/cationic lipid complexes.

Comparative Analysis of Predictive Models for Liver Toxicity Using ToxCast Assays and Quantitative Structure-Activity Relationships (MCBIOS)

Science.gov (United States)

Comparative Analysis of Predictive Models for Liver Toxicity Using ToxCast Assays and Quantitative Structure-Activity Relationships Jie Liu1,2, Richard Judson1, Matthew T. Martin1, Huixiao Hong3, Imran Shah1 1National Center for Computational Toxicology (NCCT), US EPA, RTP, NC...

Synthesis, Antifungal Activity and Structure-Activity Relationships of Novel 3-(Difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic Acid Amides.

Science.gov (United States)

Du, Shijie; Tian, Zaimin; Yang, Dongyan; Li, Xiuyun; Li, Hong; Jia, Changqing; Che, Chuanliang; Wang, Mian; Qin, Zhaohai

2015-05-08

A series of novel 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid amides were synthesized and their activities were tested against seven phytopathogenic fungi by an in vitro mycelia growth inhibition assay. Most of them displayed moderate to excellent activities. Among them N-(2-(5-bromo-1H-indazol-1-yl)phenyl)-3-(difluoro-methyl)-1-methyl-1H-pyrazole-4-carboxamide (9m) exhibited higher antifungal activity against the seven phytopathogenic fungi than boscalid. Topomer CoMFA was employed to develop a three-dimensional quantitative structure-activity relationship model for the compounds. In molecular docking, the carbonyl oxygen atom of 9m could form hydrogen bonds towards the hydroxyl of TYR58 and TRP173 on SDH.

Synthesis, Antifungal Activity and Structure-Activity Relationships of Novel 3-(Difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic Acid Amides

Directory of Open Access Journals (Sweden)

Shijie Du

2015-05-01

Full Text Available A series of novel 3-(difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid amides were synthesized and their activities were tested against seven phytopathogenic fungi by an in vitro mycelia growth inhibition assay. Most of them displayed moderate to excellent activities. Among them N-(2-(5-bromo-1H-indazol-1-ylphenyl-3-(difluoro-methyl-1-methyl-1H-pyrazole-4-carboxamide (9m exhibited higher antifungal activity against the seven phytopathogenic fungi than boscalid. Topomer CoMFA was employed to develop a three-dimensional quantitative structure-activity relationship model for the compounds. In molecular docking, the carbonyl oxygen atom of 9m could form hydrogen bonds towards the hydroxyl of TYR58 and TRP173 on SDH.

Nε-Acryloyllysine Piperazides as Irreversible Inhibitors of Transglutaminase 2: Synthesis, Structure-Activity Relationships, and Pharmacokinetic Profiling.

Science.gov (United States)

Wodtke, Robert; Hauser, Christoph; Ruiz-Gómez, Gloria; Jäckel, Elisabeth; Bauer, David; Lohse, Martin; Wong, Alan; Pufe, Johanna; Ludwig, Friedrich-Alexander; Fischer, Steffen; Hauser, Sandra; Greif, Dieter; Pisabarro, M Teresa; Pietzsch, Jens; Pietsch, Markus; Löser, Reik

2018-05-24

Transglutaminase 2 (TGase 2)-catalyzed transamidation represents an important post-translational mechanism for protein modification with implications in physiological and pathophysiological conditions, including fibrotic and neoplastic processes. Consequently, this enzyme is considered a promising target for the diagnosis of and therapy for these diseases. In this study, we report on the synthesis and kinetic characterization of N ε -acryloyllysine piperazides as irreversible inhibitors of TGase 2. Systematic structural modifications on 54 new compounds were performed with a major focus on fluorine-bearing substituents due to the potential of such compounds to serve as radiotracer candidates for positron emission tomography. The determined inhibitory activities ranged from 100 to 10 000 M -1 s -1 , which resulted in comprehensive structure-activity relationships. Structure-activity correlations using various substituent parameters accompanied by covalent docking studies provide an advanced understanding of the molecular recognition for this inhibitor class within the active site of TGase 2. Selectivity profiling of selected compounds for other transglutaminases demonstrated an excellent selectivity toward transglutaminase 2. Furthermore, an initial pharmacokinetic profiling of selected inhibitors was performed, including the assessment of potential membrane permeability and liver microsomal stability.

Preliminary verification of structure design for CN HCCB TBM with 1 × 4 configuration

Energy Technology Data Exchange (ETDEWEB)

Zhao, Zhou, E-mail: zhaozhou@swip.ac.cn; Zhou, Bing; Wang, Qijie; Cao, Qixiang; Feng, Kaiming; Wang, Xiaoyu; Zhang, Guoshu

2016-02-15

Highlights: • A new and simplification structural design scheme with 1 × 4 configuration is proposed for CN HCCB TBM. • The detail conceptual structural design for 1 × 4 TBM is completed. • The preliminary hydraulic analysis, thermo-hydraulic analysis and structural analysis for 1 × 4 TBM had been carried out. - Abstract: Based on the conceptual design of CN HCCB TBM with 1 × 4 configuration, the preliminary hydraulic analysis, thermo-hydraulic analysis and structural analysis had been carried out for it. Hydraulic and thermo-hydraulic analyses show that the coolant manifold system could meet the fluid design requirement preliminarily and the temperature of RAFMs structural parts, Be and Li{sub 4}SiO{sub 4} pebble beds are within the allowable range, and no zone shows a stress higher than the allowable limit in the preliminary structural analysis. These results indicate the design for CN HCCB TBM with 1 × 4 configuration is preliminary reasonable.

Preliminary verification of structure design for CN HCCB TBM with 1 × 4 configuration

International Nuclear Information System (INIS)

Zhao, Zhou; Zhou, Bing; Wang, Qijie; Cao, Qixiang; Feng, Kaiming; Wang, Xiaoyu; Zhang, Guoshu

2016-01-01

Highlights: • A new and simplification structural design scheme with 1 × 4 configuration is proposed for CN HCCB TBM. • The detail conceptual structural design for 1 × 4 TBM is completed. • The preliminary hydraulic analysis, thermo-hydraulic analysis and structural analysis for 1 × 4 TBM had been carried out. - Abstract: Based on the conceptual design of CN HCCB TBM with 1 × 4 configuration, the preliminary hydraulic analysis, thermo-hydraulic analysis and structural analysis had been carried out for it. Hydraulic and thermo-hydraulic analyses show that the coolant manifold system could meet the fluid design requirement preliminarily and the temperature of RAFMs structural parts, Be and Li_4SiO_4 pebble beds are within the allowable range, and no zone shows a stress higher than the allowable limit in the preliminary structural analysis. These results indicate the design for CN HCCB TBM with 1 × 4 configuration is preliminary reasonable.

Quantitative structure-activity relationship modeling on in vitro endocrine effects and metabolic stability involving 26 selected brominated flame retardants

NARCIS (Netherlands)

Harju, M.; Hamers, T.; Kamstra, J.H.; Sonneveld, E.; Boon, J.P.

2007-01-01

In this work, quantitative structure-activity relationships (QSARs) were developed to aid human and environmental risk assessment processes for brominated flame retardants (BFRs). Brominated flame retardants, such as the high-production-volume chemicals polybrominated diphenyl ethers (PBDEs),

Structure-activity relationship of antiparasitic and cytotoxic indoloquinoline alkaloids, and their tricyclic and bicyclic analogues.

Science.gov (United States)

Van Baelen, Gitte; Hostyn, Steven; Dhooghe, Liene; Tapolcsányi, Pál; Mátyus, Péter; Lemière, Guy; Dommisse, Roger; Kaiser, Marcel; Brun, Reto; Cos, Paul; Maes, Louis; Hajós, György; Riedl, Zsuzsanna; Nagy, Ildikó; Maes, Bert U W; Pieters, Luc

2009-10-15

Based on the indoloquinoline alkaloids cryptolepine (1), neocryptolepine (2), isocryptolepine (3) and isoneocryptolepine (4), used as lead compounds for new antimalarial agents, a series of tricyclic and bicyclic analogues, including carbolines, azaindoles, pyrroloquinolines and pyrroloisoquinolines was synthesized and biologically evaluated. None of the bicyclic compounds was significantly active against the chloroquine-resistant strain Plasmodium falciparum K1, in contrast to the tricyclic derivatives. The tricyclic compound 2-methyl-2H-pyrido[3,4-b]indole (9), or 2-methyl-beta-carboline, showed the best in vitro activity, with an IC(50) value of 0.45 microM against P. falciparum K1, without apparent cytotoxicity against L6 cells (SI>1000). However, this compound was not active in the Plasmodium berghei mouse model. Structure-activity relationships are discussed and compared with related naturally occurring compounds.

Structure-Activity Relationship and Molecular Mechanics Reveal the Importance of Ring Entropy in the Biosynthesis and Activity of a Natural Product.

Science.gov (United States)

Tran, Hai L; Lexa, Katrina W; Julien, Olivier; Young, Travis S; Walsh, Christopher T; Jacobson, Matthew P; Wells, James A

2017-02-22

Macrocycles are appealing drug candidates due to their high affinity, specificity, and favorable pharmacological properties. In this study, we explored the effects of chemical modifications to a natural product macrocycle upon its activity, 3D geometry, and conformational entropy. We chose thiocillin as a model system, a thiopeptide in the ribosomally encoded family of natural products that exhibits potent antimicrobial effects against Gram-positive bacteria. Since thiocillin is derived from a genetically encoded peptide scaffold, site-directed mutagenesis allows for rapid generation of analogues. To understand thiocillin's structure-activity relationship, we generated a site-saturation mutagenesis library covering each position along thiocillin's macrocyclic ring. We report the identification of eight unique compounds more potent than wild-type thiocillin, the best having an 8-fold improvement in potency. Computational modeling of thiocillin's macrocyclic structure revealed a striking requirement for a low-entropy macrocycle for activity. The populated ensembles of the active mutants showed a rigid structure with few adoptable conformations while inactive mutants showed a more flexible macrocycle which is unfavorable for binding. This finding highlights the importance of macrocyclization in combination with rigidifying post-translational modifications to achieve high-potency binding.

Structure-Activity Relationships of New Natural Product-Based Diaryloxazoles with Selective Activity against Androgen Receptor-Positive Breast Cancer Cells.

Science.gov (United States)

Robles, Andrew J; McCowen, Shelby; Cai, Shengxin; Glassman, Michaels; Ruiz, Francisco; Cichewicz, Robert H; McHardy, Stanton F; Mooberry, Susan L

2017-11-22

Targeted therapies for ER+/PR+ and HER2-amplified breast cancers have improved patient survival, but there are no therapies for triple negative breast cancers (TNBC) that lack expression of estrogen and progesterone receptors (ER/PR), or amplification or overexpression of HER2. Gene expression profiling of TNBC has identified molecular subtypes and representative cell lines. An extract of the Texas native plant Amyris texana was found to have selective activity against MDA-MB-453 cells, a model of the luminal androgen receptor (LAR) subtype of TNBC. Bioassay-guided fractionation identified two oxazole natural products with selective activity against this cell line. Conducted analog synthesis and structure-activity relationship studies provided analogs with more potent and selective activity against two LAR subtype cell line models, culminating in the discovery of compound 30 (CIDD-0067106). Lead compounds discovered have potent and selective antiproliferative activities, and mechanisms of action studies show they inhibit the activity of the mTORC1 pathway.

Preliminary earthquake locations in the Kenai Peninsula recorded by the MOOS Array and their relationship to structure in the 1964 great earthquake zone

Science.gov (United States)

Li, J.; Abers, G. A.; Christensen, D. H.; Kim, Y.; Calkins, J. A.

2011-12-01

of velocity structure from scattered wave migration, we can test whether the thrust zone is above the Yakutat terrane or between the Yakutat terrane and the subducting Pacific plate. Our refined relocations will also improve our understanding of other active faults (e.g., splay faults) and their relationship to the plate boundary.

Synthesis, quantitative structure-property relationship study of novel fluorescence active 2-pyrazolines and application

Science.gov (United States)

Girgis, Adel S.; Basta, Altaf H.; El-Saied, Houssni; Mohamed, Mohamed A.; Bedair, Ahmad H.; Salim, Ahmad S.

2018-03-01

A variety of fluorescence-active fluorinated pyrazolines 13-33 was synthesized in good yields through cyclocondensation reaction of propenones 1-9 with aryl hydrazines 10-12. Some of the synthesized compounds provided promising fluorescence properties with quantum yield (Φ) higher than that of quinine sulfate (standard reference). Quantitative structure-property relationship studies were undertaken supporting the exhibited fluorescence properties and estimating the parameters governing properties. Five synthesized fluorescence-active pyrazolines (13, 15, 18, 19 and 23) with variable Φ were selected for treating two types of paper sheets (Fabriano and Bible paper). These investigated fluorescence compounds, especially compounds 19 and 23, provide improvements in strength properties of paper sheets. Based on the observed performance they can be used as markers in security documents.

Structure-Activity Relationship of the Antimalarial Ozonide Artefenomel (OZ439).

Science.gov (United States)

Dong, Yuxiang; Wang, Xiaofang; Kamaraj, Sriraghavan; Bulbule, Vivek J; Chiu, Francis C K; Chollet, Jacques; Dhanasekaran, Manickam; Hein, Christopher D; Papastogiannidis, Petros; Morizzi, Julia; Shackleford, David M; Barker, Helena; Ryan, Eileen; Scheurer, Christian; Tang, Yuanqing; Zhao, Qingjie; Zhou, Lin; White, Karen L; Urwyler, Heinrich; Charman, William N; Matile, Hugues; Wittlin, Sergio; Charman, Susan A; Vennerstrom, Jonathan L

2017-04-13

Building on insights gained from the discovery of the antimalarial ozonide arterolane (OZ277), we now describe the structure-activity relationship (SAR) of the antimalarial ozonide artefenomel (OZ439). Primary and secondary amino ozonides had higher metabolic stabilities than tertiary amino ozonides, consistent with their higher pK a and lower log D 7.4 values. For primary amino ozonides, addition of polar functional groups decreased in vivo antimalarial efficacy. For secondary amino ozonides, additional functional groups had variable effects on metabolic stability and efficacy, but the most effective members of this series also had the highest log D 7.4 values. For tertiary amino ozonides, addition of polar functional groups with H-bond donors increased metabolic stability but decreased in vivo antimalarial efficacy. Primary and tertiary amino ozonides with cycloalkyl and heterocycle substructures were superior to their acyclic counterparts. The high curative efficacy of these ozonides was most often associated with high and prolonged plasma exposure, but exposure on its own did not explain the presence or absence of either curative efficacy or in vivo toxicity.

Using quantitative structure-activity relationships (QSAR) to predict toxic endpoints for polycyclic aromatic hydrocarbons (PAH).

Science.gov (United States)

Bruce, Erica D; Autenrieth, Robin L; Burghardt, Robert C; Donnelly, K C; McDonald, Thomas J

2008-01-01

Quantitative structure-activity relationships (QSAR) offer a reliable, cost-effective alternative to the time, money, and animal lives necessary to determine chemical toxicity by traditional methods. Additionally, humans are exposed to tens of thousands of chemicals in their lifetimes, necessitating the determination of chemical toxicity and screening for those posing the greatest risk to human health. This study developed models to predict toxic endpoints for three bioassays specific to several stages of carcinogenesis. The ethoxyresorufin O-deethylase assay (EROD), the Salmonella/microsome assay, and a gap junction intercellular communication (GJIC) assay were chosen for their ability to measure toxic endpoints specific to activation-, induction-, and promotion-related effects of polycyclic aromatic hydrocarbons (PAH). Shape-electronic, spatial, information content, and topological descriptors proved to be important descriptors in predicting the toxicity of PAH in these bioassays. Bioassay-based toxic equivalency factors (TEF(B)) were developed for several PAH using the quantitative structure-toxicity relationships (QSTR) developed. Predicting toxicity for a specific PAH compound, such as a bioassay-based potential potency (PP(B)) or a TEF(B), is possible by combining the predicted behavior from the QSTR models. These toxicity estimates may then be incorporated into a risk assessment for compounds that lack toxicity data. Accurate toxicity predictions are made by examining each type of endpoint important to the process of carcinogenicity, and a clearer understanding between composition and toxicity can be obtained.

Structure activity relationships to assess new chemicals under TSCA

Energy Technology Data Exchange (ETDEWEB)

Auletta, A.E. [Environmental Protection Agency, Washington, DC (United States)

1990-12-31

Under Section 5 of the Toxic Substances Control Act (TSCA), manufacturers must notify the US Environmental Protection Agency (EPA) 90 days before manufacturing, processing, or importing a new chemical substance. This is referred to as a premanufacture notice (PMN). The PMN must contain certain information including chemical identity, production volume, proposed uses, estimates of exposure and release, and any health or environmental test data that are available to the submitter. Because there is no explicit statutory authority that requires testing of new chemicals prior to their entry into the market, most PMNs are submitted with little or no data. As a result, EPA has developed special techniques for hazard assessment of PMN chemicals. These include (1) evaluation of available data on the chemical itself, (2) evaluation of data on analogues of the PMN, or evaluation of data on metabolites or analogues of metabolites of the PMN, (3) use of quantitative structure activity relationships (QSARs), and (4) knowledge and judgement of scientific assessors in the interpretation and integration of the information developed in the course of the assessment. This approach to evaluating potential hazards of new chemicals is used to identify those that are most in need of addition review of further testing. It should not be viewed as a replacement for testing. 4 tabs.

Structure-activity relationship of prenyl-substituted polyphenols from Artocarpus heterophyllus as inhibitors of melanin biosynthesis in cultured melanoma cells.

Science.gov (United States)

Arung, Enos Tangke; Shimizu, Kuniyoshi; Kondo, Ryuichiro

2007-09-01

A series of prenylated, flavone-based polyphenols, compounds 1-8, were isolated from the wood of Artocarpus heterophyllus. These compounds, which have previously been shown not to inhibit tyrosinase activity, were found to be active inhibitors of the in vivo melanin biosynthesis in B16 melanoma cells, with little or no cytotoxicity. To clarify the structural requirement for inhibition, some structure-activity relationships were studied, in comparison with related compounds lacking prenyl side chains. Our experiments indicate that both prenyl and OH groups, as well as the type of substitution pattern, are crucial for the inhibition of melanin production in B16 melanoma cells.

Noncoded amino acids in protein engineering: Structure-activity relationship studies of hirudin-thrombin interaction.

Science.gov (United States)

De Filippis, Vincenzo; Acquasaliente, Laura; Pontarollo, Giulia; Peterle, Daniele

2018-01-01

The advent of recombinant DNA technology allowed to site-specifically insert, delete, or mutate almost any amino acid in a given protein, significantly improving our knowledge of protein structure, stability, and function. Nevertheless, a quantitative description of the physical and chemical basis that makes a polypeptide chain to efficiently fold into a stable and functionally active conformation is still elusive. This mainly originates from the fact that nature combined, in a yet unknown manner, different properties (i.e., hydrophobicity, conformational propensity, polarizability, and hydrogen bonding capability) into the 20 standard natural amino acids, thus making difficult, if not impossible, to univocally relate the change in protein stability or function to the alteration of physicochemical properties caused by amino acid exchange(s). In this view, incorporation of noncoded amino acids with tailored side chains, allowing to finely tune the structure at a protein site, would facilitate to dissect the effects of a given mutation in terms of one or a few physicochemical properties, thus much expanding the scope of physical organic chemistry in the study of proteins. In this review, relevant applications from our laboratory will be presented on the use of noncoded amino acids in structure-activity relationships studies of hirudin binding to thrombin. © 2017 International Union of Biochemistry and Molecular Biology, Inc.

Varic acid analogues from fungus as PTP1B inhibitors: Biological evaluation and structure-activity relationships.

Science.gov (United States)

Sun, Wenlong; Zhuang, Chunlin; Li, Xia; Zhang, Bowei; Lu, Xinhua; Zheng, Zhihui; Dong, Yuesheng

2017-08-01

Protein tyrosine phosphatase 1B (PTP1B) inhibitors as potential therapies for diabetes and obesity have attracted much attention in recent years. Six varic acid analogues were isolated from two strains of fungi and evaluated for PTP1B inhibition activities. The structure-activity relationships were also characterized and predicted by molecular modeling. Further kinetic studies indicated the reversible and competitive inhibition manner of varic acid analogues. Trivaric acid showed insulin-sensitizing effect not only in vitro but also in vivo, representing a promising lead compound for further optimization. Copyright © 2017 Elsevier Ltd. All rights reserved.

Preliminary evaluation of microstructure and mechanical properties on low activation ferritic steels

International Nuclear Information System (INIS)

Hsu, C.Y.; Lechtenberg, T.A.

1985-01-01

Radioactive waste disposal has become a primary concern for the selection of materials for the structural components for fusion reactors. One way to minimize this potential environmental problem is to use structural materials in which the induced radioactivity decays quickly to levels that allow for near-surface disposal under 10CFR61 rules. The primary objective of this work is to develop low activation ferritic steels that exhibit mechanical and physical properties approximately equivalent to the HT-9 and 9Cr-1Mo steels, but which only contain elements that would permit near-surface disposal under 10CFR61 after exposure to fusion neutrons. A preliminary evaluation of the microstructure and mechanical properties of a 9Cr-2.5W-0.3V-0.15C (GA3X) low activation ferritic steel has been performed. An optimum heat treatment condition has been defined for GA3X steel. The properties and microstructure of the quenched and tempered specimens were characterized via hardness measurement and optical metallographic observation. The hot-microhardness and ductility parameter measurements were used to estimate the tensile properties at elevated temperatures. The estimated tensile strengths of GA3X steel at elevated temperatures are comparable to both 9Cr-1Mo and the modified 9Cr-1Mo steels. These preliminary results are encouraging in that they suggest that suitable low activation alloys can be successfully produced in this ferritic alloy class

The contact activation proteins: a structure/function overview

NARCIS (Netherlands)

Meijers, J. C.; McMullen, B. A.; Bouma, B. N.

1992-01-01

In recent years, extensive knowledge has been obtained on the structure/function relationships of blood coagulation proteins. In this overview, we present recent developments on the structure/function relationships of the contact activation proteins: factor XII, high molecular weight kininogen,

Antiproliferative terpenoids from almond hulls (Prunus dulcis): identification and structure-activity relationships.

Science.gov (United States)

Amico, Vincenzo; Barresi, Vincenza; Condorelli, Daniele; Spatafora, Carmela; Tringali, Corrado

2006-02-08

Bioassay-guided fractionation of the EtOAc crude extract from Sicilian almond hulls, a waste material from Prunus dulcis crop, allowed identification of 10 constituents, isolated as pure compounds (1-5, 7, and 10) or unseparable mixtures (5 + 6 and 8 + 9). All compounds were subjected to spectroscopic analysis and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide bioassay on MCF-7 human breast cancer cells. In addition to the main components oleanolic (1), ursolic (2), and betulinic (3) acids, the 2-hydroxy analogues alphitolic (4), corosolic (5), and maslinic (6) acids, as well as the related aldehydes, namely, betulinic (7), oleanolic (8), and ursolic (9), were identified. From a more polar fraction, the beta-sitosterol 3-O-glucoside (10) was also identified. A sample of commercially available betulin (11) was also included in bioassays as further support to a structure-activity relationship study. Betulinic acid showed antiproliferative activity toward MCF-7 cells (GI50 = 0.27 microM), higher than the anticancer drug 5-fluorouracil.

p53-independent structure-activity relationships of 3-ring mesogenic compounds' activity as cytotoxic effects against human non-small cell lung cancer lines.

Science.gov (United States)

Fukushi, Saori; Yoshino, Hironori; Yoshizawa, Atsushi; Kashiwakura, Ikuo

2016-07-25

We recently demonstrated the cytotoxicity of liquid crystal precursors (hereafter referred to as "mesogenic compounds") in the human non-small cell lung cancer (NSCLC) cell line A549 which carry wild-type p53. p53 mutations are observed in 50 % of NSCLC and contribute to their resistance to chemotherapy. To develop more effective and cancer-specific agents, in this study, we investigated the structure-activity relationships of mesogenic compounds with cytotoxic effects against multiple NSCLC cells. The pharmacological effects of mesogenic compounds were examined in human NSCLC cells (A549, LU99, EBC-1, and H1299) and normal WI-38 human fibroblast. Analyses of the cell cycle, cell-death induction, and capsases expression were performed. The 3-ring compounds possessing terminal alkyl and hydroxyl groups (compounds C1-C5) showed cytotoxicity in NSCLC cells regardless of the p53 status. The compounds C1 and C3, which possess a pyrimidine at the center of the core, induced G2/M arrest, while the compounds without a pyrimidine (C2, C4, and C5) caused G1 arrest; all compounds produced caspase-mediated cell death. These events occurred in a p53-independent manner. Furthermore, it was suggested that compounds induced cell death through p53-independent DNA damage-signaling pathway. Compounds C2, C4, and C5 did not show strong cytotoxicity in WI-38 cells, whereas C1 and C3 did. However, the cytotoxicity of compound C1 against WI-38 cells was improved by modulating the terminal alkyl chain lengths of the compound. We showed the p53-indepdent structure-activity relationships of mesogenic compounds related to the cytotoxic effects. These structure-activity relationships will be helpful in the development of more effective and cancer-specific agents.

Redox properties of structural Fe in clay minerals: 3. Relationships between smectite redox and structural properties.

Science.gov (United States)

Gorski, Christopher A; Klüpfel, Laura E; Voegelin, Andreas; Sander, Michael; Hofstetter, Thomas B

2013-01-01

Structural Fe in clay minerals is an important redox-active species in many pristine and contaminated environments as well as in engineered systems. Understanding the extent and kinetics of redox reactions involving Fe-bearing clay minerals has been challenging due to the inability to relate structural Fe(2+)/Fe(total) fractions to fundamental redox properties, such as reduction potentials (EH). Here, we overcame this challenge by using mediated electrochemical reduction (MER) and oxidation (MEO) to characterize the fraction of redox-active structural Fe (Fe(2+)/Fe(total)) in smectites over a wide range of applied EH-values (-0.6 V to +0.6 V). We examined Fe(2+)/Fe(total )- EH relationships of four natural Fe-bearing smectites (SWy-2, SWa-1, NAu-1, NAu-2) in their native, reduced, and reoxidized states and compared our measurements with spectroscopic observations and a suite of mineralogical properties. All smectites exhibited unique Fe(2+)/Fe(total) - EH relationships, were redox active over wide EH ranges, and underwent irreversible electron transfer induced structural changes that were observable with X-ray absorption spectroscopy. Variations among the smectite Fe(2+)/Fe(total) - EH relationships correlated well with both bulk and molecular-scale properties, including Fe(total) content, layer charge, and quadrupole splitting values, suggesting that multiple structural parameters determined the redox properties of smectites. The Fe(2+)/Fe(total) - EH relationships developed for these four commonly studied clay minerals may be applied to future studies interested in relating the extent of structural Fe reduction or oxidation to EH-values.

Synthesis and structure-activity relationship exploration of some potent anti-cancer phenyl amidrazone derivatives.

Science.gov (United States)

Habashneh, Almeqdad Y; El-Abadelah, Mustafa M; Bardaweel, Sanaa K; Taha, Mutasem O

2017-12-04

Amidrazones have been reported to have significant anti-tumor properties against several cancer cell lines. The current project aims to profile the structure-anticancer activity relationship of phenyl-amidrazons. Fifteen phenyl-amidrazone-piperazine derivatives were prepared and tested against four cancer cell lines (leukemia, prostate, breast and colon cancers). Six compounds illustrated low micromolar anticancer IC50 values, while the remaining compounds were either inactive or of moderate potencies. All compounds were virtually nontoxic against normal fibroblast cells. Docking into the oncogenic kinase bcr/abl illustrated the critical importance of (i) p-halogen substituent on the ligand's phenyl ring and (ii) the presence of positive ionizable moiety at the ligand's piperazine fragment for anticancer activity. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Structure-activity relationships and molecular docking of thirteen synthesized flavonoids as horseradish peroxidase inhibitors.

Science.gov (United States)

Mahfoudi, Reguia; Djeridane, Amar; Benarous, Khedidja; Gaydou, Emile M; Yousfi, Mohamed

2017-10-01

For the first time, the structure-activity relationships of thirteen synthesized flavonoids have been investigated by evaluating their ability to modulate horseradish peroxidase (HRP) catalytic activity. Indeed, a modified spectrophotometrically method was carried out and optimized using 4-methylcatechol (4-MC) as peroxidase co-substrate. The results show that these flavonoids exhibit a great capacity to inhibit peroxidase with Ki values ranged from 0.14±0.01 to 65±0.04mM. Molecular docking has been achieved using Auto Dock Vina program to discuss the nature of interactions and the mechanism of inhibition. According to the docking results, all the flavonoids have shown great binding affinity to peroxidase. These molecular modeling studies suggested that pyran-4-one cycle acts as an inhibition key for peroxidase. Therefore, potent peroxidase inhibitors are flavonoids with these structural requirements: the presence of the hydroxyl (OH) group in 7, 5 and 4' positions and the absence of the methoxy (O-CH 3 ) group. Apigenin contributed better in HRP inhibitory activity. The present study has shown that the studied flavonoids could be promising HRP inhibitors, which can help in developing new molecules to control thyroid diseases. Copyright © 2017 Elsevier Inc. All rights reserved.

Structure-activity relationships and prediction of the phototoxicity and phototoxic potential of new drugs.

Science.gov (United States)

Barratt, Martin D

2004-11-01

Relationships between the structure and properties of chemicals can be programmed into knowledge-based systems such as DEREK for Windows (DEREK is an acronym for "Deductive Estimation of Risk from Existing Knowledge"). The DEREK for Windows computer system contains a subset of over 60 rules describing chemical substructures (toxophores) responsible for skin sensitisation. As part of the European Phototox Project, the rule base was supplemented by a number of rules for the prospective identification of photoallergens, either by extension of the scope of existing rules or by the generation of new rules where a sound mechanistic rationale for the biological activity could be established. The scope of the rules for photoallergenicity was then further refined by assessment against a list of chemicals identified as photosensitisers by the Centro de Farmacovigilancia de la Comunidad Valenciana, Valencia, Spain. This paper contains an analysis of the mechanistic bases of activity for eight important groups of photoallergens and phototoxins, together with rules for the prospective identification of the photobiological activity of new or untested chemicals belonging to those classes. The mechanism of action of one additional chemical, nitrofurantoin, is well established; however, it was deemed inappropriate to write a rule on the basis of a single chemical structure.

Active Plasmonics: Principles, Structures, and Applications.

Science.gov (United States)

Jiang, Nina; Zhuo, Xiaolu; Wang, Jianfang

2018-03-28

Active plasmonics is a burgeoning and challenging subfield of plasmonics. It exploits the active control of surface plasmon resonance. In this review, a first-ever in-depth description of the theoretical relationship between surface plasmon resonance and its affecting factors, which forms the basis for active plasmon control, will be presented. Three categories of active plasmonic structures, consisting of plasmonic structures in tunable dielectric surroundings, plasmonic structures with tunable gap distances, and self-tunable plasmonic structures, will be proposed in terms of the modulation mechanism. The recent advances and current challenges for these three categories of active plasmonic structures will be discussed in detail. The flourishing development of active plasmonic structures opens access to new application fields. A significant part of this review will be devoted to the applications of active plasmonic structures in plasmonic sensing, tunable surface-enhanced Raman scattering, active plasmonic components, and electrochromic smart windows. This review will be concluded with a section on the future challenges and prospects for active plasmonics.

Structure-activity relationships of novel salicylaldehyde isonicotinoyl hydrazone (SIH analogs: iron chelation, anti-oxidant and cytotoxic properties.

Directory of Open Access Journals (Sweden)

Eliška Potůčková

Full Text Available Salicylaldehyde isonicotinoyl hydrazone (SIH is a lipophilic, tridentate iron chelator with marked anti-oxidant and modest cytotoxic activity against neoplastic cells. However, it has poor stability in an aqueous environment due to the rapid hydrolysis of its hydrazone bond. In this study, we synthesized a series of new SIH analogs (based on previously described aromatic ketones with improved hydrolytic stability. Their structure-activity relationships were assessed with respect to their stability in plasma, iron chelation efficacy, redox effects and cytotoxic activity against MCF-7 breast adenocarcinoma cells. Furthermore, studies assessed the cytotoxicity of these chelators and their ability to afford protection against hydrogen peroxide-induced oxidative injury in H9c2 cardiomyoblasts. The ligands with a reduced hydrazone bond, or the presence of bulky alkyl substituents near the hydrazone bond, showed severely limited biological activity. The introduction of a bromine substituent increased ligand-induced cytotoxicity to both cancer cells and H9c2 cardiomyoblasts. A similar effect was observed when the phenolic ring was exchanged with pyridine (i.e., changing the ligating site from O, N, O to N, N, O, which led to pro-oxidative effects. In contrast, compounds with long, flexible alkyl chains adjacent to the hydrazone bond exhibited specific cytotoxic effects against MCF-7 breast adenocarcinoma cells and low toxicity against H9c2 cardiomyoblasts. Hence, this study highlights important structure-activity relationships and provides insight into the further development of aroylhydrazone iron chelators with more potent and selective anti-neoplastic effects.

ICI 56,780 Optimization: Structure-Activity Relationship Studies of 7-(2-Phenoxyethoxy)-4(1H)-quinolones with Antimalarial Activity.

Science.gov (United States)

Maignan, Jordany R; Lichorowic, Cynthia L; Giarrusso, James; Blake, Lynn D; Casandra, Debora; Mutka, Tina S; LaCrue, Alexis N; Burrows, Jeremy N; Willis, Paul A; Kyle, Dennis E; Manetsch, Roman

2016-07-28

Though malaria mortality rates are down 48% globally since 2000, reported occurrences of resistance against current therapeutics threaten to reverse that progress. Recently, antimalarials that were once considered unsuitable therapeutic agents have been revisited to improve physicochemical properties and efficacy required for selection as a drug candidate. One such compound is 4(1H)-quinolone ICI 56,780, which is known to be a causal prophylactic that also displays blood schizonticidal activity against P. berghei. Rapid induction of parasite resistance, however, stalled its further development. We have completed a full structure-activity relationship study on 4(1H)-quinolones, focusing on the reduction of cross-resistance with atovaquone for activity against the clinical isolates W2 and TM90-C2B, as well as the improvement of microsomal stability. These studies revealed several frontrunner compounds with superb in vivo antimalarial activity. The best compounds were found to be curative with all mice surviving a Plasmodium berghei infection after 30 days.

Preliminary structure-activity relationship studies on some novel s ...

African Journals Online (AJOL)

yl)-1, 3, 4-oxadiazole-2-thiol were synthesized through reaction with different saturated and unsaturated ... inhibitor, while compound 5b with n-propyl substitution is a strong antibacterial agent. ... sulfonyl chloride (30 mmol) in 30 mL distilled.

α-Glucosidase inhibition by flavonoids: an in vitro and in silico structure-activity relationship study.

Science.gov (United States)

Proença, Carina; Freitas, Marisa; Ribeiro, Daniela; Oliveira, Eduardo F T; Sousa, Joana L C; Tomé, Sara M; Ramos, Maria J; Silva, Artur M S; Fernandes, Pedro A; Fernandes, Eduarda

2017-12-01

α-Glucosidase inhibitors are described as the most effective in reducing post-prandial hyperglycaemia (PPHG) from all available anti-diabetic drugs used in the management of type 2 diabetes mellitus. As flavonoids are promising modulators of this enzyme's activity, a panel of 44 flavonoids, organised in five groups, was screened for their inhibitory activity of α-glucosidase, based on in vitro structure-activity relationship studies. Inhibitory kinetic analysis and molecular docking calculations were also applied for selected compounds. A flavonoid with two catechol groups in A- and B-rings, together with a 3-OH group at C-ring, was the most active, presenting an IC 50 much lower than the one found for the most widely prescribed α-glucosidase inhibitor, acarbose. The present work suggests that several of the studied flavonoids have the potential to be used as alternatives for the regulation of PPHG.

Quantitative structure activity relationship (QSAR) of piperine analogs for bacterial NorA efflux pump inhibitors.

Science.gov (United States)

Nargotra, Amit; Sharma, Sujata; Koul, Jawahir Lal; Sangwan, Pyare Lal; Khan, Inshad Ali; Kumar, Ashwani; Taneja, Subhash Chander; Koul, Surrinder

2009-10-01

Quantitative structure activity relationship (QSAR) analysis of piperine analogs as inhibitors of efflux pump NorA from Staphylococcus aureus has been performed in order to obtain a highly accurate model enabling prediction of inhibition of S. aureus NorA of new chemical entities from natural sources as well as synthetic ones. Algorithm based on genetic function approximation method of variable selection in Cerius2 was used to generate the model. Among several types of descriptors viz., topological, spatial, thermodynamic, information content and E-state indices that were considered in generating the QSAR model, three descriptors such as partial negative surface area of the compounds, area of the molecular shadow in the XZ plane and heat of formation of the molecules resulted in a statistically significant model with r(2)=0.962 and cross-validation parameter q(2)=0.917. The validation of the QSAR models was done by cross-validation, leave-25%-out and external test set prediction. The theoretical approach indicates that the increase in the exposed partial negative surface area increases the inhibitory activity of the compound against NorA whereas the area of the molecular shadow in the XZ plane is inversely proportional to the inhibitory activity. This model also explains the relationship of the heat of formation of the compound with the inhibitory activity. The model is not only able to predict the activity of new compounds but also explains the important regions in the molecules in quantitative manner.

Antimalarial benzoheterocyclic 4-aminoquinolines: Structure-activity relationship, in vivo evaluation, mechanistic and bioactivation studies.

Science.gov (United States)

Ongarora, Dennis S B; Strydom, Natasha; Wicht, Kathryn; Njoroge, Mathew; Wiesner, Lubbe; Egan, Timothy J; Wittlin, Sergio; Jurva, Ulrik; Masimirembwa, Collen M; Chibale, Kelly

2015-09-01

A novel class of benzoheterocyclic analogues of amodiaquine designed to avoid toxic reactive metabolite formation was synthesized and evaluated for antiplasmodial activity against K1 (multidrug resistant) and NF54 (sensitive) strains of the malaria parasite Plasmodium falciparum. Structure-activity relationship studies led to the identification of highly promising analogues, the most potent of which had IC50s in the nanomolar range against both strains. The compounds further demonstrated good in vitro microsomal metabolic stability while those subjected to in vivo pharmacokinetic studies had desirable pharmacokinetic profiles. In vivo antimalarial efficacy in Plasmodium berghei infected mice was evaluated for four compounds, all of which showed good activity following oral administration. In particular, compound 19 completely cured treated mice at a low multiple dose of 4×10mg/kg. Mechanistic and bioactivation studies suggest hemozoin formation inhibition and a low likelihood of forming quinone-imine reactive metabolites, respectively. Copyright © 2015 Elsevier Ltd. All rights reserved.

Dihydro-β-agarofuran sesquiterpenes from celastraceae species as anti-tumour-promoting agents: Structure-activity relationship.

Science.gov (United States)

Núñez, Marvin J; Jiménez, Ignacio A; Mendoza, Cristina R; Chavez-Sifontes, Marvin; Martinez, Morena L; Ichiishi, Eiichiro; Tokuda, Ryo; Tokuda, Harukuni; Bazzocchi, Isabel L

2016-03-23

Inhibition of tumour promotion in multistage chemical carcinogenesis is considered a promising strategy for cancer chemoprevention. In an ongoing investigation of bioactive secondary metabolites from Celastraceae species, five new dihydro-β-agarofuran sesquiterpenes (1-5), named Chiapens A-E, and seventeen known ones, were isolated from Maytenus chiapensis. Their structures were elucidated by extensive NMR spectroscopic and mass spectrometric techniques, and their absolute configurations were determined by circular dichroism studies, chemical correlations and biogenic means. The isolated compounds, along with twenty known sesquiterpenes, previously isolated from Zinowiewia costaricensis, have been tested for their inhibitory effects on Epstein-Barr virus early antigen (EBV-EA) activation induced by 12-O-tetradecanoylphorpol-13-acetate (TPA). Thirty three compounds from this series showed stronger effects than that of β-carotene, the reference inhibitor. The structure-activity relationship (SAR) analysis revealed that the type of substituent, in particular at the C-1 position of the sesquiterpene scaffold, was able to modulate the anti-tumour promoting activity. Compounds 3, 6, and 33 showed significant effects in an in vivo two-stage mouse-skin carcinogenesis model. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Identification of Lilial as a fragrance sensitizer in a perfume by bioassay-guided chemical fractionation and structure-activity relationships.

Science.gov (United States)

Arnau, E G; Andersen, K E; Bruze, M; Frosch, P J; Johansen, J D; Menné, T; Rastogi, S C; White, I R; Lepoittevin, J P

2000-12-01

Fragrance materials are among the most common causes of allergic contact dermatitis. The aim of this study was to identify in a perfume fragrance allergens not included in the fragrance mix, by use of bioassay-guided chemical fractionation and chemical analysis/structure-activity relationships (SARs). The basis for the investigation was a 45-year-old woman allergic to her own perfume. She had a negative patch test to the fragrance mix and agreed to participate in the study. Chemical fractionation of the perfume concentrate was used for repeated patch testing and/or repeated open application test on the pre-sensitized patient. The chemical composition of the fractions giving a positive patch-test response and repeated open application test reactions was obtained by gas chromatography-mass spectrometry. From the compounds identified, those that contained a "structural alert" in their chemical structure, indicating an ability to modify skin proteins and thus behave as a skin sensitizer, were tested on the patient. The patient reacted positively to the synthetic fragrance p-t-butyl-alpha-methylhydrocinnamic aldehyde (Lilial), a widely used fragrance compound not present in the fragrance mix. The combination of bioassay-guided chemical fractionation and chemical analysis/structure-activity relationships seems to be a valuable tool for the investigation of contact allergy to fragrance materials.

PLS-based quantitative structure-activity relationship for substituted benzamides of clebopride type. Application of experimental design in drug design.

Science.gov (United States)

Norinder, U; Högberg, T

1992-04-01

The advantageous approach of using an experimentally designed training set as the basis for establishing a quantitative structure-activity relationship with good predictive capability is described. The training set was selected from a fractional factorial design scheme based on a principal component description of physico-chemical parameters of aromatic substituents. The derived model successfully predicts the activities of additional substituted benzamides of 6-methoxy-N-(4-piperidyl)salicylamide type. The major influence on activity of the 3-substituent is demonstrated.

Biosynthetically Guided Structure-Activity Relationship Studies of Merochlorin A, an Antibiotic Marine Natural Product.

Science.gov (United States)

López-Pérez, Borja; Pepper, Henry P; Ma, Rong; Fawcett, Benjamin J; Pehere, Ashok D; Wei, Qi; Ji, Zengchun; Polyak, Steven W; Dai, Huanqin; Song, Fuhang; Abell, Andrew D; Zhang, Lixin; George, Jonathan H

2017-12-07

The onset of new multidrug-resistant strains of bacteria demands continuous development of antibacterial agents with new chemical scaffolds and mechanisms of action. We present the first structure-activity relationship (SAR) study of 16 derivatives of a structurally novel antibiotic merochlorin A that were designed using a biosynthetic blueprint. Our lead compounds are active against several Gram-positive bacteria such as Staphylococcus aureus (SA), methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus faecium (VRE) and Bacillus subtilis, inhibit intracellular growth of Mycobacterium bovis, and are relatively nontoxic to human cell lines. Furthermore, derivative 12 c {(±)-(3aR,4S,5R,10bS)-5-bromo-7,9-dimethoxy-4-methyl-4-(4-methylpent-3-en-1-yl)-2-(propan-2-ylidene)-1,2,3,3a,4,5-hexahydro-6H-5,10b-methanobenzo[e]azulene-6,11-dione} was found to inhibit the growth of Bacillus Calmette-Guérin (BCG)-infected cells at concentrations similar to rifampicin. These results outperform the natural product, underscoring the potential of merochlorin analogues as a new class of antibiotics. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Relationship structure-antioxidant activity of hindered phenolic compounds

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Weng, X. C.

2014-12-01

Full Text Available The relationship between the structure and the antioxidant activity of 21 hindered phenolic compounds was investigated by Rancimat and DPPH· tests. 3-tert-butyl-5-methylbenzene-1,2-diol is the strongest antioxidant in the Rancimat test but not in the DPPH· test because its two hydroxyl groups have very strong steric synergy. 2,6-Ditert-butyl-4-hydroxy-methylphenol exhibits a strong antioxidant activity as 2,6-ditertbutyl- 4-methoxyphenol does in lard. 2,6-Ditert-butyl-4- hydroxy-methylphenol also exhibits stronger activity than 2-tert-butyl-4- methoxyphenol. The methylene of 2,6-ditert-butyl-4-hydroxy-methylphenol can provide a hydrogen atom to active free radicals like a phenolic hydroxyl group does because it is greatly activated by both the aromatic ring and hydroxyl group. Five factors affect the antioxidant activities of the phenolic compounds: how stable the phenolic compound free radicals are after providing hydrogen atoms; how many hy drogen atoms each of the phenolic compounds can provide; how fast the phenolic compounds provide hydrogen atoms; how easily the phenolic compound free radicals can combine with more active free radicals, and whether or not a new antioxidant can form after the phenolic compound provides hydrogen atoms.La relación entre estructura y la actividad antioxidante de 21 compuestos fenólicos con impedimentos estéricos fue investigado mediante ensayos con Rancimat y DPPH·. El 3-terc-butil-5-metilbenceno-1,2-diol es el antioxidante más potente en los ensayos mediante Rancimat pero no mediante ensayos con DPPH·, porque sus dos grupos hidroxilo tienen una fuerte sinergia estérica. El 2,6-Di-terc-butil-4-hidroxi-metil-fenol mostró una actividad antioxidante tan fuerte como el 2,6-di-ter-butil-4-metoxifenol en ensayos con manteca de cerdo. El 2,6-di-terc-butil-4-hidroxi-metilfenol también mostró una actividad más fuerte que el 2-terc-butil-4-metoxifenol. El grupo metileno del 2,6-di-ter-butil-4-hidroxi

Structure-activity relationship analysis of cytotoxic cyanoguanidines: selection of CHS 828 as candidate drug

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Gullbo Joachim

2009-06-01

ten cell lines were compared. Substances with similar structures correlated well, whilst substances with large differences in molecular structure demonstrated lower correlation coefficients. Conclusion According to this structure-activity relationship (SAR study, CHS 828 meets the requirements for optimal cytotoxic activity for this class of compounds.

Scalable total synthesis and comprehensive structure-activity relationship studies of the phytotoxin coronatine.

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Littleson, Mairi M; Baker, Christopher M; Dalençon, Anne J; Frye, Elizabeth C; Jamieson, Craig; Kennedy, Alan R; Ling, Kenneth B; McLachlan, Matthew M; Montgomery, Mark G; Russell, Claire J; Watson, Allan J B

2018-03-16

Natural phytotoxins are valuable starting points for agrochemical design. Acting as a jasmonate agonist, coronatine represents an attractive herbicidal lead with novel mode of action, and has been an important synthetic target for agrochemical development. However, both restricted access to quantities of coronatine and a lack of a suitably scalable and flexible synthetic approach to its constituent natural product components, coronafacic and coronamic acids, has frustrated development of this target. Here, we report gram-scale production of coronafacic acid that allows a comprehensive structure-activity relationship study of this target. Biological assessment of a >120 member library combined with computational studies have revealed the key determinants of potency, rationalising hypotheses held for decades, and allowing future rational design of new herbicidal leads based on this template.

Structure-transfection activity relationships in a series of novel cationic lipids with heterocyclic head-groups.

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Ivanova, Ekaterina A; Maslov, Mikhail A; Kabilova, Tatyana O; Puchkov, Pavel A; Alekseeva, Anna S; Boldyrev, Ivan A; Vlassov, Valentin V; Serebrennikova, Galina A; Morozova, Nina G; Zenkova, Marina A

2013-11-07

Cationic liposomes are promising candidates for the delivery of various therapeutic nucleic acids. Here, we report a convenient synthesis of carbamate-type cationic lipids with various hydrophobic domains (tetradecanol, dialkylglycerol, cholesterol) and positively charged head-groups (pyridinium, N-methylimidazolium, N-methylmorpholinium) and data on the structure-transfection activity relationships. It was found that single-chain lipids possess high surface activity, which correlates with high cytotoxicity due to their ability to disrupt the cellular membrane by combined hydrophobic and electrostatic interactions. Liposomes containing these lipids also display high cytotoxicity with respect to all cell lines. Irrespective of chemical structures, all cationic lipids form liposomes with similar sizes and surface potentials. The characteristics of complexes composed of cationic liposomes and nucleic acids depend mostly on the type of nucleic acid and P/N ratios. In the case of oligodeoxyribonucleotide delivery, the transfection activity depends on the type of cationic head-group regardless of the type of hydrophobic domain: all types of cationic liposomes mediate efficient oligonucleotide transfer into 80-90% of the eukaryotic cells, and liposomes based on lipids with N-methylmorpholinium cationic head-group display the highest transfection activity. In the case of plasmid DNA and siRNA, the type of hydrophobic domain determines the transfection activity: liposomes composed of cholesterol-based lipids were the most efficient in DNA transfer, while liposomes containing glycerol-based lipids exhibited reasonable activity in siRNA delivery under serum-free conditions.

Structure-activity relationships of an antimicrobial peptide plantaricin s from two-peptide class IIb bacteriocins.

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Soliman, Wael; Wang, Liru; Bhattacharjee, Subir; Kaur, Kamaljit

2011-04-14

Class IIb bacteriocins are ribosomally synthesized antimicrobial peptides comprising two different peptides synergistically acting in equal amounts for optimal potency. In this study, we demonstrate for the first time potent (nanomolar) antimicrobial activity of a representative class IIb bacteriocin, plantaricin S (Pls), against four pathogenic gram-positive bacteria, including Listeria monocytogenes. The structure-activity relationships for Pls were studied using activity assays, circular dichroism (CD), and molecular dynamics (MD) simulations. The two Pls peptides and five Pls derived fragments were synthesized. The CD spectra of the Pls and selected fragments revealed helical conformations in aqueous 2,2,2-trifluoroethanol. The MD simulations showed that when the two Pls peptides are in antiparallel orientation, the helical regions interact and align, mediated by strong attraction between conserved GxxxG/AxxxA motifs. The results strongly correlate with the antimicrobial activity suggesting that helix-helix alignment of the two Pls peptides and interaction between the conserved motifs are crucial for interaction with the target cell membrane.

Social Relationships, Leisure Activity, and Health in Older Adults

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Chang, Po-Ju; Wray, Linda; Lin, Yeqiang

2015-01-01

Objective Although the link between enhanced social relationships and better health has generally been well established, few studies have examined the role of leisure activity in this link. This study examined how leisure influences the link between social relationships and health in older age. Methods Using data from the 2006 and 2010 waves of the nationally representative U.S. Health and Retirement Study and structural equation modelling analyses, we examined data on 2,965 older participants to determine if leisure activities mediated the link between social relationships and health in 2010, controlling for race, education level, and health in 2006. Results The results demonstrated that leisure activities mediate the link between social relationships and health in these age groups. Perceptions of positive social relationships were associated with greater involvement in leisure activities, and greater involvement in leisure activities was associated with better health in older age. Discussion & Conclusions The contribution of leisure to health in these age groups is receiving increasing attention, and the results of this study add to the literature on this topic, by identifying the mediating effect of leisure activity on the link between social relationships and health. Future studies aimed at increasing leisure activity may contribute to improved health outcomes in older adults. PMID:24884905

Social relationships, leisure activity, and health in older adults.

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Chang, Po-Ju; Wray, Linda; Lin, Yeqiang

2014-06-01

Although the link between enhanced social relationships and better health has generally been well established, few studies have examined the role of leisure activity in this link. This study examined how leisure influences the link between social relationships and health in older age. Using data from the 2006 and 2010 waves of the nationally representative U.S. Health and Retirement Study and structural equation modeling analyses, we examined data on 2,965 older participants to determine if leisure activities mediated the link between social relationships and health in 2010, controlling for race, education level, and health in 2006. The results demonstrated that leisure activities mediate the link between social relationships and health in these age groups. Perceptions of positive social relationships were associated with greater involvement in leisure activities, and greater involvement in leisure activities was associated with better health in older age. The contribution of leisure to health in these age groups is receiving increasing attention, and the results of this study add to the literature on this topic, by identifying the mediating effect of leisure activity on the link between social relationships and health. Future studies aimed at increasing leisure activity may contribute to improved health outcomes in older adults. PsycINFO Database Record (c) 2014 APA, all rights reserved.

Synthesis, structure-activity relationship, and pharmacological profile of analogs of the ASIC-3 inhibitor A-317567.

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Kuduk, Scott D; Di Marco, Christina N; Bodmer-Narkevitch, Vera; Cook, Sean P; Cato, Matthew J; Jovanovska, Aneta; Urban, Mark O; Leitl, Michael; Sain, Nova; Liang, Annie; Spencer, Robert H; Kane, Stefanie A; Hartman, George D; Bilodeau, Mark T

2010-01-20

The synthesis, structure-activity relationship (SAR), and pharmacological evaluation of analogs of the acid-sensing ion channel (ASIC) inhibitor A-317567 are reported. It was found that the compound with an acetylenic linkage was the most potent ASIC-3 channel blocker. This compound reversed mechanical hypersensitivity in the rat iodoacetate model of osteoarthritis pain, although sedation was noted. Sedation was also observed in ASIC-3 knockout mice, questioning whether sedation and antinociception are mediated via a non-ASIC-3 specific mechanism.

Synthesis and structure-activity relationship of N-alkyl Gly-boro-Pro inhibitors of DPP4, FAP, and DPP7.

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Hu, Yi; Ma, Lifu; Wu, Min; Wong, Melissa S; Li, Bei; Corral, Sergio; Yu, Zhizhou; Nomanbhoy, Tyzoon; Alemayehu, Senaiet; Fuller, Stacy R; Rosenblum, Jonathan S; Rozenkrants, Natasha; Minimo, Lauro C; Ripka, William C; Szardenings, Anna K; Kozarich, John W; Shreder, Kevin R

2005-10-01

The structure-activity relationship of various N-alkyl Gly-boro-Pro derivatives against three dipeptidyl peptidases (DPPs) was studied. In a series of N-cycloalkyl analogs, DPP4 and fibroblast activation protein-alpha (FAP) optimally preferred N-cycloheptyl whereas DPP7 tolerated even larger cycloalkyl rings. Gly alpha-carbon derivatization of N-cyclohexyl or N-(2-adamantyl) Gly-boro-Pro resulted in a significant decrease in potency against all the three DPPs.

The synthesis, structure-toxicity relationship of cisplatin derivatives for the mechanism research of cisplatin-induced nephrotoxicity.

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Hu, Jing; Wu, Tian-Ming; Li, Hong-Ze; Zuo, Ze-Ping; Zhao, Ying-Lan; Yang, Li

2017-08-01

Cisplatin is a widely used antineoplastic drug, while its nephrotoxicity limits the clinical application. Although several mechanisms contributing to nephrotoxicity have been reported, the direct protein targets are unclear. Herein we reported the synthesis of 29 cisplatin derivatives and the structure-toxicity relationship (STR) of these compounds with MTT assay in human renal proximal tubule cells (HK-2) and pig kidney epithelial cells (LLC-PK1). To the best of our knowledge, this study represented the first report regarding the structure-toxicity relationship (STR) of cisplatin derivatives. The potency of biotin-pyridine conjugated derivative 3 met the requirement for target identification, and the preliminary chemical proteomics results suggested that it is a promising tool for further target identification of cisplatin-induced nephrotoxicity. Copyright © 2017. Published by Elsevier Ltd.

Structure-activity relationship study of oxindole-based inhibitors of cyclin-dependent kinases based on least-squares support vector machines

International Nuclear Information System (INIS)

Li Jiazhong; Liu Huanxiang; Yao Xiaojun; Liu Mancang; Hu Zhide; Fan Botao

2007-01-01

The least-squares support vector machines (LS-SVMs), as an effective modified algorithm of support vector machine, was used to build structure-activity relationship (SAR) models to classify the oxindole-based inhibitors of cyclin-dependent kinases (CDKs) based on their activity. Each compound was depicted by the structural descriptors that encode constitutional, topological, geometrical, electrostatic and quantum-chemical features. The forward-step-wise linear discriminate analysis method was used to search the descriptor space and select the structural descriptors responsible for activity. The linear discriminant analysis (LDA) and nonlinear LS-SVMs method were employed to build classification models, and the best results were obtained by the LS-SVMs method with prediction accuracy of 100% on the test set and 90.91% for CDK1 and CDK2, respectively, as well as that of LDA models 95.45% and 86.36%. This paper provides an effective method to screen CDKs inhibitors

Three-dimensional quantitative structure-activity relationships and docking studies of some structurally diverse flavonoids and design of new aldose reductase inhibitors

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Utpal Chandra De

2015-01-01

Full Text Available Aldose reductase (AR plays an important role in the development of several long-term diabetic complications. Inhibition of AR activities is a strategy for controlling complications arising from chronic diabetes. Several AR inhibitors have been reported in the literature. Flavonoid type compounds are shown to have significant AR inhibition. The objective of this study was to perform a computational work to get an idea about structural insight of flavonoid type compounds for developing as well as for searching new flavonoid based AR inhibitors. The data-set comprising 68 flavones along with their pIC 50 values ranging from 0.44 to 4.59 have been collected from literature. Structure of all the flavonoids were drawn in Chembiodraw Ultra 11.0, converted into corresponding three-dimensional structure, saved as mole file and then imported to maestro project table. Imported ligands were prepared using LigPrep option of maestro 9.6 version. Three-dimensional quantitative structure-activity relationships and docking studies were performed with appropriate options of maestro 9.6 version installed in HP Z820 workstation with CentOS 6.3 (Linux. A model with partial least squares factor 5, standard deviation 0.2482, R 2 = 0.9502 and variance ratio of regression 122 has been found as the best statistical model.

QUANTITATIVE ELECTRONIC STRUCTURE - ACTIVITY RELATIONSHIP OF ANTIMALARIAL COMPOUND OF ARTEMISININ DERIVATIVES USING PRINCIPAL COMPONENT REGRESSION APPROACH

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Paul Robert Martin Werfette

2010-06-01

Full Text Available Analysis of quantitative structure - activity relationship (QSAR for a series of antimalarial compound artemisinin derivatives has been done using principal component regression. The descriptors for QSAR study were representation of electronic structure i.e. atomic net charges of the artemisinin skeleton calculated by AM1 semi-empirical method. The antimalarial activity of the compound was expressed in log 1/IC50 which is an experimental data. The main purpose of the principal component analysis approach is to transform a large data set of atomic net charges to simplify into a data set which known as latent variables. The best QSAR equation to analyze of log 1/IC50 can be obtained from the regression method as a linear function of several latent variables i.e. x1, x2, x3, x4 and x5. The best QSAR model is expressed in the following equation,  (;;   Keywords: QSAR, antimalarial, artemisinin, principal component regression

Preliminary Structure-Activity Relationship on Theonellasterol, a New Chemotype of FXR Antagonist, from the Marine Sponge Theonella swinhoei

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Stefano Fiorucci

2012-11-01

Full Text Available Using theonellasterol as a novel FXR antagonist hit, we prepared a series of semi-synthetic derivatives in order to gain insight into the structural requirements for exhibiting antagonistic activity. These derivatives are characterized by modification at the exocyclic carbon-carbon double bond at C-4 and at the hydroxyl group at C-3 and were prepared from theonellasterol using simple reactions. Pharmacological investigation showed that the introduction of a hydroxyl group at C-4 as well as the oxidation at C-3 with or without concomitant modification at the exomethylene functionality preserve the ability of theonellasterol to inhibit FXR transactivation caused by CDCA. Docking analysis showed that the placement of these molecules in the FXR-LBD is well stabilized when on ring A functional groups, able to form hydrogen bonds and π interactions, are present.

Synthesis and structure-activity relationship of α-keto amides as enterovirus 71 3C protease inhibitors.

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Zeng, Debin; Ma, Yuying; Zhang, Rui; Nie, Quandeng; Cui, Zhengjie; Wang, Yaxin; Shang, Luqing; Yin, Zheng

2016-04-01

α-Keto amide derivatives as enterovirus 71 (EV71) 3C protease (3C(pro)) inhibitors have been synthesized and assayed for their biochemical and antiviral activities. structure-activity relationship (SAR) study indicated that small moieties were primarily tolerated at P1' and the introduction of para-fluoro benzyl at P2 notably improved the potency of inhibitor. Inhibitors 8v, 8w and 8x exhibited satisfactory activity (IC50=1.32±0.26μM, 1.88±0.35μM and 1.52±0.31μM, respectively) and favorable CC50 values (CC50>100μM). α-Keto amide may represent a good choice as a warhead for EV71 3C(pro) inhibitor. Copyright © 2016 Elsevier Ltd. All rights reserved.

Isolation of Insecticidal Constituent from Ruta graveolens and Structure-Activity Relationship Studies against Stored-Food Pests (Coleoptera).

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Jeon, Ju-Hyun; Lee, Sang-Guei; Lee, Hoi-Seon

2015-08-01

Isolates from essential oil extracted from the flowers and leaves of Ruta graveolens and commercial phenolic analogs were evaluated using fumigant and contact toxicity bioassays against adults of the stored-food pests Sitophilus zeamais, Sitophilus oryzae, and Lasioderma serricorne. The insecticidal activity of these compounds was then compared with that of the synthetic insecticide dichlorvos. To investigate the structure-activity relationships, the activity of 2-isopropyl-5-methylphenol and its analogs was examined against these stored-food pests. Based on the 50% lethal dose, the most toxic compound against S. zeamais was 3-isopropylephenol, followed by 2-isopropylphenol, 4-isopropylphenol, 5-isopropyl-2-methylphenol, 2-isopropyl-5-methylphenol, 3-methylphenol, and 2-methylphenol. Similar results were observed with phenolic compounds against S. oryzae. However, when 2-isopropyl-5-methylphenol isolated from R. graveolens oil and its structurally related analogs were used against L. serricorne, little or no insecticidal activity was found regardless of bioassay. These results indicate that introducing and changing the positions of functional groups in the phenol skeleton have an important effect on insecticidal activity of these compounds against stored-food pests.

Quantitative structure-activity relationships for green algae growth inhibition by polymer particles.

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Nolte, Tom M; Peijnenburg, Willie J G M; Hendriks, A Jan; van de Meent, Dik

2017-07-01

After use and disposal of chemical products, many types of polymer particles end up in the aquatic environment with potential toxic effects to primary producers like green algae. In this study, we have developed Quantitative Structure-Activity Relationships (QSARs) for a set of highly structural diverse polymers which are capable to estimate green algae growth inhibition (EC50). The model (N = 43, R 2  = 0.73, RMSE = 0.28) is a regression-based decision tree using one structural descriptor for each of three polymer classes separated based on charge. The QSAR is applicable to linear homo polymers as well as copolymers and does not require information on the size of the polymer particle or underlying core material. Highly branched polymers, non-nitrogen cationic polymers and polymeric surfactants are not included in the model and thus cannot be evaluated. The model works best for cationic and non-ionic polymers for which cellular adsorption, disruption of the cell wall and photosynthesis inhibition were the mechanisms of action. For anionic polymers, specific properties of the polymer and test characteristics need to be known for detailed assessment. The data and QSAR results for anionic polymers, when combined with molecular dynamics simulations indicated that nutrient depletion is likely the dominant mode of toxicity. Nutrient depletion in turn, is determined by the non-linear interplay between polymer charge density and backbone flexibility. Copyright © 2017 Elsevier Ltd. All rights reserved.

Rational design, synthesis, biologic evaluation, and structure-activity relationship studies of novel 1-indanone alpha(1)-adrenoceptor antagonists.

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Li, Minyong; Xia, Lin

2007-11-01

In the present report, a novel series of 1-indanone alpha(1)-adrenoceptor antagonists were designed and synthesized based on 3D-pharmacophore model. Their in vitro alpha(1)-adrenoceptor antagonistic assay showed that three compounds (2a, 2m, and 2o) had similar or improved alpha(1)-adrenoceptor antagonistic activities relative to the positive control prazosin. Based on these results, a three-dimensional quantitative structure-activity relationship study was performed using a Self-Organizing Molecular Field Analysis method to provide insight for the future development of alpha(1)-adrenoceptor antagonists.

Structure-activity relationship of pentacylic triterpene esters from Uncaria rhynchophylla as inhibitors of phospholipase Cgamma1.

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Lee, Ji Suk; Yoo, Hunseung; Suh, Young Ger; Jung, Jae Kyung; Kim, Jinwoong

2008-10-01

A systematic structure-activity relationship of 3beta-hydroxy-27- P- E-coumaroyloxyurs-12-en-28-oic acid ( 7), a triterpene ester isolated from UNCARIA RHYNCHOPHYLLA as a phospholipase Cgamma1 inhibitor, was undertaken with a view toward elucidating its chemical mode of action on PLCgamma1. Related derivatives and analogues of 7 were synthesized and their inhibitory activities against PLCgamma1 were evaluated IN VITRO. The results indicate that 3-OH and 27-esterification may be essential, and that 28-COOH and the 2' double bond appear to be important for activity. Furthermore, the compound possessing a P-coumaroyloxy at position 27 rather than at the 3 and 28 positions shows the greatest inhibitory activity against PLCgamma1. Therefore, this inhibitor will be providing a chemical lead for the further development of cancer chemopreventive or cancer chemotherapeutic agents that have lower toxicity against normal tissues.

A Structure-Activity Relationship (SAR Study of Neolignan Compounds with Anti-schistosomiasis Activity

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Alves Claúdio N.

2002-01-01

Full Text Available A set of eighteen neolignan derivative compounds with anti-schistosomiasis activity was studied by using the quantum mechanical semi-empirical method PM3 and other theoretical methods in order to calculate selected molecular properties (variables or descriptors to be correlated to their biological activities. Exploratory data analysis (principal component analysis, PCA, and hierarchical cluster analysis, HCA, discriminant analysis (DA and the Kth nearest neighbor (KNN method were employed for obtaining possible relationships between the calculated descriptors and the biological activities studied and predicting the anti-schistosomiasis activity of new compounds from a test set. The molecular descriptors responsible for the separation between active and inactive compounds were: hydration energy (HE, molecular refractivity (MR and charge on the C19 carbon atom (Q19. These descriptors give information on the kind of interaction that can occur between the compounds and their respective biological receptor. The prediction study was done with a new set of ten derivative compounds by using the PCA, HCA, DA and KNN methods and only five of them were predicted as active against schistosomiasis.

Distributing Correlation Coefficients of Linear Structure-Activity/Property Models

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Sorana D. BOLBOACA

2011-12-01

Full Text Available Quantitative structure-activity/property relationships are mathematical relationships linking chemical structure and activity/property in a quantitative manner. These in silico approaches are frequently used to reduce animal testing and risk-assessment, as well as to increase time- and cost-effectiveness in characterization and identification of active compounds. The aim of our study was to investigate the pattern of correlation coefficients distribution associated to simple linear relationships linking the compounds structure with their activities. A set of the most common ordnance compounds found at naval facilities with a limited data set with a range of toxicities on aquatic ecosystem and a set of seven properties was studied. Statistically significant models were selected and investigated. The probability density function of the correlation coefficients was investigated using a series of possible continuous distribution laws. Almost 48% of the correlation coefficients proved fit Beta distribution, 40% fit Generalized Pareto distribution, and 12% fit Pert distribution.

Structure-activity relationships of mononuclear metal-thiosemicarbazone complexes endowed with potent antiplasmodial and antiamoebic activities.

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Bahl, Deepa; Athar, Fareeda; Soares, Milena Botelho Pereira; de Sá, Matheus Santos; Moreira, Diogo Rodrigo Magalhães; Srivastava, Rajendra Mohan; Leite, Ana Cristina Lima; Azam, Amir

2010-09-15

A useful concept for the rational design of antiparasitic drug candidates is the complexation of bioactive ligands with transition metals. In view of this, an investigation was conducted into a new set of metal complexes as potential antiplasmodium and antiamoebic agents, in order to examine the importance of metallic atoms, as well as the kind of sphere of co-ordination, in these biological properties. Four functionalized furyl-thiosemicarbazones (NT1-4) treated with divalent metals (Cu, Co, Pt, and Pd) to form the mononuclear metallic complexes of formula [M(L)2Cl2] or [M(L)Cl2] were examined. The pharmacological characterization, including assays against Plasmodium falciparum and Entamoeba histolytica, cytotoxicity to mammalian cells, and interaction with pBR 322 plasmid DNA was performed. Structure-activity relationship data revealed that the metallic complexation plays an essential role in antiprotozoal activity, rather than the simple presence of the ligand or metal alone. Important steps towards identification of novel antiplasmodium (NT1Cu, IC50 of 4.6 microM) and antiamoebic (NT2Pd, IC50 of 0.6 microM) drug prototypes were achieved. Of particular relevance to this work, these prototypes were able to reduce the proliferation of these parasites at concentrations that are not cytotoxic to mammalian cells. Copyright (c) 2010. Published by Elsevier Ltd.

Attraction Pheromone of The Benthic Diatom Seminavis robusta: Studies on Structure-Activity Relationships.

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Lembke, Christine; Stettin, Daniel; Speck, Franziska; Ueberschaar, Nico; De Decker, Sam; Vyverman, Wim; Pohnert, Georg

2018-04-01

Recently the first pheromone of a marine diatom was identified to be the diketopiperazine (S,S)-diproline. This compound facilitates attraction between mating partners in the benthic diatom Seminavis robusta. Interestingly, sexualized S. robusta cells are attracted to both the natural pheromone (S,S)-diproline as well as to its enantiomer (R,R)-diproline. Usually stereospecificity is a prerequisite for successful substrate-receptor interactions, and especially pheromone perception is often highly enantioselective. Here we introduce a structure-activity relationship study, to learn more about the principles of pheromone reception in diatoms. We analyzed the activity of nine different diketopiperazines in attraction and interference assays. The pheromone diproline itself, as well as a pipecolic acid derived diketopiperazine with two expanded aliphatic ring systems, showed the highest attractivity. Hydroxylatoin of the aliphatic rings abolished any bioactivity. Diketopiperazines derived from acyclic amino acids were not attrative as well. All stereoisomers of both the diproline and the pipecolic acid derived diketopiperazine were purified by enantioselective high-performance liquid chromatography, and application in bioactivity tests confirmed that attraction pheromone perception in this diatom is indeed not stereospecific. However, the lack of activity of diketopiperazines derived from acyclic amino acids suggests a specificity that prevents misguidance to sources of other naturally occurring diketopiperazines.

Quantitative structure carcinogenicity relationship for detecting structural alerts in nitroso-compounds

International Nuclear Information System (INIS)

Helguera, Aliuska Morales; Cordeiro, M. Natalia D.S.; Perez, Miguel Angel Cabrera; Combes, Robert D.; Gonzalez, Maykel Perez

2008-01-01

In this work, Quantitative Structure-Activity Relationship (QSAR) modelling was used as a tool for predicting the carcinogenic potency of a set of 39 nitroso-compounds, which have been bioassayed in male rats by using the oral route of administration. The optimum QSAR model provided evidence of good fit and performance of predicitivity from training set. It was able to account for about 84% of the variance in the experimental activity and exhibited high values of the determination coefficients of cross validations, leave one out and bootstrapping (q 2 LOO = 78.53 and q 2 Boot = 74.97). Such a model was based on spectral moments weighted with Gasteiger-Marsilli atomic charges, polarizability and hydrophobicity, as well as with Abraham indexes, specifically the summation solute hydrogen bond basicity and the combined dipolarity/polarizability. This is the first study to have explored the possibility of combining Abraham solute descriptors with spectral moments. A reasonable interpretation of these molecular descriptors from a toxicological point of view was achieved by means of taking into account bond contributions. The set of relationships so derived revealed the importance of the length of the alkyl chains for determining carcinogenic potential of the chemicals analysed, and were able to explain the difference between mono-substituted and di-substituted nitrosoureas as well as to discriminate between isomeric structures with hydroxyl-alkyl and alkyl substituents in different positions. Moreover, they allowed the recognition of structural alerts in classical structures of two potent nitrosamines, consistent with their biotransformation. These results indicate that this new approach has the potential for improving carcinogenicity predictions based on the identification of structural alerts

Structural investigations of biogenic iron oxide samples. Preliminary results

International Nuclear Information System (INIS)

Balasoiu, M.; Kuklin, A.I.; Orelovich, O.L.; Kovalev, Yu.S.; Arzumanyan, G.M.; Kurkin, T.S.; Stolyar, S.V.; Iskhakov, R.S.; Rajkher, Yu.L.

2008-01-01

Some preliminary results on morphology and structure of iron oxide particles formed inside Klebsiella oxytoca bacteria are presented. In particular, by means of optical microscopy, scanning electron microscopy and small-angle X-ray scattering the effect of the bacteria age (the duration of growth) on the nanoparticles properties is studied

GirlPOWER! Strengthening Mentoring Relationships through a Structured, Gender-Specific Program

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Pryce, Julia M.; Silverthorn, Naida; Sanchez, Bernadette; DuBois, David L.

2010-01-01

The authors examine GirlPOWER! an innovative program that uses structure and group-based activities to enhance one-to-one mentoring relationships for young adolescent girls from the perspective of the focus, purpose, and authorship dimensions of mentoring relationships that Karcher and Nakkula described. The discussion draws on several sources of…

Molecular characterization of the receptor binding structure-activity relationships of influenza B virus hemagglutinin.

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Carbone, V; Kim, H; Huang, J X; Baker, M A; Ong, C; Cooper, M A; Li, J; Rockman, S; Velkov, T

2013-01-01

Selectivity of α2,6-linked human-like receptors by B hemagglutinin (HA) is yet to be fully understood. This study integrates binding data with structure-recognition models to examine the impact of regional-specific sequence variations within the receptor-binding pocket on selectivity and structure activity relationships (SAR). The receptor-binding selectivity of influenza B HAs corresponding to either B/Victoria/2/1987 or the B/Yamagata/16/88 lineages was examined using surface plasmon resonance, solid-phase ELISA and gel-capture assays. Our SAR data showed that the presence of asialyl sugar units is the main determinant of receptor preference of α2,6 versus α2,3 receptor binding. Changes to the type of sialyl-glycan linkage present on receptors exhibit only a minor effect upon binding affinity. Homology-based structural models revealed that structural properties within the HA pocket, such as a glyco-conjugate at Asn194 on the 190-helix, sterically interfere with binding to avian receptor analogs by blocking the exit path of the asialyl sugars. Similarly, naturally occurring substitutions in the C-terminal region of the 190-helix and near the N-terminal end of the 140-loop narrows the horizontal borders of the binding pocket, which restricts access of the avian receptor analog LSTa. This study helps bridge the gap between ligand structure and receptor recognition for influenza B HA; and provides a consensus SAR model for the binding of human and avian receptor analogs to influenza B HA.

Heterocyclic Schiff bases as non toxic antioxidants: Solvent effect, structure activity relationship and mechanism of action

Science.gov (United States)

Shanty, Angamaly Antony; Mohanan, Puzhavoorparambil Velayudhan

2018-03-01

Phenolic heterocyclic imine based Schiff bases from Thiophene-2-carboxaldehyde and Pyrrole-2-carboxaldehyde were synthesized and characterized as novel antioxidants. The solvent effects of these Schiff bases were determined and compared with standard antioxidants, BHA employing DPPH assay and ABTS assay. Fixed reaction time and Steady state measurement were used for study. IC50 and EC50 were calculated. Structure-activity relationship revealed that the electron donating group in the phenolic ring increases the activity where as the electron withdrawing moiety decreases the activity. The Schiff base derivatives showed antioxidant property by two different pathways namely SPLET and HAT mechanisms in DPPH assay. While in ABTS method, the reaction between ABTS radical and Schiff bases involves electron transfer followed by proton transfer (ET-PT) mechanism. The cytotoxicity of these compounds has been evaluated by MTT assay. The results showed that all these compounds are non toxic in nature.

Biological activity of antitumoural MGBG: the structural variable.

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Marques, M P M; Gil, F P S C; Calheiros, R; Battaglia, V; Brunati, A M; Agostinelli, E; Toninello, A

2008-05-01

The present study aims at determining the structure-activity relationships (SAR's) ruling the biological function of MGBG (methylglyoxal bis(guanylhydrazone)), a competitive inhibitor of S-adenosyl-L-methionine decarboxylase displaying anticancer activity, involved in the biosynthesis of the naturally occurring polyamines spermidine and spermine. In order to properly understand its biochemical activity, MGBG's structural preferences at physiological conditions were ascertained, by quantum mechanical (DFT) calculations.

QUANTITAVE STRUCTURE-ACTIVITY RELATIONSHIP ANALYSIS (QSAR OF ANTIMALARIAL 1,10-PHENANTHROLINE DERIVATIVES COMPOUNDS

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Ruslin Hadanu

2010-06-01

Full Text Available Quantitative Electronic Structure-Activity Relationship (QSAR analysis of a series of 1,10-phenanthroline derivatives as antiplasmodial compounds have been conducted using atomic net charges (q, dipole moment (μ ELUMO, EHOMO, polarizability (α and log P as the descriptors. The descriptors were obtained from computational chemistry method using semi-empirical PM3. Antiplasmodial activities were taken as the activity of the drugs  against  chloroquine-resistant Plasmodium falciparum FCR3 strain and are presented as the value of ln (1/IC50 where IC50 is an effective concentration inhibiting 50% of the parasite growth. The best model of QSAR model was determine by multiple linear regression method and giving equation of QSAR: ln 1/IC50  =  3.732 + (5.098 qC5 + (7.051 qC7 + (36.696 qC9 + (41.467 qC11 -(135.497 qC12 + (0.332 μ -                    (0.170 α + (0.757 log P. The equation was significant on the 95% level with statistical parameters: n=16; r=0.987; r2= 0.975; SE=0.317;  Fcalc/Ftable = 15.337 and gave the PRESS=0.707. Its means that there were only a relatively few deviations between the experimental and theoretical data of antimalarial activity.   Keywords: QSAR, antimalarial, semi-empirical method, 1,10-phenanthroline.

Remote sensing as a preliminary analysis for the detection of active tectonic structures: an application to the Albanian orogenic system

Directory of Open Access Journals (Sweden)

Andrea Favretto

2013-12-01

Full Text Available As is well known, both the traditional direct geological and geophysical survey methods used to identify geologic features are very expensive and time-consuming procedures. In this regard, remote sensing methods applied to multispectral and medium spatial resolution satellite images allow a more focused approach with respect to the more specific geologic methods. This is achieved by a preliminary land inspection carried out by the semi-automated analysis of satellite imagery. This avoids wasting resources as the geological/geophysical survey methods can be later applied only to those zones suspected of having certain tectonic activity (derived by the remotely sensed imagery. This paper will evaluate an ASTER sensor satellite image (and its derived Digital Elevation Model or DEM, in order to point out the suspected presence of active geologic structures (faults. The area in question is west – central Albania. The results of the remote sensing procedures are later compared with the established data for the same area taken by satellite images, in order to verify the reliability of the adopted method. The source of the established data has been from the bibliography.

Obscure phenomena in statistical analysis of quantitative structure-activity relationships. Part 1: Multicollinearity of physicochemical descriptors.

Science.gov (United States)

Mager, P P; Rothe, H

1990-10-01

Multicollinearity of physicochemical descriptors leads to serious consequences in quantitative structure-activity relationship (QSAR) analysis, such as incorrect estimators and test statistics of regression coefficients of the ordinary least-squares (OLS) model applied usually to QSARs. Beside the diagnosis of the known simple collinearity, principal component regression analysis (PCRA) also allows the diagnosis of various types of multicollinearity. Only if the absolute values of PCRA estimators are order statistics that decrease monotonically, the effects of multicollinearity can be circumvented. Otherwise, obscure phenomena may be observed, such as good data recognition but low predictive model power of a QSAR model.

Benzazepines: Structure-activity relationships between D1 receptor blockade and selected pharmacological effects

International Nuclear Information System (INIS)

Iorio, L.C.; Billiard, W.; Gold, E.H.

1986-01-01

This chapter describes the displacement of 3 H-23390 and 3 H-spiperone binding by dopamine agonists and antagonists. The authors undertook an evaluation of the ability of selected analogs of SCH 23390 to displace 3 H-SCH 23390 and 3 H-spiperone. Structure-activity relationships of SCH 23390 analogs: 7-position substituents, is shown. It is shown that, in general, benzazepines with a variety of substituents in the 7-position retain their selectivity for D 1 sites. Substituents at the 8-position and at the N-position are also discussed. The authors determine a correlation between displacement of 3 H-SCH 23390 and blockade of dopamine-sensitive adenylate cyclase (DSAC). These effects and inhibition of conditioned avoidance responsing (CAS) in rats was also studied. A detailed evaluation is presented of the effects of SCH 23390 and haloperidol in the Inclined Screen and CAR tests

Synthesis and structure-activity relationship of the first nonpeptidergic inverse agonists for the human cytomegalovirus encoded chemokine receptor US28.

Science.gov (United States)

Hulshof, Janneke W; Casarosa, Paola; Menge, Wiro M P B; Kuusisto, Leena M S; van der Goot, Henk; Smit, Martine J; de Esch, Iwan J P; Leurs, Rob

2005-10-06

US28 is a human cytomegalovirus (HCMV) encoded G-protein-coupled receptor that signals in a constitutively active manner. Recently, we identified 1 [5-(4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl)-2,2-diphenylpentanenitrile] as the first reported nonpeptidergic inverse agonist for a viral-encoded chemokine receptor. Interestingly, this compound is able to partially inhibit the viral entry of HIV-1. In this study we describe the synthesis of 1 and several of its analogues and unique structure-activity relationships for this first class of small-molecule ligands for the chemokine receptor US28. Moreover, the compounds have been pharmacologically characterized as inverse agonists on US28. By modification of lead structure 1, it is shown that a 4-phenylpiperidine moiety is essential for affinity and activity. Other structural features of 1 are shown to be of less importance. These compounds define the first SAR of ligands on a viral GPCR (US28) and may therefore serve as important tools to investigate the significance of US28-mediated constitutive activity during viral infection.

Business System Planning Project, Preliminary System Design

International Nuclear Information System (INIS)

EVOSEVICH, S.

2000-01-01

CH2M HILL Hanford Group, Inc. (CHG) is currently performing many core business functions including, but not limited to, work control, planning, scheduling, cost estimating, procurement, training, and human resources. Other core business functions are managed by or dependent on Project Hanford Management Contractors including, but not limited to, payroll, benefits and pension administration, inventory control, accounts payable, and records management. In addition, CHG has business relationships with its parent company CH2M HILL, U.S. Department of Energy, Office of River Protection and other River Protection Project contractors, government agencies, and vendors. The Business Systems Planning (BSP) Project, under the sponsorship of the CH2M HILL Hanford Group, Inc. Chief Information Officer (CIO), have recommended information system solutions that will support CHG business areas. The Preliminary System Design was developed using the recommendations from the Alternatives Analysis, RPP-6499, Rev 0 and will become the design base for any follow-on implementation projects. The Preliminary System Design will present a high-level system design, providing a high-level overview of the Commercial-Off-The-Shelf (COTS) modules and identify internal and external relationships. This document will not define data structures, user interface components (screens, reports, menus, etc.), business rules or processes. These in-depth activities will be accomplished at implementation planning time

Imidazole derivatives as angiotensin II AT1 receptor blockers: Benchmarks, drug-like calculations and quantitative structure-activity relationships modeling

Science.gov (United States)

Alloui, Mebarka; Belaidi, Salah; Othmani, Hasna; Jaidane, Nejm-Eddine; Hochlaf, Majdi

2018-03-01

We performed benchmark studies on the molecular geometry, electron properties and vibrational analysis of imidazole using semi-empirical, density functional theory and post Hartree-Fock methods. These studies validated the use of AM1 for the treatment of larger systems. Then, we treated the structural, physical and chemical relationships for a series of imidazole derivatives acting as angiotensin II AT1 receptor blockers using AM1. QSAR studies were done for these imidazole derivatives using a combination of various physicochemical descriptors. A multiple linear regression procedure was used to design the relationships between molecular descriptor and the activity of imidazole derivatives. Results validate the derived QSAR model.

Quantitative structure-activity relationships of salicylamide neuroleptic agents.

Science.gov (United States)

Gupta, S P; Saha, R N; Singh, P

1990-05-01

The in vitro antidopamine activity of substituted N-[(1-alkyl-2-pyrrolidinyl)methyl]-6-methoxysalicylamides was found to be well correlated with the hydrophobic and electronic nature of substituents at the 3-position, and with the steric nature of groups replacing the hydrogen atom of the salicyl hydroxy group. In contrast, only the hydrophobic and steric characteristics were found to be important in the in vivo activity of these neuroleptics. This difference suggests that different mechanisms are probably involved in their in vitro and in vivo actions, and that the relevant receptors are slightly different in structure. The in vitro results suggest that electron donation by the 3-substituent strengthens the formation of a hydrogen bond between the carbonyl group of the amide moiety and a hydrogen of the receptor.

Structure-Activity Relationship Analysis of 3-phenylcoumarin-Based Monoamine Oxidase B Inhibitors

Science.gov (United States)

Rauhamäki, Sanna; Postila, Pekka A.; Niinivehmas, Sanna; Kortet, Sami; Schildt, Emmi; Pasanen, Mira; Manivannan, Elangovan; Ahinko, Mira; Koskimies, Pasi; Nyberg, Niina; Huuskonen, Pasi; Multamäki, Elina; Pasanen, Markku; Juvonen, Risto O.; Raunio, Hannu; Huuskonen, Juhani; Pentikäinen, Olli T.

2018-03-01

Monoamine oxidase B (MAO-B) catalyzes deamination of monoamines such as neurotransmitters dopamine and norepinephrine. Accordingly, small-molecule MAO-B inhibitors potentially alleviate the symptoms of dopamine-linked neuropathologies such as depression or Parkinson’s disease. Coumarin with a functionalized 3-phenyl ring system is a promising scaffold for building potent MAO-B inhibitors. Here, a vast set of 3-phenylcoumarin derivatives was designed using virtual combinatorial chemistry or rationally de novo and synthesized using microwave chemistry. The derivatives inhibited the MAO-B at 100 nM - 1 µM. The IC50 value of the most potent derivative 1 was 56 nM. A docking-based structure-activity relationship analysis summarizes the atom-level determinants of the MAO-B inhibition by the derivatives. Finally, the cross-reactivity of the derivatives was tested against monoamine oxidase A and a specific subset of enzymes linked to estradiol metabolism, known to have coumarin-based inhibitors. Overall, the results indicate that the 3-phenylcoumarins, especially derivative 1, present unique pharmacological features worth considering in future drug development.

Relationship challenges and relationship maintenance activities following disclosure of transsexualism.

Science.gov (United States)

Alegría, C Aramburu

2010-12-01

• Transsexual persons are increasing their visibility in society, and health care providers and others (such as social workers) will be called upon to help with issues that transsexual persons face. Challenges that face transsexual persons often include issues involving relationships. Psychiatric and mental health nurses and other caregivers can increase their therapeutic skills in working with couples that include transsexual persons by becoming aware of these challenges and subsequent activities that can help with them. • This research study looks at couple relationships in which one partner reveals male-to-female transsexual identity. These are relationships that were established as man-woman and now will transition into relationships that include a male-to-female person and a female partner. • Common challenges for these couples include issues related to: (1) sexual identity and relationship uncertainty; (2) male-to-female transition decision making; and (3) presenting in public. • Relationship maintenance activities that helped the couples in the study maintain and strengthen their relationships through these challenges include: (1) communication; (2) self-talk (for example, putting the situation in perspective); (3) social networks; (4) positive interactions; (5) impression management (for example, managing displays of affection in public); and (6) social activism. This qualitative study describes the relational dynamics that help sustain relationships of couples that include male-to-female transsexual persons (MTF) and their natal female partners (NF) following disclosure of transsexualism. Relationship challenges and relationship maintenance activities are identified. Each partner in 17 MTF-NF couples participated in individual surveys and interviews. The data were coded for themes related to relationship challenges and activities. MTF-NF couples experience challenges within the contexts of their relationships and of society. These challenges

Purification, crystallization and preliminary X-ray structure analysis of the laccase from Ganoderma lucidum

International Nuclear Information System (INIS)

Lyashenko, Andrey V.; Belova, Oksana; Gabdulkhakov, Azat G.; Lashkov, Alexander A.; Lisov, Alexandr V.; Leontievsky, Alexey A.; Mikhailov, Al’bert M.

2011-01-01

The purification, crystallization and preliminary X-ray structure analysis of the laccase from G. lucidum are reported. The ligninolytic enzymes of the basidiomycetes play a key role in the global carbon cycle. A characteristic property of these enzymes is their broad substrate specificity, which has led to their use in various biotechnologies, thus stimulating research into the three-dimensional structures of ligninolytic enzymes. This paper presents the purification, crystallization and preliminary X-ray analysis of the laccase from the ligninolytic basidiomycete Ganoderma lucidum

Deciphering structure-activity relationships in a series of Tat/TAR inhibitors.

Science.gov (United States)

Pascale, Lise; González, Alejandro López; Di Giorgio, Audrey; Gaysinski, Marc; Teixido Closa, Jordi; Tejedor, Roger Estrada; Azoulay, Stéphane; Patino, Nadia

2016-11-01

A series of pentameric "Polyamide Amino Acids" (PAAs) compounds derived from the same trimeric precursor have been synthesized and investigated as HIV TAR RNA ligands, in the absence and in the presence of a Tat fragment. All PAAs bind TAR with similar sub-micromolar affinities but their ability to compete efficiently with the Tat fragment strongly differs, IC50 ranging from 35 nM to >2 μM. While NMR and CD studies reveal that all PAA interact with TAR at the same site and induce globally the same RNA conformational change upon binding, a comparative thermodynamic study of PAA/TAR equilibria highlights distinct TAR binding modes for Tat competitor and non-competitor PAAs. This led us to suggest two distinct interaction modes that have been further validated by molecular modeling studies. While the binding of Tat competitor PAAs induces a contraction at the TAR bulge region, the binding of non-competitor ones widens it. This could account for the distinct PAA ability to compete with Tat fragment. Our work illustrates how comparative thermodynamic studies of a series of RNA ligands of same chemical family are of value for understanding their binding modes and for rationalizing structure-activity relationships.

Molecular Descriptors Family on Vertex Cutting: Relationships between Acelazolamide Structures and their Inhibitory Activity

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Sorana D. BOLBOACĂ

2009-12-01

Full Text Available Aim: To investigate the relationship between the structural information of acetazolamides and their inhibitory activity on carbonic anhydrase II. Material and Method: A sample of previously reported acetazolamides was studied. A pool of descriptors was calculated based on matrix representation and vertex cut in order to be included in the multiple linear regression analysis. The best performing model in terms of goodness-of-fit was analysed in order to assess its validity and reliability. The model was compared with previously reported models using a series of information and prediction criteria besides the Steiger’s Z test. Results: A model with a 99.77% determination coefficient proved to be the best performing model. The obtained model proved to have a less than 5% average of the absolute difference between the observed and the estimated inhibitory activity. The information and prediction criteria showed that the obtained model was better than the previously reported models. This conclusion is also sustained by the results of Steiger’s Z test (7.78; p = 3.66·10-15. Conclusion: The inhibitory activity on carbonic anhydrase II of acetazolamides proved to be of geometric and topologic nature and depended on the compounds’ melting point, relative atomic mass and atomic electronegativity.

Structure-Activity Relationship Study of Sesquiterpene Lactones and Their Semi-Synthetic Amino Derivatives as Potential Antitrypanosomal Products

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Stefanie Zimmermann

2014-03-01

Full Text Available Sesquiterpene lactones (STLs are natural products that have potent antitrypanosomal activity in vitro and, in the case of cynaropicrin, also reduce parasitemia in the murine model of trypanosomiasis. To explore their structure-antitrypanosomal activity relationships, a set of 34 natural and semi-synthetic STLs and amino-STLs was tested in vitro against T. b. rhodesiense (which causes East African sleeping sickness and mammalian cancer cells (rat bone myoblast L6 cells. It was found that the α-methylene-γ-lactone moiety is necessary for both antitrypanosomal effects and cytotoxicity. Antitrypanosomal selectivity is facilitated by 2-(hydroxymethylacrylate or 3,4-dihydroxy-2-methylenebutylate side chains, and by the presence of cyclopentenone rings. Semi-synthetic STL amines with morpholino and dimethylamino groups showed improved in vitro activity over the native STLs. The dimethylamino derivative of cynaropicrin was prepared and tested orally in the T. b. rhodesiense acute mouse model, where it showed reduced toxicity over cynaropicrin, but also lost antitrypanosomal activity.

Role of grain refinement in hardening of structural steels at preliminary thermomechanical treatment

International Nuclear Information System (INIS)

Bukhvalov, A.B.; Grigor'eva, E.V.; Davydova, L.S.; Degtyarev, M.V.; Levit, V.I.; Smirnova, N.A.; Smirnov, L.V.

1981-01-01

The hardening mechanism during preliminary thermomechanical treatment with deformation by cold rolling or hydroextrusion is studied on structural 37KhN3M1 and 38KhN3MFA steels. Specimens have been tested on static tension, impact strength and fracture toughness. It is shown that hydroextrusion application instead of rolling does not change the hardening effect of preliminary thermomechanical treatment (PTMT). It is established that the increase of preliminary deformation degree and the use of accelerated short term hardening heating provides a bett er grain refinement and the increase of PTMT hardening effect [ru

Structural complexities in the active layers of organic electronics.

Science.gov (United States)

Lee, Stephanie S; Loo, Yueh-Lin

2010-01-01

The field of organic electronics has progressed rapidly in recent years. However, understanding the direct structure-function relationships between the morphology in electrically active layers and the performance of devices composed of these materials has proven difficult. The morphology of active layers in organic electronics is inherently complex, with heterogeneities existing across multiple length scales, from subnanometer to micron and millimeter range. A major challenge still facing the organic electronics community is understanding how the morphology across all of the length scales in active layers collectively determines the device performance of organic electronics. In this review we highlight experiments that have contributed to the elucidation of structure-function relationships in organic electronics and also point to areas in which knowledge of such relationships is still lacking. Such knowledge will lead to the ability to select active materials on the basis of their inherent properties for the fabrication of devices with prespecified characteristics.

Relationship between smartphone addiction and physical activity in Chinese international students in Korea

OpenAIRE

Kim, Sung-Eun; Kim, Jin-Woo; Jee, Yong-Seok

2015-01-01

Background and Aims Excessive usage of smartphones may induce social problems, such as depression and impairment of social and emotional functioning. Moreover, its usage can impede physical activity, but the relationship between smartphone addiction and physical activity is obscure. Therefore, we examined the relationship and the impact of excessive smartphone use on physical activity. Methods This study collected data through the structured questionnaire consisting of general characteristics...

Preliminary thermal-hydraulic and structural strength analyses for pre-moderator of cold moderator

International Nuclear Information System (INIS)

Aso, Tomokazu; Kaminaga, Masanori; Terada, Atsuhiko; Hino, Ryutaro

2001-08-01

A light-water cooled pre-moderator with a thin-walled structure made of aluminum alloy is installed around a liquid hydrogen moderator in order to enhance the neutron performance of a MW-scale spallation target system which is being developed in the Japan Atomic Energy Research Institute (JAERI). Since the pre-moderator is needed to be located close to a target working as a neutron source, it is indispensable to remove nuclear heat deposition in the pre-moderator effectively by means of smooth water flow without flow stagnation. Also, the structural integrity of the thin-walled structure should be kept against the water pressure. Preliminary thermal-hydraulic analytical results showed that the water temperature rise could be suppressed less than 1degC while keeping the smooth water flow, which would assure the expected neutron performance. As for the structural integrity, several measures to meet allowable stress conditions of aluminum alloy were proposed on the basis of the preliminary structural strength analyses. (author)

Ensemble averaged structure–function relationship for nanocrystals: effective superparamagnetic Fe clusters with catalytically active Pt skin [Ensemble averaged structure-function relationship for composite nanocrystals: magnetic bcc Fe clusters with catalytically active fcc Pt skin

Energy Technology Data Exchange (ETDEWEB)

Petkov, Valeri [Central Michigan University, Mt. Pleasant, MI (United States); Prasai, Binay [Central Michigan University, Mt. Pleasant, MI (United States); Shastri, Sarvjit [Argonne National Lab. (ANL), Argonne, IL (United States). X-ray Science Division; Park, Hyun-Uk [Sungkyunkwan University, Suwon (Korea). Department of Chemistry; Kwon, Young-Uk [Sungkyunkwan University, Suwon (Korea). Department of Chemistry; Skumryev, Vassil [Institucio Catalana de Recerca i Estudis Avançats (ICREA), Barcelona (Spain); Universitat Autònoma de Barcelona (Spain). Department of Physics

2017-09-12

Practical applications require the production and usage of metallic nanocrystals (NCs) in large ensembles. Besides, due to their cluster-bulk solid duality, metallic NCs exhibit a large degree of structural diversity. This poses the question as to what atomic-scale basis is to be used when the structure–function relationship for metallic NCs is to be quantified precisely. In this paper, we address the question by studying bi-functional Fe core-Pt skin type NCs optimized for practical applications. In particular, the cluster-like Fe core and skin-like Pt surface of the NCs exhibit superparamagnetic properties and a superb catalytic activity for the oxygen reduction reaction, respectively. We determine the atomic-scale structure of the NCs by non-traditional resonant high-energy X-ray diffraction coupled to atomic pair distribution function analysis. Using the experimental structure data we explain the observed magnetic and catalytic behavior of the NCs in a quantitative manner. Lastly, we demonstrate that NC ensemble-averaged 3D positions of atoms obtained by advanced X-ray scattering techniques are a very proper basis for not only establishing but also quantifying the structure–function relationship for the increasingly complex metallic NCs explored for practical applications.

Broad spectrum antibacterial and antifungal polymeric paint materials: synthesis, structure-activity relationship, and membrane-active mode of action.

Science.gov (United States)

Hoque, Jiaul; Akkapeddi, Padma; Yadav, Vikas; Manjunath, Goutham B; Uppu, Divakara S S M; Konai, Mohini M; Yarlagadda, Venkateswarlu; Sanyal, Kaustuv; Haldar, Jayanta

2015-01-28

Microbial attachment and subsequent colonization onto surfaces lead to the spread of deadly community-acquired and hospital-acquired (nosocomial) infections. Noncovalent immobilization of water insoluble and organo-soluble cationic polymers onto a surface is a facile approach to prevent microbial contamination. In the present study, we described the synthesis of water insoluble and organo-soluble polymeric materials and demonstrated their structure-activity relationship against various human pathogenic bacteria including drug-resistant strains such as methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), and beta lactam-resistant Klebsiella pneumoniae as well as pathogenic fungi such as Candida spp. and Cryptococcus spp. The polymer coated surfaces completely inactivated both bacteria and fungi upon contact (5 log reduction with respect to control). Linear polymers were more active and found to have a higher killing rate than the branched polymers. The polymer coated surfaces also exhibited significant activity in various complex mammalian fluids such as serum, plasma, and blood and showed negligible hemolysis at an amount much higher than minimum inhibitory amounts (MIAs). These polymers were found to have excellent compatibility with other medically relevant polymers (polylactic acid, PLA) and commercial paint. The cationic hydrophobic polymer coatings disrupted the lipid membrane of both bacteria and fungi and thus showed a membrane-active mode of action. Further, bacteria did not develop resistance against these membrane-active polymers in sharp contrast to conventional antibiotics and lipopeptides, thus the polymers hold great promise to be used as coating materials for developing permanent antimicrobial paint.

Antitumor potential of crown ethers: structure-activity relationships, cell cycle disturbances, and cell death studies of a series of ionophores.

Science.gov (United States)

Marjanović, Marko; Kralj, Marijeta; Supek, Fran; Frkanec, Leo; Piantanida, Ivo; Smuc, Tomislav; Tusek-Bozić, Ljerka

2007-03-08

The present paper demonstrates the antiproliferative ability and structure-activity relationships (SAR) of 14 crown and aza-crown ether analogues on five tumor-cell types. The most active compounds were di-tert-butyldicyclohexano-18-crown-6 (3), which exhibited cytotoxicity in the submicromolar range, and di-tert-butyldibenzo-18-crown-6 (5) (IC50 values of approximately 2 microM). Also, 3 and 5 induced marked influence on the cell cycle phase distribution--strong G1 arrest, followed by the induction of apoptosis. A computational SAR modeling effort offers insight into possible mechanisms of crown ether biological activity, presumably involving penetration into cell membranes, and points out structural features of molecules important for this activity. The results reveal that crown ethers possess marked tumor-cell growth inhibitory activity, the extent of which depends on the characteristics of the hydrophilic macrocylic cavity and the surrounding hydrophobic ring. Our work supports the hypothesis that crown ether compounds inhibit tumor-cell growth by disrupting potassium ion homeostasis, which in turn leads to cell cycle perturbations and apoptosis.

Evolution of the international workshops on quantitative structure-activity relationships (QSARs) in environmental toxicology.

Science.gov (United States)

Kaiser, K L E

2007-01-01

This presentation will review the evolution of the workshops from a scientific and personal perspective. From their modest beginning in 1983, the workshops have developed into larger international meetings, regularly held every two years. Their initial focus on the aquatic sphere soon expanded to include properties and effects on atmospheric and terrestrial species, including man. Concurrent with this broadening of their scientific scope, the workshops have become an important forum for the early dissemination of all aspects of qualitative and quantitative structure-activity research in ecotoxicology and human health effects. Over the last few decades, the field of quantitative structure/activity relationships (QSARs) has quickly emerged as a major scientific method in understanding the properties and effects of chemicals on the environment and human health. From substances that only affect cell membranes to those that bind strongly to a specific enzyme, QSARs provides insight into the biological effects and chemical and physical properties of substances. QSARs are useful for delineating the quantitative changes in biological effects resulting from minor but systematic variations of the structure of a compound with a specific mode of action. In addition, more holistic approaches are being devised that result in our ability to predict the effects of structurally unrelated compounds with (potentially) different modes of action. Research in QSAR environmental toxicology has led to many improvements in the manufacturing, use, and disposal of chemicals. Furthermore, it has led to national policies and international agreements, from use restrictions or outright bans of compounds, such as polychlorinated biphenyls (PCBs), mirex, and highly chlorinated pesticides (e.g. DDT, dieldrin) for the protection of avian predators, to alternatives for ozone-depleting compounds, to better waste treatment systems, to more powerful and specific acting drugs. Most of the recent advances

Synthesis, biological evaluation, and structure-activity relationship of clonazepam, meclonazepam, and 1,4-benzodiazepine compounds with schistosomicidal activity.

Science.gov (United States)

Menezes, Carla M S; Rivera, Gildardo; Alves, Marina A; do Amaral, Daniel N; Thibaut, Jean Pierre B; Noël, François; Barreiro, Eliezer J; Lima, Lídia M

2012-06-01

The inherent morbidity and mortality caused by schistosomiasis is a serious public health problem in developing countries. Praziquantel is the only drug in therapeutic use, leading to a permanent risk of parasite resistance. In search for new schistosomicidal drugs, meclonazepam, the 3-methyl-derivative of clonazepam, is still considered an interesting lead-candidate because it has a proven schistosomicidal effect in humans but adverse effects on the central nervous system did not allow its clinical use. Herein, the synthesis, in vitro biological evaluation, and molecular modeling of clonazepam, meclonazepam, and analogues are reported to establish the first structure-activity relationship for schistosomicidal benzodiazepines. Our findings indicate that the amide moiety [N(1) H-C(2) (=O)] is the principal pharmacophoric unit of 1,4-benzodiazepine schistosomicidal compounds and that substitution on the amide nitrogen atom (N(1) position) is not tolerated. © 2012 John Wiley & Sons A/S.

Structure-function relationships governing activity and stability of a DNA alkylation damage repair thermostable protein.

Science.gov (United States)

Perugino, Giuseppe; Miggiano, Riccardo; Serpe, Mario; Vettone, Antonella; Valenti, Anna; Lahiri, Samarpita; Rossi, Franca; Rossi, Mosè; Rizzi, Menico; Ciaramella, Maria

2015-10-15

Alkylated DNA-protein alkyltransferases repair alkylated DNA bases, which are among the most common DNA lesions, and are evolutionary conserved, from prokaryotes to higher eukaryotes. The human ortholog, hAGT, is involved in resistance to alkylating chemotherapy drugs. We report here on the alkylated DNA-protein alkyltransferase, SsOGT, from an archaeal species living at high temperature, a condition that enhances the harmful effect of DNA alkylation. The exceptionally high stability of SsOGT gave us the unique opportunity to perform structural and biochemical analysis of a protein of this class in its post-reaction form. This analysis, along with those performed on SsOGT in its ligand-free and DNA-bound forms, provides insights in the structure-function relationships of the protein before, during and after DNA repair, suggesting a molecular basis for DNA recognition, catalytic activity and protein post-reaction fate, and giving hints on the mechanism of alkylation-induced inactivation of this class of proteins. © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.

Electrochemical quantification of the structure/antioxidant activity relationship of flavonoids

International Nuclear Information System (INIS)

Ferreira, Rafael de Queiroz; Greco, Sandro José; Delarmelina, Maicon; Weber, Karen Cacilda

2015-01-01

Highlights: • CRAC assay simply and rapidly quantifies the reducing capacity of antioxidant compounds based on the consumption of a standard oxidizer (Ce 4+ ). • The electronic properties of studied flavonoid compounds and their antioxidant activity can be well correlated by this three variables: (i) polarizability, (ii) change at carbon 3’ (iii) change at carbon 5. • Hierarchical antioxidant classification generated by CRAC assay: morin > kaempferol ≅ quercetin > fisetin > apigenin > luteolin > catechin > chrysin. • Antioxidant hierarchy for groups present in the studied flavonoids compound generated by CRAC assay: OH(C2′C4′) > OH(C4′) ≅ OH(C3′C4′) > C2=C3 + 4-oxo > OH(C3,C5) + 4-oxo > OH(C3) + 4-oxo > OH(C5) + 4-oxo > OH(C3,C5). - Abstract: Ceric Reducing/Antioxidant Capacity (CRAC) is an electrochemical test that has recently emerged as an alternative to the spectrophotometric tests employed in the determination of antioxidant capacity. CRAC simply and rapidly quantifies the reducing capacity of antioxidant compounds based on the consumption of a standard oxidizer (Ce 4+ ). In this study, eight samples of flavonoids from three distinct groups were evaluated and showed the following antioxidant hierarchy: morin > kaempferol ≅ quercetin > fisetin > apigenin > luteolin > catechin > chrysin. This hierarchy is correlated with the behavior expected according to the structure/antioxidant activity relationship (SAR) of these polyphenolic compounds. Additionally, other correlations were established using SAR to explain the antioxidant behavior of the compounds with unrelated groups: OH(C2′C4′) > OH(C4′) ≅ OH(C3′C4′) > C2 = C3 + 4-oxo > OH(C3,C5) + 4-oxo > OH(C3) + 4-oxo > OH(C5) + 4-oxo > OH(C3,C5). Therefore, the use of these two tools together is very important for the study of the antioxidant behavior of flavonoids, contributing uniquely to the understanding of electronic transfer mechanisms involved in the antioxidant processes

Structure-Activity Relationship Studies of the Cyclic Depsipeptide Natural Product YM-254890, Targeting the Gq Protein.

Science.gov (United States)

Zhang, Hang; Xiong, Xiao-Feng; Boesgaard, Michael W; Underwood, Christina R; Bräuner-Osborne, Hans; Strømgaard, Kristian

2017-06-07

Extracellular signals perceived by G protein-coupled receptors are transmitted via G proteins, and subsequent intracellular signaling cascades result in a plethora of physiological responses. The natural product cyclic depsipeptides YM-254890 and FR900359 are the only known compounds that specifically inhibit signaling mediated by the G q subfamily. In this study we exploit a newly developed synthetic strategy for this compound class in the design, synthesis, and pharmacological evaluation of eight new analogues of YM-254890. These structure-activity relationship studies led to the discovery of three new analogues, YM-13, YM-14, and YM-18, which displayed potent and selective G q inhibitory activity. This provides pertinent information for the understanding of the G q inhibitory mechanism by this class of compounds and importantly provides a pathway for the development of labeled YM-254890 analogues. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

The uridine diphosphate glucuronosyltransferases: quantitative structure-activity relationships for hydroxyl polychlorinated biphenyl substrates

Energy Technology Data Exchange (ETDEWEB)

Wang, Degao [Dalian University of Technology, Department of Environmental Science and Technology, Dalian (China)

2005-10-01

Quantitative structure-activity relationships (QSARs), which relate the glucuronidation of hydroxyl polychlorinated biphenyls (OH-PCBs) - catalyzed by the uridine diphosphate glucuronosyltransferases (UGTs) - to their physicochemical properties and molecular structural parameters, can be used to predict the rate constants and interpret the mechanism of glucuronidation. In this study, QSARs have been developed that use 23 semi-empirical calculated quantum chemical descriptors to predict the logarithms of the constants 1/K{sub m} and V{sub max}, related to enzyme kinetics. A partial least squares regression method was used to select the optimal set of descriptors to minimize the multicollinearity between the descriptors, as well as to maximize the cross-validated coefficient (Q{sup 2} {sub cum}) values. The key descriptors affecting log(1/K{sub m}) were E{sub lumo}- E{sub homo} (the energy gap between the lowest unoccupied molecular orbital and the highest occupied molecular orbital) and q{sub C}{sup -} (the largest negative net atomic charge on a carbon atom), while the key descriptors affecting log V{sub max} were the polarizability {alpha}, the Connolly solvent-excluded volume (CSEV), and logP (the logarithm of the partition coefficient for octanol/water). From the results obtained it can be concluded that hydrophobic and electronic aspects of OH-PCBs are important in the glucuronidation of OH-PCBs. (orig.)

A categorical structure-activity relationship analysis of the developmental toxicity of antithyroid drugs.

Science.gov (United States)

Cunningham, Albert R; Carrasquer, C Alex; Mattison, Donald R

2009-01-01

The choice of therapeutic strategies for hyperthyroidism during pregnancy is limited. Surgery and radioiodine are typically avoided, leaving propylthiouracil and methimazole in the US. Carbimazole, a metabolic precursor of methimazole, is available in some countries outside of the US. In the US propylthiouracil is recommended because of concern about developmental toxicity from methimazole and carbimazole. Despite this recommendation, the data on developmental toxicity of all three agents are extremely limited and insufficient to support a policy given the broad use of methimazole and carbimazole around the world. In the absence of new human or animal data we describe the development of a new structure-activity relationship (SAR) model for developmental toxicity using the cat-SAR expert system. The SAR model was developed from data for 323 compounds evaluated for human developmental toxicity with 130 categorized as developmental toxicants and 193 as nontoxicants. Model cross-validation yielded a concordance between observed and predicted results between 79% to 81%. Based on this model, propylthiouracil, methimazole, and carbimazole were observed to share some structural features relating to human developmental toxicity. Thus given the need to treat women with Graves's disease during pregnancy, new molecules with minimized risk for developmental toxicity are needed. To help meet this challenge, the cat-SAR method would be a useful in screening new drug candidates for developmental toxicity as well as for investigating their mechanism of action.

Comparative pharmacodynamic analysis of imidazoline compounds using rat model of ocular mydriasis with a test of quantitative structure-activity relationships.

Science.gov (United States)

Raczak-Gutknecht, Joanna; Nasal, Antoni; Frąckowiak, Teresa; Kornicka, Anita; Sączewski, Franciszek; Wawrzyniak, Renata; Kubik, Łukasz; Kaliszan, Roman

2017-09-10

Imidazol(in)e derivatives, having the chemical structure similar to clonidine, exert diverse pharmacological activities connected with their interactions with alpha2-adrenergic receptors, e.g. hypotension, bradycardia, sedation as well as antinociceptive, anxiolytic, antiarrhythmic, muscle relaxant and mydriatic effects. The mechanism of pupillary dilation observed after systemic administration of imidazol(in)es to rats, mice and cats depends on the stimulation of postsynaptic alpha2-adrenoceptors within the brain. It was proved that the central nervous system (CNS)-localized I1-imidazoline receptors are not engaged in those effects. It appeared interesting to analyze the CNS-mediated pharmacodynamics of imidazole(in)e agents in terms of their chromatographic and calculation chemistry-derived parameters. In the present study a systematic determination and comparative pharmacometric analysis of mydriatic effects in rats were performed on a series of 20 imidazol(in)e agents, composed of the well-known drugs and of the substances used in experimental pharmacology. The eye pupil dilatory activities of the compounds were assessed in anesthetized Wistar rats according to the established Koss method. Among twenty imidazol(in)e derivatives studied, 18 produced diverse dose-dependent mydriatic effects. In the quantitative structure-activity relationships (QSAR) analysis, the pharmacological data (half maximum mydriatic effect - ED 50 in μmol/kg) were considered along with the structural parameters of the agents from molecular modeling. The theoretically calculated lipophilicity parameters, CLOGP, of imidazol(in)es, as well as their lipophilicity parameters from HPLC, logk w , were also considered. The attempts to derive statistically significant QSAR equations for a full series of the agents under study were unsuccessful. However, for a subgroup of eight apparently structurally related imidazol(in)es a significant relationship between log(1/ED 50 ) and logk w values was

Design, synthesis and structure-activity relationships studies on the D ring of the natural product triptolide.

Science.gov (United States)

Xu, Hongtao; Tang, Huanyu; Feng, Huijin; Li, Yuanchao

2014-02-01

Triptolide is a diterpene triepoxide natural product isolated from Tripterygium wilfordii Hook F, a traditional Chinese medicinal herb. Triptolide has previously been shown to possess antitumor, anti-inflammatory, immunosuppressive, and antifertility activities. Earlier reports suggested that the five-membered unsaturated lactone ring (D ring) is essential for potent cytotoxicity, however, to the best of our knowledge, systematic structure-activity relationship studies have not yet been reported. Here, four types of D ring-modified triptolide analogues were designed, synthesized and evaluated against human ovarian (SKOV-3) and prostate (PC-3) carcinoma cell lines. The results suggest that the D ring is essential to potency, however it can be modified, for example to C18 hydrogen bond acceptor and/or donor furan ring analogues, without complete loss of cytotoxic activity. Interestingly, evaluation of the key series of C19 analogues showed that this site is exquisitely sensitive to polarity. Together, these results will guide further optimization of this natural product lead compound for the development of potent and potentially clinically useful triptolide analogues. Copyright © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Stereodivergent Synthesis of 1,3-Syn-Polyol Natural Product for Stereochemical-Based Structure Activity Relationship Studies

Science.gov (United States)

Zheng, Jiamin

The 1,3-syn-diol functionality is very common in many natural products. An important class containing this moiety are the 1,3-syn-polyol/pyranone natural products, which have been isolated from a variety of plant sources, and possess biological activities like plant growth inhibition as well as antifeedant, antifungal, antibacterial, and antitumor properties. The feature of this class is a 6-membered lactone where the lactoe oxygen is part of a 1,3-syn-diol motif. To pursue the 1,3-syn-polyol/pyranone natural products, an iterative hydration of polyene strategy was utilized to provide the 1,3- syn-diol functionality, and asymmetric synthetic strategies were explored to form the requisite stereochemistry. The versatility of the asymmetric approach was demonstrated in the synthesis of eupatorium pyranone and also in an ongoing project aimed at the synthesis of SIA7248. As an outgrowth of our work on the total syntheses of 1,3-syn -polyol natural products inspired a stereo-divergent synthesis of 1,3-syn-polyol natural products and their analogs for stereochemical-based structure-activity relationship (SSAR) studies. To identify the key structural factors important for the anticancer activity of the 1,3-syn-polyol/pyranones, a stereo-divergent 16-member library of pyranone/polyol congeners was designed, synthesized and tested with variations in both stereochemistry and numbers of polyol repeat units. Having access to stereochemical isomers of the biologically active natural products allowed us to design experiments that help illustrate their mechanisms of action.

The quantitative structure-insecticidal activity relationships from plant derived compounds against chikungunya and zika Aedes aegypti (Diptera:Culicidae) vector.

Science.gov (United States)

Saavedra, Laura M; Romanelli, Gustavo P; Rozo, Ciro E; Duchowicz, Pablo R

2018-01-01

The insecticidal activity of a series of 62 plant derived molecules against the chikungunya, dengue and zika vector, the Aedes aegypti (Diptera:Culicidae) mosquito, is subjected to a Quantitative Structure-Activity Relationships (QSAR) analysis. The Replacement Method (RM) variable subset selection technique based on Multivariable Linear Regression (MLR) proves to be successful for exploring 4885 molecular descriptors calculated with Dragon 6. The predictive capability of the obtained models is confirmed through an external test set of compounds, Leave-One-Out (LOO) cross-validation and Y-Randomization. The present study constitutes a first necessary computational step for designing less toxic insecticides. Copyright © 2017 Elsevier B.V. All rights reserved.

Preliminary structural assessment of DEMO vacuum vessel against a vertical displacement event

International Nuclear Information System (INIS)

Mozzillo, Rocco; Tarallo, Andrea; Marzullo, Domenico; Bachmann, Christian; Di Gironimo, Giuseppe; Mazzone, Giuseppe

2016-01-01

Highlights: • The paper focuses on a preliminary structural analysis of the current concept design of DEMO vacuum vessel. • The Vacuum Vessel was checked against the VDE in combinations with the weight force of all components that the vessel shall bear. • Different configurations for the vacuum vessel supports are considered, showing that the best solution is VV supported at the lower port. • The analyses evaluated the “P damage” according to RCC-MRx code. - Abstract: This paper focuses on a preliminary structural analysis of the current concept design of DEMO vacuum vessel (VV). The VV structure is checked against a vertical load due to a Vertical Displacement Event in combination with the weight force of all components that the main vessel shall bear. Different configurations for the supports are considered. Results show that the greatest safety margins are reached when the tokamak is supported through the lower ports rather than the equatorial ports, though all analyzed configurations are compliant with RCC-MRx design rules.

Preliminary structural assessment of DEMO vacuum vessel against a vertical displacement event

Energy Technology Data Exchange (ETDEWEB)

Mozzillo, Rocco, E-mail: rocco.mozzillo@unina.it [CREATE, University of Naples Federico II, DII, P.le Tecchio 80, 80125, Naples (Italy); Tarallo, Andrea; Marzullo, Domenico [CREATE, University of Naples Federico II, DII, P.le Tecchio 80, 80125, Naples (Italy); Bachmann, Christian [EUROfusion PMU, Boltzmannstraße 2, 85748 Garching (Germany); Di Gironimo, Giuseppe [CREATE, University of Naples Federico II, DII, P.le Tecchio 80, 80125, Naples (Italy); Mazzone, Giuseppe [Unità Tecnica Fusione - ENEA C.R. Frascati, Via E. Fermi 45, 00044 Frascati (Italy)

2016-11-15

Highlights: • The paper focuses on a preliminary structural analysis of the current concept design of DEMO vacuum vessel. • The Vacuum Vessel was checked against the VDE in combinations with the weight force of all components that the vessel shall bear. • Different configurations for the vacuum vessel supports are considered, showing that the best solution is VV supported at the lower port. • The analyses evaluated the “P damage” according to RCC-MRx code. - Abstract: This paper focuses on a preliminary structural analysis of the current concept design of DEMO vacuum vessel (VV). The VV structure is checked against a vertical load due to a Vertical Displacement Event in combination with the weight force of all components that the main vessel shall bear. Different configurations for the supports are considered. Results show that the greatest safety margins are reached when the tokamak is supported through the lower ports rather than the equatorial ports, though all analyzed configurations are compliant with RCC-MRx design rules.

Deep neural nets as a method for quantitative structure-activity relationships.

Science.gov (United States)

Ma, Junshui; Sheridan, Robert P; Liaw, Andy; Dahl, George E; Svetnik, Vladimir

2015-02-23

Neural networks were widely used for quantitative structure-activity relationships (QSAR) in the 1990s. Because of various practical issues (e.g., slow on large problems, difficult to train, prone to overfitting, etc.), they were superseded by more robust methods like support vector machine (SVM) and random forest (RF), which arose in the early 2000s. The last 10 years has witnessed a revival of neural networks in the machine learning community thanks to new methods for preventing overfitting, more efficient training algorithms, and advancements in computer hardware. In particular, deep neural nets (DNNs), i.e. neural nets with more than one hidden layer, have found great successes in many applications, such as computer vision and natural language processing. Here we show that DNNs can routinely make better prospective predictions than RF on a set of large diverse QSAR data sets that are taken from Merck's drug discovery effort. The number of adjustable parameters needed for DNNs is fairly large, but our results show that it is not necessary to optimize them for individual data sets, and a single set of recommended parameters can achieve better performance than RF for most of the data sets we studied. The usefulness of the parameters is demonstrated on additional data sets not used in the calibration. Although training DNNs is still computationally intensive, using graphical processing units (GPUs) can make this issue manageable.

Molecular structures and functional relationships in clostridial neurotoxins.

Science.gov (United States)

Swaminathan, Subramanyam

2011-12-01

The seven serotypes of Clostridium botulinum neurotoxins (A-G) are the deadliest poison known to humans. They share significant sequence homology and hence possess similar structure-function relationships. Botulinum neurotoxins (BoNT) act via a four-step mechanism, viz., binding and internalization to neuronal cells, translocation of the catalytic domain into the cytosol and finally cleavage of one of the three soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNARE) causing blockage of neurotransmitter release leading to flaccid paralysis. Crystal structures of three holotoxins, BoNT/A, B and E, are available to date. Although the individual domains are remarkably similar, their domain organization is different. These structures have helped in correlating the structural and functional domains. This has led to the determination of structures of individual domains and combinations of them. Crystal structures of catalytic domains of all serotypes and several binding domains are now available. The catalytic domains are zinc endopeptidases and share significant sequence and structural homology. The active site architecture and the catalytic mechanism are similar although the binding mode of individual substrates may be different, dictating substrate specificity and peptide cleavage selectivity. Crystal structures of catalytic domains with substrate peptides provide clues to specificity and selectivity unique to BoNTs. Crystal structures of the receptor domain in complex with ganglioside or the protein receptor have provided information about the binding of botulinum neurotoxin to the neuronal cell. An overview of the structure-function relationship correlating the 3D structures with biochemical and biophysical data and how they can be used for structure-based drug discovery is presented here. Journal compilation © 2011 FEBS. No claim to original US government works.

Relationship between Structural Characteristics of Activated Carbons and Their Concentrating Efficiency with Respect to Nitroorganics.

Science.gov (United States)

Leboda, R.; Gun'ko, V. M.; Tomaszewski, W.; Trznadel, B. J.

2001-07-15

The relationships between structural properties of activated microporous, micro-mesoporous, mesoporous, and graphitized carbons determined on the basis of nitrogen adsorption at 77.4 K and the efficiency of concentrating (solid-phase extraction (SPE) technique) several nitroorganic compounds from polar solvents were investigated. Microporosity, mesoporosity, fractality, and other characteristics of adsorbents were analyzed to evaluate the dependence of the effectiveness of the SPE technique with respect to nitrate esters, cyclic nitroamines, and nitroaromatics on the origin and texture of carbons. The values of the free energy of solvation and dipole moment of nitroorganic compounds in polar liquids computed with the SM5.42/PM3 method with consideration of geometry relaxation in solution were utilized to elucidate features of their concentration of carbon adsorbents. Copyright 2001 Academic Press.

Dietary Protection Against Free Radicals: A Case for Multiple Testing to Establish Structure-activity Relationships for Antioxidant Potential of Anthocyanic Plant Species

Directory of Open Access Journals (Sweden)

Chiara Cheng Lim

2009-03-01

Full Text Available DNA damage by reactive species is associated with susceptibility to chronic human degenerative disorders. Anthocyanins are naturally occurring antioxidants, that may prevent or reverse such damage. There is considerable interest in anthocyanic food plants as good dietary sources, with the potential for reducing susceptibility to chronic disease. While structure-activity relationships have provided guidelines on molecular structure in relation to free hydroxyl- radical scavenging, this may not cover the situation in food plants where the anthocyanins are part of a complex mixture, and may be part of complex structures, including anthocyanic vacuolar inclusions (AVIs. Additionally, new analytical methods have revealed new structures in previously-studied materials. We have compared the antioxidant activities of extracts from six anthocyanin-rich edible plants (red cabbage, red lettuce, blueberries, pansies, purple sweetpotato skin, purple sweetpotato flesh and Maori potato flesh using three chemical assays (DPPH, TRAP and ORAC, and the in vitro Comet assay. Extracts from the flowering plant, lisianthus, were used for comparison. The extracts showed differential effects in the chemical assays, suggesting that closely related structures have different affinities to scavenge different reactive species. Integration of anthocyanins to an AVI led to more sustained radical scavenging activity as compared with the free anthocyanin. All but the red lettuce extract could reduce endogenous DNA damage in HT-29 colon cancer cells. However, while extracts from purple sweetpotato skin and flesh, Maori potato and pansies, protected cells against subsequent challenge by hydrogen peroxide at 0oC, red cabbage extracts were pro-oxidant, while other extracts had no effect. When the peroxide challenge was at 37oC, all of the extracts appeared pro-oxidant. Maori potato extract, consistently the weakest antioxidant in all the chemical assays, was more effective in the

Application of quantitative structure-activity relationship to the determination of binding constant based on fluorescence quenching

Energy Technology Data Exchange (ETDEWEB)

Wen Yingying [Department of Applied Chemistry, Yantai University, Yantai 264005 (China); Liu Huitao, E-mail: liuht-ytu@163.co [Department of Applied Chemistry, Yantai University, Yantai 264005 (China); Luan Feng; Gao Yuan [Department of Applied Chemistry, Yantai University, Yantai 264005 (China)

2011-01-15

Quantitative structure-activity relationship (QSAR) model was used to predict and explain binding constant (log K) determined by fluorescence quenching. This method allowed us to predict binding constants of a variety of compounds with human serum albumin (HSA) based on their structures alone. Stepwise multiple linear regression (MLR) and nonlinear radial basis function neural network (RBFNN) were performed to build the models. The statistical parameters provided by the MLR model (R{sup 2}=0.8521, RMS=0.2678) indicated satisfactory stability and predictive ability while the RBFNN predictive ability is somewhat superior (R{sup 2}=0.9245, RMS=0.1736). The proposed models were used to predict the binding constants of two bioactive components in traditional Chinese medicines (isoimperatorin and chrysophanol) whose experimental results were obtained in our laboratory and the predicted results were in good agreement with the experimental results. This QSAR approach can contribute to a better understanding of structural factors of the compounds responsible for drug-protein interactions, and can be useful in predicting the binding constants of other compounds. - Research Highlights: QSAR models for binding constants of some compounds to HSA were developed. The models provide a simple and straightforward way to predict binding constant. QSAR can give some insight into structural features related to binding behavior.

Structure-In Vitro Activity Relationships of Pentamidine Analogues and Dication-Substituted Bis-Benzimidazoles as New Antifungal Agents

Science.gov (United States)

Del Poeta, Maurizio; Schell, Wiley A.; Dykstra, Christine C.; Jones, Susan; Tidwell, Richard R.; Czarny, Agnieszka; Bajic, Miroslav; Bajic, Marina; Kumar, Arvind; Boykin, David; Perfect, John R.

1998-01-01

Twenty analogues of pentamidine, 7 primary metabolites of pentamidine, and 30 dicationic substituted bis-benzimidazoles were screened for their inhibitory and fungicidal activities against Candida albicans and Cryptococcus neoformans. A majority of the compounds had MICs at which 80% of the strains were inhibited (MIC80s) comparable to those of amphotericin B and fluconazole. Unlike fluconazole, many of these compounds were found to have potent fungicidal activity. The most potent compound against C. albicans had an MIC80 of ≤0.09 μg/ml, and the most potent compound against C. neoformans had an MIC80 of 0.19 μg/ml. Selected compounds were also found to be active against Aspergillus fumigatus, Fusarium solani, Candida species other than C. albicans, and fluconazole-resistant strains of C. albicans and C. neoformans. It is clear from the data presented here that further studies on the structure-activity relationships, mechanisms of action and toxicities, and in vivo efficacies of these compounds are warranted to determine their clinical potential. PMID:9756747

An automated pulse labelling method for structure-activity relationship studies with antibacterial oxazolidinones.

Science.gov (United States)

Eustice, D C; Brittelli, D R; Feldman, P A; Brown, L J; Borkowski, J J; Slee, A M

1990-01-01

The 3-aryl-2-oxooxazolidinones are a new class of synthetic antibacterial agents that potently inhibit protein synthesis. An automated pulse labelling method with [3H]-lysine was developed with Bacillus subtilis to obtain additional quantitative activity data for structure-activity relationship studies with the oxazolidinones. Inhibition constants were calculated after a Logit fit of the data into the formula: % of control = 100/(1 + e[-B(X - A)]), where B is the slope of the model, X is the natural log of the inhibitor concentration and A is the natural log of the inhibitor concentration required to inhibit protein synthesis by 50% (ln IC50). When substituents at the 5-methyl position of the heterocyclic ring (B-substituent) were NHCOCH3, OH or Cl, the correlation coefficient was 0.87 between the MIC and IC50 values (for all compounds with MICs less than or equal to 16 micrograms/ml). The D-isomers of DuP 721 (A-substituent = CH3CO) and DuP 105 (A-substituent = CH3SO) gave MICs of 128 micrograms/ml and IC50s of greater than or equal to 50 micrograms/ml for protein synthesis, showing that only the L-isomers were active. By MIC testing, oxazolidinones with the B-substituent of NHCOCH3 and the A-substituent of CH3CO, NO2, CH3S, CH3SO2 or (CH3)2CH had comparable antibacterial potency; however, pulse labelling analysis showed that compounds with an A-substituent of CH3CO or NO2 were more potent inhibitors of protein synthesis.

Quantitative structure-activity relationship analysis of substituted arylazo pyridone dyes in photocatalytic system: Experimental and theoretical study

Energy Technology Data Exchange (ETDEWEB)

Dostanić, J., E-mail: jasmina@nanosys.ihtm.bg.ac.rs [University of Belgrade, Institute of Chemistry, Technology and Metallurgy, Department of Catalysis and Chemical Engineering, Njegoševa 12, 11000 Belgrade (Serbia); Lončarević, D. [University of Belgrade, Institute of Chemistry, Technology and Metallurgy, Department of Catalysis and Chemical Engineering, Njegoševa 12, 11000 Belgrade (Serbia); Zlatar, M. [University of Belgrade, Institute of Chemistry, Technology and Metallurgy, Department of Chemistry, Njegoševa 12, 11000 Belgrade (Serbia); Vlahović, F. [University of Belgrade, Innovation center of the Faculty of Chemistry, 11000 Belgrade (Serbia); Jovanović, D.M. [University of Belgrade, Institute of Chemistry, Technology and Metallurgy, Department of Catalysis and Chemical Engineering, Njegoševa 12, 11000 Belgrade (Serbia)

2016-10-05

Highlights: • Electronic effects of para substituted arylazo pyridone dyes. • Linear relationship between Hammett σ{sub p} constants and dyes photoreactivity. • The photocatalytic reactions facilitated by el.-acceptors and retarded by el.-donors. • Fukui functions to analyze the reactivity on concurrent sites within a molecule. • Hydroxyl radicals sustain attack from two reaction sites, depending on a substituent type. - Abstract: A series of arylazo pyridone dyes was synthesized by changing the type of the substituent group in the diazo moiety, ranging from strong electron-donating to strong electron-withdrawing groups. The structural and electronic properties of the investigated dyes was calculated at the M062X/6-31 + G(d,p) level of theory. The observed good linear correlations between atomic charges and Hammett σ{sub p} constants provided a basis to discuss the transmission of electronic substituent effects through a dye framework. The reactivity of synthesized dyes was tested through their decolorization efficiency in TiO{sub 2} photocatalytic system (Degussa P-25). Quantitative structure-activity relationship analysis revealed a strong correlation between reactivity of investigated dyes and Hammett substituent constants. The reaction was facilitated by electron-withdrawing groups, and retarded by electron-donating ones. Quantum mechanical calculations was used in order to describe the mechanism of the photocatalytic oxidation reactions of investigated dyes and interpret their reactivities within the framework of the Density Functional Theory (DFT). According to DFT based reactivity descriptors, i.e. Fukui functions and local softness, the active site moves from azo nitrogen atom linked to benzene ring to pyridone carbon atom linked to azo bond, going from dyes with electron-donating groups to dyes with electron-withdrawing groups.

Quantitative structure-activity relationship analysis of substituted arylazo pyridone dyes in photocatalytic system: Experimental and theoretical study

International Nuclear Information System (INIS)

Dostanić, J.; Lončarević, D.; Zlatar, M.; Vlahović, F.; Jovanović, D.M.

2016-01-01

Highlights: • Electronic effects of para substituted arylazo pyridone dyes. • Linear relationship between Hammett σ_p constants and dyes photoreactivity. • The photocatalytic reactions facilitated by el.-acceptors and retarded by el.-donors. • Fukui functions to analyze the reactivity on concurrent sites within a molecule. • Hydroxyl radicals sustain attack from two reaction sites, depending on a substituent type. - Abstract: A series of arylazo pyridone dyes was synthesized by changing the type of the substituent group in the diazo moiety, ranging from strong electron-donating to strong electron-withdrawing groups. The structural and electronic properties of the investigated dyes was calculated at the M062X/6-31 + G(d,p) level of theory. The observed good linear correlations between atomic charges and Hammett σ_p constants provided a basis to discuss the transmission of electronic substituent effects through a dye framework. The reactivity of synthesized dyes was tested through their decolorization efficiency in TiO_2 photocatalytic system (Degussa P-25). Quantitative structure-activity relationship analysis revealed a strong correlation between reactivity of investigated dyes and Hammett substituent constants. The reaction was facilitated by electron-withdrawing groups, and retarded by electron-donating ones. Quantum mechanical calculations was used in order to describe the mechanism of the photocatalytic oxidation reactions of investigated dyes and interpret their reactivities within the framework of the Density Functional Theory (DFT). According to DFT based reactivity descriptors, i.e. Fukui functions and local softness, the active site moves from azo nitrogen atom linked to benzene ring to pyridone carbon atom linked to azo bond, going from dyes with electron-donating groups to dyes with electron-withdrawing groups.

Synthesis, Crystal Structure and Biological Activities of Novel Anthranilic(Isophthalic) Acid Esters

Institute of Scientific and Technical Information of China (English)

YAN Tao; YU Guan-ping; LIU Peng-fei; XIONG Li-xia; YU Shu-jing; LI Zheng-ming

2012-01-01

In search of environmentally benign insecticides with high activity,low toxicity and low resistance,a series of novel anthranilic(isophthalic) acid esters was designed and synthesized based on the structure of ryanodine modulating agent.All the compounds were characterized by 1H NMR spectra,elemental analysis or high resolution mass spectrometry(HRMS).The preliminary results of biological activity assessment indicate that some of the title compounds exhibit certain but unremarkable insecticidal activity against Mythimna separata Walker at 200 mg/L and fungicidal activities against five funguses at 50 mg/L.

Structure-activity relationship studies on a Trp dendrimer with dual activities against HIV and enterovirus A71. Modifications on the amino acid.

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Martínez-Gualda, Belén; Sun, Liang; Rivero-Buceta, Eva; Flores, Aida; Quesada, Ernesto; Balzarini, Jan; Noppen, Sam; Liekens, Sandra; Schols, Dominique; Neyts, Johan; Leyssen, Pieter; Mirabelli, Carmen; Camarasa, María-José; San-Félix, Ana

2017-03-01

We have recently described a new class of dendrimers with tryptophan (Trp) on the surface that show dual antiviral activities against HIV and EV71 enterovirus. The prototype compound of this family is a pentaerythritol derivative with 12 Trps on the periphery. Here we complete the structure-activity relationship studies of this family to identify key features that might be significant for the antiviral activity. With this aim, novel dendrimers containing different amino acids (aromatic and non-aromatic), tryptamine (a "decarboxylated" analogue of Trp) and N-methyl Trp on the periphery have been prepared. Dendrimer with N-Methyl Trp was the most active against HIV-1 and HIV-2 while dendrimer with tyrosine was endowed with the most potent antiviral activity against EV71. This tyrosine dendrimer proved to inhibit a large panel of EV71 clinical isolates (belonging to different clusters) in the low nanomolar/high picomolar range. In addition, a new synthetic procedure (convergent approach) has been developed for the synthesis of the prototype and some other dendrimers. This convergent approach proved more efficient (higher yields, easier purification) than the divergent approach previously reported. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

Structure-Antioxidative and Anti-Inflammatory Activity Relationships of Purpurin and Related Anthraquinones in Chemical and Cell Assays

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Woo Nam

2017-02-01

Full Text Available Anthraquinone (9,10-anthraquinone and several hydroxy derivatives, including purpurin (1,2,4-trihydroxyanthraquinone, anthrarufin (1,5-dihydroxyanthraquinone, and chrysazin (1,8-dihydroxyanthraquinone, were evaluated for antioxidative and anti-inflammatory activities in chemical assays and mammalian cells (murine macrophage RAW 264.7 cells. Several tests were used to assess their activities: 1,1-diphenyl-2-picrylhydrazyl (DPPH free radical; ABTS radical cation; hydrogen peroxide scavenging; reduction of potassium ferricyanide; chelation of ferrous ions; inhibition of lipid peroxidation; inhibition of nitric oxide generation; scavenging of the intracellular hydroxyl radical; expression of NLRP3 polypeptide for inflammasome assembly; and quantitation of proinflammatory cytokine interleukin 1β (IL-1β for inflammasome activation. The results show that purpurin, from the root of the madder plant (Rubia tinctorum L., exhibited the highest antioxidative activity in both chemical and cultured cell antioxidant assays. The antioxidative activities of the other three anthraquinones were lower than that of purpurin. In addition, purpurin could down-regulate NLRP3 inflammasome assembly and activation, suggesting that it might protect foods against oxidative damage and prevent in vivo oxidative stress and inflammation. Structure-activity relationships and the significance of the results for food quality and human health are discussed.

A Categorical Structure-Activity Relationship Analysis of the Developmental Toxicity of Antithyroid Drugs

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Cunningham AlbertR

2009-11-01

Full Text Available The choice of therapeutic strategies for hyperthyroidism during pregnancy is limited. Surgery and radioiodine are typically avoided, leaving propylthiouracil and methimazole in the US. Carbimazole, a metabolic precursor of methimazole, is available in some countries outside of the US. In the US propylthiouracil is recommended because of concern about developmental toxicity from methimazole and carbimazole. Despite this recommendation, the data on developmental toxicity of all three agents are extremely limited and insufficient to support a policy given the broad use of methimazole and carbimazole around the world. In the absence of new human or animal data we describe the development of a new structure-activity relationship (SAR model for developmental toxicity using the cat-SAR expert system. The SAR model was developed from data for 323 compounds evaluated for human developmental toxicity with 130 categorized as developmental toxicants and 193 as nontoxicants. Model cross-validation yielded a concordance between observed and predicted results between 79% to 81%. Based on this model, propylthiouracil, methimazole, and carbimazole were observed to share some structural features relating to human developmental toxicity. Thus given the need to treat women with Graves's disease during pregnancy, new molecules with minimized risk for developmental toxicity are needed. To help meet this challenge, the cat-SAR method would be a useful in screening new drug candidates for developmental toxicity as well as for investigating their mechanism of action.

A Categorical Structure-Activity Relationship Analysis of the Developmental Toxicity of Antithyroid Drugs

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Albert R. Cunningham

2009-01-01

Full Text Available The choice of therapeutic strategies for hyperthyroidism during pregnancy is limited. Surgery and radioiodine are typically avoided, leaving propylthiouracil and methimazole in the US. Carbimazole, a metabolic precursor of methimazole, is available in some countries outside of the US. In the US propylthiouracil is recommended because of concern about developmental toxicity from methimazole and carbimazole. Despite this recommendation, the data on developmental toxicity of all three agents are extremely limited and insufficient to support a policy given the broad use of methimazole and carbimazole around the world. In the absence of new human or animal data we describe the development of a new structure-activity relationship (SAR model for developmental toxicity using the cat-SAR expert system. The SAR model was developed from data for 323 compounds evaluated for human developmental toxicity with 130 categorized as developmental toxicants and 193 as nontoxicants. Model cross-validation yielded a concordance between observed and predicted results between 79% to 81%. Based on this model, propylthiouracil, methimazole, and carbimazole were observed to share some structural features relating to human developmental toxicity. Thus given the need to treat women with Graves's disease during pregnancy, new molecules with minimized risk for developmental toxicity are needed. To help meet this challenge, the cat-SAR method would be a useful in screening new drug candidates for developmental toxicity as well as for investigating their mechanism of action.

UVISS preliminary visibility analysis

DEFF Research Database (Denmark)

Betto, Maurizio

1998-01-01

The goal of this work is to obtain a preliminary assessment of the sky visibility for anastronomical telescope located on the express pallet of the International SpaceStation (ISS)} taking into account the major constraints imposed on the instrument by the ISSattitude and structure. Part of the w......The goal of this work is to obtain a preliminary assessment of the sky visibility for anastronomical telescope located on the express pallet of the International SpaceStation (ISS)} taking into account the major constraints imposed on the instrument by the ISSattitude and structure. Part...... of the work is also to setup the kernel of a software tool for the visibility analysis thatshould be easily expandable to consider more complex strucures for future activities.This analysis is part of the UVISS assessment study and it is meant to provide elementsfor the definition and the selection...

2-(Substituted phenyl-3,4-dihydroisoquinolin-2-iums as Novel Antifungal Lead Compounds: Biological Evaluation and Structure-Activity Relationships

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Xin-Juan Yang

2013-08-01

Full Text Available The title compounds are a class of structurally simple analogues of quaternary benzo[c]phenanthridine alkaloids (QBAs. In order to develop novel QBA-like antifungal drugs, in this study, 24 of the title compounds with various substituents on the N-phenyl ring were evaluated for bioactivity against seven phytopathogenic fungi using the mycelial growth rate method and their SAR discussed. Almost all the compounds showed definite activities in vitro against each of the test fungi at 50 μg/mL and a broad antifungal spectrum. In most cases, the mono-halogenated compounds 2–12 exhibited excellent activities superior to the QBAs sanguinarine and chelerythrine. Compound 8 possessed the strongest activities on each of the fungi with EC50 values of 8.88–19.88 µg/mL and a significant concentration-dependent relationship. The SAR is as follows: the N-phenyl group is a high sensitive structural moiety for the activity and the characteristics and position of substituents intensively influence the activity. Generally, electron-withdrawing substituents remarkably enhance the activity while electron-donating substituents cause a decrease of the activity. In most cases, ortha- and para-halogenated isomers were more active than the corresponding m-halogenated isomers. Thus, the title compounds emerged as promising lead compounds for the development of novel biomimetic antifungal agrochemicals. Compounds 8 and 2 should have great potential as new broad spectrum antifungal agents for plant protection.

Croatian banking sector research: relationship between ownership structure, concentration, owners’ type and bank performance

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Igor Tomičić

2012-12-01

Full Text Available Banks are important financial intermediaries of any national economy, and corporate governance has an important role in banking sector; especially due to processes of the globalization and the internationalization, and also because of the sensitivity of the activities between the interest groups. The objective of this paper is to examine the relationship between ownership structure, concentration, owners’ type and bank performance. The authors made a research of banks' ownership structure using publicly available data. Using statistical tools authors discovered relationships between bank ownership structure and bank performance indicators (average asset, total asset, average equity, profit (loss before taxes, profit (loss after taxes, ROAA, ROAE. Further they discuss the relationships between ownership structure and a number of consequences for the bank performance. The authors discovered significant correlation between bank ownership structure and performance indicators variables that are described in the paper.

Compound toxicity screening and structure-activity relationship modeling in Escherichia coli.

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Planson, Anne-Gaëlle; Carbonell, Pablo; Paillard, Elodie; Pollet, Nicolas; Faulon, Jean-Loup

2012-03-01

Synthetic biology and metabolic engineering are used to develop new strategies for producing valuable compounds ranging from therapeutics to biofuels in engineered microorganisms. When developing methods for high-titer production cells, toxicity is an important element to consider. Indeed the production rate can be limited due to toxic intermediates or accumulation of byproducts of the heterologous biosynthetic pathway of interest. Conversely, highly toxic molecules are desired when designing antimicrobials. Compound toxicity in bacteria plays a major role in metabolic engineering as well as in the development of new antibacterial agents. Here, we screened a diversified chemical library of 166 compounds for toxicity in Escherichia coli. The dataset was built using a clustering algorithm maximizing the chemical diversity in the library. The resulting assay data was used to develop a toxicity predictor that we used to assess the toxicity of metabolites throughout the metabolome. This new tool for predicting toxicity can thus be used for fine-tuning heterologous expression and can be integrated in a computational-framework for metabolic pathway design. Many structure-activity relationship tools have been developed for toxicology studies in eukaryotes [Valerio (2009), Toxicol Appl Pharmacol, 241(3): 356-370], however, to the best of our knowledge we present here the first E. coli toxicity prediction web server based on QSAR models (EcoliTox server: http://www.issb.genopole.fr/∼faulon/EcoliTox.php). Copyright © 2011 Wiley Periodicals, Inc.

Delineating the relationship between stress mindset and primary appraisals: preliminary findings.

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Kilby, Christopher J; Sherman, Kerry A

2016-01-01

Stress mindset theory suggests that positive stress beliefs lead to positive, rather than negative, outcomes when engaging with stressors. Similarly, the Transactional Model of Stress predicts that perceiving a stressor as challenging leads to positive outcomes whereas negative perceptions of the stressor as threatening invoke negative outcomes. The aim of this study was to provide preliminary data examining the nature of the relationship between stress mindset and primary appraisals. It was predicted that positive beliefs about stress would be associated with perceiving a stressful situation as more challenging, and inversely related to perceptions of threat. Participants (N = 124) initially completed measures assessing stress mindset, lifetime and current perceived stress, trait anxiety, and self-efficacy. Then participants received a set of instructions regarding a stressful mathematics task, followed by completion of post-manipulation stress mindset and primary appraisals measures, prior to completing the mathematics task. Multiple linear regression analyses revealed that participants who held a greater number of positive beliefs (as opposed to negative beliefs) about stress also perceived the stressor as being more challenging. However, there was no significant relationship between valence of beliefs and threat appraisals. These findings provide initial evidence for the nature of the relationship between valence of stress beliefs and challenge appraisals. Further research is needed to understand how stress beliefs impact on the way in which an individual copes with stressful situations.

An ontology-based exploration of the concepts and relationships in the activities and participation component of the international classification of functioning, disability and health.

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Della Mea, Vincenzo; Simoncello, Andrea

2012-02-28

The International Classification of Functioning, Disability and Health (ICF) is a classification of health and health-related issues, aimed at describing and measuring health and disability at both individual and population levels. Here we discuss a preliminary qualitative and quantitative analysis of the relationships used in the Activities and Participation component of ICF, and a preliminary mapping to SUMO (Suggested Upper Merged Ontology) concepts. The aim of the analysis is to identify potential logical problems within this component of ICF, and to understand whether activities and participation might be defined more formally than in the current version of ICF. In the relationship analysis, we used four predicates among those available in SUMO for processes (Patient, Instrument, Agent, and subProcess). While at the top level subsumption was used in most cases (90%), at the lower levels the percentage of other relationships rose to 41%. Chapters were heterogeneous in the relationships used and some of the leaves of the tree seemed to represent properties or parts of the parent concept rather than subclasses. Mapping of ICF to SUMO proved partially feasible, with the activity concepts being mapped mostly (but not totally) under the IntentionalProcess concept in SUMO. On the other hand, the participation concept has not been mapped to any upper level concept. Our analysis of the relationships within ICF revealed issues related to confusion between classes and their properties, incorrect classifications, and overemphasis on subsumption, confirming what already observed by other researchers. However, it also suggested some properties for Activities that could be included in a more formal model: number of agents involved, the instrument used to carry out the activity, the object of the activity, complexity of the task, and an enumeration of relevant subtasks.

An ontology-based exploration of the concepts and relationships in the activities and participation component of the international classification of functioning, disability and health

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Della Mea Vincenzo

2012-02-01

Full Text Available Abstract Background The International Classification of Functioning, Disability and Health (ICF is a classification of health and health-related issues, aimed at describing and measuring health and disability at both individual and population levels. Here we discuss a preliminary qualitative and quantitative analysis of the relationships used in the Activities and Participation component of ICF, and a preliminary mapping to SUMO (Suggested Upper Merged Ontology concepts. The aim of the analysis is to identify potential logical problems within this component of ICF, and to understand whether activities and participation might be defined more formally than in the current version of ICF. Results In the relationship analysis, we used four predicates among those available in SUMO for processes (Patient, Instrument, Agent, and subProcess. While at the top level subsumption was used in most cases (90%, at the lower levels the percentage of other relationships rose to 41%. Chapters were heterogeneous in the relationships used and some of the leaves of the tree seemed to represent properties or parts of the parent concept rather than subclasses. Mapping of ICF to SUMO proved partially feasible, with the activity concepts being mapped mostly (but not totally under the IntentionalProcess concept in SUMO. On the other hand, the participation concept has not been mapped to any upper level concept. Conclusions Our analysis of the relationships within ICF revealed issues related to confusion between classes and their properties, incorrect classifications, and overemphasis on subsumption, confirming what already observed by other researchers. However, it also suggested some properties for Activities that could be included in a more formal model: number of agents involved, the instrument used to carry out the activity, the object of the activity, complexity of the task, and an enumeration of relevant subtasks.

The NMR structure of human obestatin in membrane-like environments: insights into the structure-bioactivity relationship of obestatin.

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Alén, Begoña O; Nieto, Lidia; Gurriarán-Rodríguez, Uxía; Mosteiro, Carlos S; Álvarez-Pérez, Juan C; Otero-Alén, María; Camiña, Jesús P; Gallego, Rosalía; García-Caballero, Tomás; Martín-Pastor, Manuel; Casanueva, Felipe F; Jiménez-Barbero, Jesús; Pazos, Yolanda

2012-01-01

The quest for therapeutic applications of obestatin involves, as a first step, the determination of its 3D solution structure and the relationship between this structure and the biological activity of obestatin. On this basis, we have employed a combination of circular dichroism (CD), nuclear magnetic resonance (NMR) spectroscopy, and modeling techniques to determine the solution structure of human obestatin (1). Other analogues, including human non-amidated obestatin (2) and the fragment peptides (6-23)-obestatin (3), (11-23)-obestatin (4), and (16-23)-obestatin (5) have also been scrutinized. These studies have been performed in a micellar environment to mimic the cell membrane (sodium dodecyl sulfate, SDS). Furthermore, structural-activity relationship studies have been performed by assessing the in vitro proliferative capabilities of these peptides in the human retinal pigmented epithelial cell line ARPE-19 (ERK1/2 and Akt phosphorylation, Ki67 expression, and cellular proliferation). Our findings emphasize the importance of both the primary structure (composition and size) and particular segments of the obestatin molecule that posses significant α-helical characteristics. Additionally, details of a species-specific role for obestatin have also been hypothesized by comparing human and mouse obestatins (1 and 6, respectively) at both the structural and bioactivity levels.

The NMR structure of human obestatin in membrane-like environments: insights into the structure-bioactivity relationship of obestatin.

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Begoña O Alén

Full Text Available The quest for therapeutic applications of obestatin involves, as a first step, the determination of its 3D solution structure and the relationship between this structure and the biological activity of obestatin. On this basis, we have employed a combination of circular dichroism (CD, nuclear magnetic resonance (NMR spectroscopy, and modeling techniques to determine the solution structure of human obestatin (1. Other analogues, including human non-amidated obestatin (2 and the fragment peptides (6-23-obestatin (3, (11-23-obestatin (4, and (16-23-obestatin (5 have also been scrutinized. These studies have been performed in a micellar environment to mimic the cell membrane (sodium dodecyl sulfate, SDS. Furthermore, structural-activity relationship studies have been performed by assessing the in vitro proliferative capabilities of these peptides in the human retinal pigmented epithelial cell line ARPE-19 (ERK1/2 and Akt phosphorylation, Ki67 expression, and cellular proliferation. Our findings emphasize the importance of both the primary structure (composition and size and particular segments of the obestatin molecule that posses significant α-helical characteristics. Additionally, details of a species-specific role for obestatin have also been hypothesized by comparing human and mouse obestatins (1 and 6, respectively at both the structural and bioactivity levels.

Using Structural Equation Modeling to Examine the Effects of Sex and Physical Activity on the Metabolic Syndrome and Health-related Quality of Life Relationship

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Peter D. Hart

2018-01-01

Full Text Available Objectives The purpose of this study was to use structural equation modeling (SEM to investigate the moderating effects of sex and the mediating effects of physical activity (PA on the metabolic syndrome (MetS and health-related quality of life (HRQOL relationship. Methods The 2013-14 NHANES was used and included 1,077 adults 50+ years of age. A latent construct of MetS was created using five observed variables: waist circumference, HDL cholesterol, triglycerides, fasting glucose, and mean arterial pressure. A PA variable was created from self-reported moderate and vigorous recreational activity and converted to quartiles of moderate-to-vigorous PA minutes per week. HRQOL was assessed from a question regarding self-rated general health and dichotomized to indicate poor/good HRQOL. Results The MetS latent model showed adequate fit (χ2/df=2.47, GFI=0.99, CFI=0.99, and RMSEA=0.04 and significantly (P<.001 predicted all observed variables. The structural model also showed adequate fit with significant direct effects of MetS on HRQOL (β= −0.118, P<0.001 and PA on HRQOL (β=0.176, P<0.001. The effect of MetS on HRQOL (β= −0.048, P=0.001 through PA revealed that PA mediates the relationship. The multi-group analysis showed that the structural model was significantly different between males and females, with PA completely mediating the MetS and HRQOL relationship in males and partially mediating the relationship in females. Conclusions Results from this study support the use of SEM for investigating moderating and mediating effects while simultaneously measuring a latent construct. Additionally, PA was a stronger mediator to the MetS and HRQOL relationship in older males than in older females.

Discovery, synthesis, and structure-activity relationships of 20(S)-protopanaxadiol (PPD) derivatives as a novel class of AMPKα2β1γ1 activators.

Science.gov (United States)

Liu, Junhua; Chen, Dakai; Liu, Peng; He, Mengna; Li, Jia; Li, Jingya; Hu, Lihong

2014-05-22

Adenosine 5'-monophosphate-activated protein kinase (AMPK) has been demonstrated as a promising drug target due to its regulatory function in glucose and lipid metabolism. 20(S)-protopanoxadiol (PPD) was firstly identified from high throughput screening as a small molecule activator of AMPK subtype α2β1γ1. In order to enhance its potency on AMPK, a series of PPD derivatives were synthesized and evaluated. Structure-activity relationship study showed that the amine derivatives at the 24-position (groups I-VI) can improve the potency (EC50: 0.7-2.3 μM) and efficacy (fold: 2.5-3.8). Among them, compounds 12 and 13 exhibited the best potency (EC50: 1.2 and 0.7 μM) and efficacy (fold: 3.7 and 3.8). Further study suggested the mechanism of AMPK activation may functioned at the allosteric position, resulting the inhibition of the lipid synthesis in HepG2 cell model. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

The relationship between self-control, job satisfaction and life satisfaction in Chinese employees: A preliminary study.

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Dou, Kai; Nie, Yan-Gang; Wang, Yu-Jie; Liu, Yao-Zhong

2016-01-01

Previous studies have demonstrated that self-control is positively related to life satisfaction, but this association in Chinese employees and its underlying mechanism are less commonly investigated. In this preliminary study the relationships between self-control and life satisfaction and the mediating effect of job satisfaction were tested. Participants were 482 full-time employees (188 male, 294 female) from different cities in China. They answered self-report questionnaires online that assessed self-control, job satisfaction, and life satisfaction. Path analyses were conducted and bootstrap technique was used to judge the significance of the mediation. Self-control was positively related to both job and life satisfaction. More importantly, job satisfaction significantly mediated the association between self-control and life satisfaction. Furthermore, there was no significant difference in the size of the mediating effect between intrinsic and extrinsic job satisfaction. Results of this preliminary study provide further evidence of the positive association between self-control and life satisfaction. Job satisfaction is found to mediate this relationship.

Preliminary investigation of airgap electrospun silk-fibroin-based structures for ligament analogue engineering.

Science.gov (United States)

Sell, S A; McClure, M J; Ayres, C E; Simpson, D G; Bowlin, G L

2011-01-01

The process of electrospinning has proven to be highly beneficial for use in a number of tissue-engineering applications due to its ease of use, flexibility and tailorable properties. There have been many publications on the creation of aligned fibrous structures created through various forms of electrospinning, most involving the use of a metal target rotating at high speeds. This work focuses on the use of a variation known as airgap electrospinning, which does not use a metal collecting target but rather a pair of grounded electrodes equidistant from the charged polymer solution to create highly aligned 3D structures. This study involved a preliminary investigation and comparison of traditionally and airgap electrospun silk-fibroin-based ligament constructs. Structures were characterized with SEM and alignment FFT, and underwent porosity, permeability, and mechanical anisotropy evaluation. Preliminary cell culture with human dermal fibroblasts was performed to determine the degree of cellular orientation and penetration. Results showed airgap electrospun structures to be anisotropic with significantly increased porosity and cellular penetration compared to their traditionally electrospun counterparts.

Optimization of triazine nitriles as rhodesain inhibitors: structure-activity relationships, bioisosteric imidazopyridine nitriles, and X-ray crystal structure analysis with human cathepsin L.

Science.gov (United States)

Ehmke, Veronika; Winkler, Edwin; Banner, David W; Haap, Wolfgang; Schweizer, W Bernd; Rottmann, Matthias; Kaiser, Marcel; Freymond, Céline; Schirmeister, Tanja; Diederich, François

2013-06-01

The cysteine protease rhodesain of Trypanosoma brucei parasites causing African sleeping sickness has emerged as a target for the development of new drug candidates. Based on a triazine nitrile moiety as electrophilic headgroup, optimization studies on the substituents for the S1, S2, and S3 pockets of the enzyme were performed using structure-based design and resulted in inhibitors with inhibition constants in the single-digit nanomolar range. Comprehensive structure-activity relationships clarified the binding preferences of the individual pockets of the active site. The S1 pocket tolerates various substituents with a preference for flexible and basic side chains. Variation of the S2 substituent led to high-affinity ligands with inhibition constants down to 2 nM for compounds bearing cyclohexyl substituents. Systematic investigations on the S3 pocket revealed its potential to achieve high activities with aromatic vectors that undergo stacking interactions with the planar peptide backbone forming part of the pocket. X-ray crystal structure analysis with the structurally related enzyme human cathepsin L confirmed the binding mode of the triazine ligand series as proposed by molecular modeling. Sub-micromolar inhibition of the proliferation of cultured parasites was achieved for ligands decorated with the best substituents identified through the optimization cycles. In cell-based assays, the introduction of a basic side chain on the inhibitors resulted in a 35-fold increase in antitrypanosomal activity. Finally, bioisosteric imidazopyridine nitriles were studied in order to prevent off-target effects with unselective nucleophiles by decreasing the inherent electrophilicity of the triazine nitrile headgroup. Using this ligand, the stabilization by intramolecular hydrogen bonding of the thioimidate intermediate, formed upon attack of the catalytic cysteine residue, compensates for the lower reactivity of the headgroup. The imidazopyridine nitrile ligand showed

Identification of Lilial as a fragrance sensitizer in a perfume by bioassay-guided chemical fractionation and structure-activity relationships

DEFF Research Database (Denmark)

Gimenéz-Arnau, Elena; Andersen, K E; Bruze, M

2000-01-01

Fragrance materials are among the most common causes of allergic contact dermatitis. The aim of this study was to identify in a perfume fragrance allergens not included in the fragrance mix, by use of bioassay-guided chemical fractionation and chemical analysis/structure-activity relationships...... (SARs). The basis for the investigation was a 45-year-old woman allergic to her own perfume. She had a negative patch test to the fragrance mix and agreed to participate in the study. Chemical fractionation of the perfume concentrate was used for repeated patch testing and/or repeated open application...

Structure-activity relationship of 9-methylstreptimidone, a compound that induces apoptosis selectively in adult T-cell leukemia cells.

Science.gov (United States)

Takeiri, Masatoshi; Ota, Eisuke; Nishiyama, Shigeru; Kiyota, Hiromasa; Umezawa, Kazuo

2012-01-01

We previously reported that 9-methylstreptimidone, a piperidine compound isolated from a culture filtrate of Streptomyces, induces apoptosis selectively in adult T-cell leukemia cells. It was screened for a compound that inhibits LPS-induced NF-kappaB and NO production in mouse macrophages. However, 9-methystreptimidone is poorly obtained from the producing microorganism and difficult to synthesize. Therefore, in the present research, we studied the structure-activity relationship to look for new selective inhibitors. We found that the structure of the unsaturated hydrophobic portion of 9-methylstreptimidone was essential for the inhibition of LPS-induced NO production. Among the 9-methylstreptimidone-related compounds tested, (+/-)-4,alpha-diepi-streptovitacin A inhibited NO production in macrophage-like cells as potently as 9-methylstreptimidone and without cellular toxicity. Moreover, this compound selectively induced apoptosis in adult T-cell leukemia MT-1 cells.

Design, Synthesis and Evaluation of Antiproliferative Activity of New Benzimidazolehydrazones

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Valentina Onnis

2016-04-01

Full Text Available The synthesis and antiproliferative activity of new benzimidazole derivatives bearing an hydrazone mojety at the 2-position is described. The new N′-(4-arylidene-1H-benzo[d]imidazole-2-carbohydrazides were evaluated for their cytostatic activity toward the murine leukemia (L1210, human T-cell leukemia (CEM, human cervix carcinoma (HeLa and human pancreas carcinoma cells (Mia Paca-2. A preliminary structure-activity relationship could be defined. Some of the compounds possess encouraging and consistent antiproliferative activity, having IC50 values in the low micromolar range.

Studies on Synthesis and Structure-Activity Relationship (SAR of Derivatives of a New Natural Product from Marine Fungi as Inhibitors of Influenza Virus Neuraminidase

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Yongcheng Lin

2011-10-01

Full Text Available Based on the natural isoprenyl phenyl ether from a mangrove-derived fungus, 32 analogues were synthesized and evaluated for inhibitory activity against influenza H1N1 neuraminidase. Compound 15 (3-(allyloxy-4-hydroxybenzaldehyde exhibited the most potent inhibitory activity, with IC50 values of 26.96 μM for A/GuangdongSB/01/2009 (H1N1, 27.73 μM for A/Guangdong/03/2009 (H1N1, and 25.13 μM for A/Guangdong/05/2009 (H1N1, respectively, which is stronger than the benzoic acid derivatives (~mM level. These are a new kind of non-nitrogenous aromatic ether Neuraminidase (NA inhibitors. Their structures are simple and the synthesis routes are not complex. The structure-activity relationship (SAR analysis revealed that the aryl aldehyde and unsubstituted hydroxyl were important to NA inhibitory activities. Molecular docking studies were carried out to explain the SAR of the compounds, and provided valuable information for further structure modification.

The chemical structures, plant origins, ethnobotany and biological activities of homoisoflavanones.

Science.gov (United States)

du Toit, Karen; Drewes, Siegfried E; Bodenstein, Johannes

2010-03-01

This work reviews the four basic structural types of homoisoflavanones. The relationships between the various structures of homoisoflavanones and their plant origins, ethnobotany and biological activities are put into perspective.

Synthesis and Antifungal Activity of Musa Phytoalexins and Structural Analogs

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Adriana Gallego

2000-07-01

Full Text Available Several perinaphthenone/phenylphenalenone compounds were synthesized to establish a relationship between structure and antifungal activity against Mycosphaerella fijiensis. Substitutions on the unsaturated carbonyl system or addition of a phenyl group reduced antibiotic activity.

Flavonoids from Agrimonia pilosa Ledeb: Free Radical Scavenging and DNA Oxidative Damage Protection Activities and Analysis of Bioactivity-Structure Relationship Based on Molecular and Electronic Structures.

Science.gov (United States)

Zhu, Liancai; Chen, Jinqiu; Tan, Jun; Liu, Xi; Wang, Bochu

2017-02-26

To clarify the substantial basis of the excellent antioxidant capacity of Agrimonia pilosa Ledeb. Fourteen flavonoids were isolated and identified from Agrimonia pilosa Ledeb, seven of which have notable DPPH radical scavenging activities, i.e., catechin, luteolin, quercetin, quercitrin, hyperoside, rutin, luteolin-7- O -β-glucoside with IC 50 values of 5.06, 7.29, 4.36, 7.12, 6.34, 6.36 and 8.12 µM, respectively. The DNA nicking assay showed that five flavonoids from Agrimonia pilosa Ledeb-taxifolin, catechin, hyperoside, quercitrin and rutin-have good protective activity against DNA oxidative damage. Further, we analyzed the bioactivity-structure relationship of these 14 flavonoids by applying quantum theory. According to their O-H bond dissociation enthalpy (BDE), C ring's spin density and stable molecular structure, the relationship between their structures and radical scavenging capacities was evaluated and clarified. We found that among flavonoid aglycones from Agrimonia pilosa Ledeb, the O-H BDE of quercetin is lowest with the values of 69.02 and the O-H BDE of apigenin is highest with the values of 79.77. It is interesting that the O-H BDE value of isovitexin (78.55) with glycoside at C-6 position is lower than that of its aglycone (79.77) and vitexin (99.20) with glycoside at C-8 position. Further analysis indicated that the glycosidation of flavonoids at C-6 in the A-ring makes a more uniform distribution of spin density and improves the stability of free radicals leading to the increase in antioxidant capacity. Flavonoids with good antioxidant capacity might contribute to the pharmacological effects of Agrimonia pilosa Ledeb.

Flavonoids from Agrimonia pilosa Ledeb: Free Radical Scavenging and DNA Oxidative Damage Protection Activities and Analysis of Bioactivity-Structure Relationship Based on Molecular and Electronic Structures

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Liancai Zhu

2017-02-01

Full Text Available To clarify the substantial basis of the excellent antioxidant capacity of Agrimonia pilosa Ledeb. Fourteen flavonoids were isolated and identified from Agrimonia pilosa Ledeb, seven of which have notable DPPH radical scavenging activities, i.e., catechin, luteolin, quercetin, quercitrin, hyperoside, rutin, luteolin-7-O-β-glucoside with IC50 values of 5.06, 7.29, 4.36, 7.12, 6.34, 6.36 and 8.12 µM, respectively. The DNA nicking assay showed that five flavonoids from Agrimonia pilosa Ledeb—taxifolin, catechin, hyperoside, quercitrin and rutin—have good protective activity against DNA oxidative damage. Further, we analyzed the bioactivity-structure relationship of these 14 flavonoids by applying quantum theory. According to their O-H bond dissociation enthalpy (BDE, C ring’s spin density and stable molecular structure, the relationship between their structures and radical scavenging capacities was evaluated and clarified. We found that among flavonoid aglycones from Agrimonia pilosa Ledeb, the O-H BDE of quercetin is lowest with the values of 69.02 and the O-H BDE of apigenin is highest with the values of 79.77. It is interesting that the O-H BDE value of isovitexin (78.55 with glycoside at C-6 position is lower than that of its aglycone (79.77 and vitexin (99.20 with glycoside at C-8 position. Further analysis indicated that the glycosidation of flavonoids at C-6 in the A-ring makes a more uniform distribution of spin density and improves the stability of free radicals leading to the increase in antioxidant capacity. Flavonoids with good antioxidant capacity might contribute to the pharmacological effects of Agrimonia pilosa Ledeb.

Structural analysis and antimicrobial activity of 2[1H]-pyrimidinethione/selenone derivatives

Science.gov (United States)

Żesławska, Ewa; Korona-Głowniak, Izabela; Szczesio, Małgorzata; Olczak, Andrzej; Żylewska, Alicja; Tejchman, Waldemar; Malm, Anna

2017-08-01

Four new crystal structures of sulfur and selenium analogues of 2[1H]-pyrimidinone derivatives were determined with the use of X-ray diffraction method. The molecular geometry and intermolecular interactions of the investigated molecules were analyzed in order to find the structural features and geometrical parameters, which can be responsible for antimicrobial activities. The influence of chalcogen substituents (sulfur and selenium) on the crystal packing was also studied. The main differences in the molecular structures exist in mutual arrangement of two aromatic rings. The intermolecular interactions in all investigated compounds are similar. Furthermore, the in vitro antibacterial and antifungal activities for these compounds were evaluated. Preliminary investigations have identified two highly potent antibacterial compounds containing selenium atom, which display selectivity towards staphylococci and micrococci. This selectivity was not observed for a control compound used as a drug, namely vancomycin. These compounds possess also good antifungal activity. This is the first report of biological activities of 2[1H]-pyrimidineselenone derivatives.

Regional brain activity during early-stage intense romantic love predicted relationship outcomes after 40 months: an fMRI assessment.

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Xu, Xiaomeng; Brown, Lucy; Aron, Arthur; Cao, Guikang; Feng, Tingyong; Acevedo, Bianca; Weng, Xuchu

2012-09-20

Early-stage romantic love is associated with activation in reward and motivation systems of the brain. Can these localized activations, or others, predict long-term relationship stability? We contacted participants from a previous fMRI study of early-stage love by Xu et al. [34] after 40 months from initial assessments. We compared brain activation during the initial assessment at early-stage love for those who were still together at 40 months and those who were apart, and surveyed those still together about their relationship happiness and commitment at 40 months. Six participants who were still with their partners at 40 months (compared to six who had broken up) showed less activation during early-stage love in the medial orbitofrontal cortex, right subcallosal cingulate and right accumbens, regions implicated in long-term love and relationship satisfaction [1,2]. These regions of deactivation at the early stage of love were also negatively correlated with relationship happiness scores collected at 40 months. Other areas involved were the caudate tail, and temporal and parietal lobes. These data are preliminary evidence that neural responses in the early stages of romantic love can predict relationship stability and quality up to 40 months later in the relationship. The brain regions involved suggest that forebrain reward functions may be predictive for relationship stability, as well as regions involved in social evaluation, emotional regulation, and mood. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Investigation of Antileishmanial Activities of Acridines Derivatives against Promastigotes and Amastigotes Form of Parasites Using Quantitative Structure Activity Relationship Analysis

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Samir Chtita

2016-01-01

Full Text Available In a search of newer and potent antileishmanial (against promastigotes and amastigotes form of parasites drug, a series of 60 variously substituted acridines derivatives were subjected to a quantitative structure activity relationship (QSAR analysis for studying, interpreting, and predicting activities and designing new compounds by using multiple linear regression and artificial neural network (ANN methods. The used descriptors were computed with Gaussian 03, ACD/ChemSketch, Marvin Sketch, and ChemOffice programs. The QSAR models developed were validated according to the principles set up by the Organisation for Economic Co-operation and Development (OECD. The principal component analysis (PCA has been used to select descriptors that show a high correlation with activities. The univariate partitioning (UP method was used to divide the dataset into training and test sets. The multiple linear regression (MLR method showed a correlation coefficient of 0.850 and 0.814 for antileishmanial activities against promastigotes and amastigotes forms of parasites, respectively. Internal and external validations were used to determine the statistical quality of QSAR of the two MLR models. The artificial neural network (ANN method, considering the relevant descriptors obtained from the MLR, showed a correlation coefficient of 0.933 and 0.918 with 7-3-1 and 6-3-1 ANN models architecture for antileishmanial activities against promastigotes and amastigotes forms of parasites, respectively. The applicability domain of MLR models was investigated using simple and leverage approaches to detect outliers and outsides compounds. The effects of different descriptors in the activities were described and used to study and design new compounds with higher activities compared to the existing ones.

Structure-Activity Relationship of Curcumin: Role of the Methoxy Group in Anti-inflammatory and Anticolitis Effects of Curcumin.

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Yang, Haixia; Du, Zheyuan; Wang, Weicang; Song, Mingyue; Sanidad, Katherine; Sukamtoh, Elvira; Zheng, Jennifer; Tian, Li; Xiao, Hang; Liu, Zhenhua; Zhang, Guodong

2017-06-07

Curcumin, a dietary compound from turmeric, has beneficial effects on inflammatory diseases such as inflammatory bowel disease. Most previous studies have focused on the structure-activity relationship of the thiol-reactive α,β-unsaturated carbonyl groups of curcumin, so little is known about the roles of methoxy groups in biological activities of curcumin. Here we synthesized a series of curcumin analogues with different substitution groups (R = H-, Br-, Cl-, F-, NO 2 -, CH 3 -, and OH-) to replace the methoxy group and evaluated their biological effects in vitro and in vivo. Curcumin, Cur-OH, and Cur-Br (25 μM) suppressed 74.91 ± 0.88, 77.75 ± 0.89, and 71.75 ± 0.90% of LPS-induced NO production, respectively (P 0.05). In the dextran sulfate sodium (DSS)-induced colitis mouse model, the Cur-Br analogue also showed a beneficial effect the same as curcumin (P 0.05). Together, the analogues have dramatically different effects on inflammation, supporting that the substitution group on the methoxy position plays an important role in the anti-inflammatory effects of curcumin. The methoxy group is a potential structural candidate for modification to design curcumin-based drugs for inflammatory diseases.

Designing quantitative structure activity relationships to predict specific toxic endpoints for polybrominated diphenyl ethers in mammalian cells.

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Rawat, S; Bruce, E D

2014-01-01

Polybrominated diphenyl ethers (PBDEs) are known as effective flame retardants and have vast industrial application in products like plastics, building materials and textiles. They are found to be structurally similar to thyroid hormones that are responsible for regulating metabolism in the body. Structural similarity with the hormones poses a threat to human health because, once in the system, PBDEs have the potential to affect thyroid hormone transport and metabolism. This study was aimed at designing quantitative structure-activity relationship (QSAR) models for predicting toxic endpoints, namely cell viability and apoptosis, elicited by PBDEs in mammalian cells. Cell viability was evaluated quantitatively using a general cytotoxicity bioassay using Janus Green dye and apoptosis was evaluated using a caspase assay. This study has thus modelled the overall cytotoxic influence of PBDEs at an early and a late endpoint by the Genetic Function Approximation method. This research was a twofold process including running in vitro bioassays to collect data on the toxic endpoints and modeling the evaluated endpoints using QSARs. Cell viability and apoptosis responses for Hep G2 cells exposed to PBDEs were successfully modelled with an r(2) of 0.97 and 0.94, respectively.

Comparison of 3D quantitative structure-activity relationship methods: Analysis of the in vitro antimalarial activity of 154 artemisinin analogues by hypothetical active-site lattice and comparative molecular field analysis

Science.gov (United States)

Woolfrey, John R.; Avery, Mitchell A.; Doweyko, Arthur M.

1998-03-01

Two three-dimensional quantitative structure-activity relationship (3D-QSAR) methods, comparative molecular field analysis (CoMFA) and hypothetical active site lattice (HASL), were compared with respect to the analysis of a training set of 154 artemisinin analogues. Five models were created, including a complete HASL and two trimmed versions, as well as two CoMFA models (leave-one-out standard CoMFA and the guided-region selection protocol). Similar r2 and q2 values were obtained by each method, although some striking differences existed between CoMFA contour maps and the HASL output. Each of the four predictive models exhibited a similar ability to predict the activity of a test set of 23 artemisinin analogues, although some differences were noted as to which compounds were described well by either model.

A New Structure-Activity Relationship (SAR) Model for Predicting Drug-Induced Liver Injury, Based on Statistical and Expert-Based Structural Alerts

Science.gov (United States)

Pizzo, Fabiola; Lombardo, Anna; Manganaro, Alberto; Benfenati, Emilio

2016-01-01

The prompt identification of chemical molecules with potential effects on liver may help in drug discovery and in raising the levels of protection for human health. Besides in vitro approaches, computational methods in toxicology are drawing attention. We built a structure-activity relationship (SAR) model for evaluating hepatotoxicity. After compiling a data set of 950 compounds using data from the literature, we randomly split it into training (80%) and test sets (20%). We also compiled an external validation set (101 compounds) for evaluating the performance of the model. To extract structural alerts (SAs) related to hepatotoxicity and non-hepatotoxicity we used SARpy, a statistical application that automatically identifies and extracts chemical fragments related to a specific activity. We also applied the chemical grouping approach for manually identifying other SAs. We calculated accuracy, specificity, sensitivity and Matthews correlation coefficient (MCC) on the training, test and external validation sets. Considering the complexity of the endpoint, the model performed well. In the training, test and external validation sets the accuracy was respectively 81, 63, and 68%, specificity 89, 33, and 33%, sensitivity 93, 88, and 80% and MCC 0.63, 0.27, and 0.13. Since it is preferable to overestimate hepatotoxicity rather than not to recognize unsafe compounds, the model's architecture followed a conservative approach. As it was built using human data, it might be applied without any need for extrapolation from other species. This model will be freely available in the VEGA platform. PMID:27920722

Photorealistic avatar and teen physical activity: Feasibility and preliminary efficacy

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Exergames played with a photorealistic avatar may enhance motivation to play, as well as frequency, duration, and intensity of game-play. This manuscript reports the feasibility and preliminary efficacy of an exergame played with a photorealistic avatar on physical activity intensity in a laboratory...

Structure-Property Relationships in Polycyanurate / Graphene Networks

Science.gov (United States)

2015-12-12

Briefing Charts 3. DATES COVERED (From - To) 17 Nov 2015 – 12 Dec 2015 4. TITLE AND SUBTITLE Structure-Property Relationships in Polycyanurate...ANSI Std. 239.18 1 DISTRIBUTION STATEMENT A. Approved for public release; distribution is unlimited. Structure-Property Relationships in...the attractive processing characteristics of LECy are retained in graphene oxide / LECy mixtures. Impurities, such as aryl phenols and transition metals

Relationship between Static Stiffness and Modal Stiffness of Structures

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Tianjian Ji Tianjian Ji

2010-02-01

Full Text Available This paper derives the relationship between the static stiffness and modal stiffness of a structure. The static stiffness and modal stiffness are two important concepts in both structural statics and dynamics. Although both stiffnesses indicate the capacity of the structure to resist deformation, they are obtained using different methods. The former is calculated by solving the equations of equilibrium and the latter can be obtained by solving an eigenvalue problem. A mathematical relationship between the two stiffnesses was derived based on the definitions of two stiffnesses. This relationship was applicable to a linear system and the derivation of relationships does not reveal any other limitations. Verification of the relationship was given by using several examples. The relationship between the two stiffnesses demonstrated that the modal stiffness of the fundamental mode was always larger than the static stiffness of a structure if the critical point and the maximum mode value are at the same node, i.e. for simply supported beam and seven storeys building are 1.5% and 15% respectively. The relationship could be applied into real structures, where the greater the number of modes being considered, the smaller the difference between the modal stiffness and the static stiffness of a structure.

Structure-Activity Relationships for Rates of Aromatic Amine Oxidation by Manganese Dioxide.

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Salter-Blanc, Alexandra J; Bylaska, Eric J; Lyon, Molly A; Ness, Stuart C; Tratnyek, Paul G

2016-05-17

New energetic compounds are designed to minimize their potential environmental impacts, which includes their transformation and the fate and effects of their transformation products. The nitro groups of energetic compounds are readily reduced to amines, and the resulting aromatic amines are subject to oxidation and coupling reactions. Manganese dioxide (MnO2) is a common environmental oxidant and model system for kinetic studies of aromatic amine oxidation. In this study, a training set of new and previously reported kinetic data for the oxidation of model and energetic-derived aromatic amines was assembled and subjected to correlation analysis against descriptor variables that ranged from general purpose [Hammett σ constants (σ(-)), pKas of the amines, and energies of the highest occupied molecular orbital (EHOMO)] to specific for the likely rate-limiting step [one-electron oxidation potentials (Eox)]. The selection of calculated descriptors (pKa, EHOMO, and Eox) was based on validation with experimental data. All of the correlations gave satisfactory quantitative structure-activity relationships (QSARs), but they improved with the specificity of the descriptor. The scope of correlation analysis was extended beyond MnO2 to include literature data on aromatic amine oxidation by other environmentally relevant oxidants (ozone, chlorine dioxide, and phosphate and carbonate radicals) by correlating relative rate constants (normalized to 4-chloroaniline) to EHOMO (calculated with a modest level of theory).

Active sensors for health monitoring of aging aerospace structures

Science.gov (United States)

Giurgiutiu, Victor; Redmond, James M.; Roach, Dennis P.; Rackow, Kirk

2000-06-01

A project to develop non-intrusive active sensors that can be applied on existing aging aerospace structures for monitoring the onset and progress of structural damage (fatigue cracks and corrosion) is presented. The state of the art in active sensors structural health monitoring and damage detection is reviewed. Methods based on (a) elastic wave propagation and (b) electro-mechanical (E/M) impedance technique are cited and briefly discussed. The instrumentation of these specimens with piezoelectric active sensors is illustrated. The main detection strategies (E/M impedance for local area detection and wave propagation for wide area interrogation) are discussed. The signal processing and damage interpretation algorithms are tuned to the specific structural interrogation method used. In the high frequency E/M impedance approach, pattern recognition methods are used to compare impedance signatures taken at various time intervals and to identify damage presence and progression from the change in these signatures. In the wave propagation approach, the acousto- ultrasonic methods identifying additional reflection generated from the damage site and changes in transmission velocity and phase are used. Both approaches benefit from the use of artificial intelligence neural networks algorithms that can extract damage features based on a learning process. Design and fabrication of a set of structural specimens representative of aging aerospace structures is presented. Three built-up specimens, (pristine, with cracks, and with corrosion damage) are used. The specimen instrumentation with active sensors fabricated at the University of South Carolina is illustrated. Preliminary results obtained with the E/M impedance method on pristine and cracked specimens are presented.

Relationship between beliefs, motivation, and worries about physical activity and physical activity participation in persons with rheumatoid arthritis.

Science.gov (United States)

Ehrlich-Jones, Linda; Lee, Jungwha; Semanik, Pamela; Cox, Cheryl; Dunlop, Dorothy; Chang, Rowland W

2011-12-01

To determine the relationship between beliefs, motivation, and worries about physical activity and physical activity participation in persons with rheumatoid arthritis (RA). A cross-sectional study used baseline data from 185 adults with RA enrolled in a randomized clinical trial assessing the effectiveness of an intervention to promote physical activity. Data included patients' self-reported beliefs that physical activity can be beneficial for their disease, motivation for physical activity participation, worries about physical activity participation, and average daily accelerometer counts of activity over a week's time. Body mass index (BMI), sex, age, race, and disease activity were measured as potential statistical moderators of physical activity. Physical activity participation was greater for those with higher scores on scales measuring beliefs that physical activity is beneficial for their disease (P for trend = 0.032) and motivation for physical activity participation (P for trend = 0.007) when adjusted for age, sex, BMI, race, and disease activity. There was a positive but nonsignificant trend in physical activity participation in relation to worries. Stronger beliefs that physical activity can be helpful for managing disease and increased motivation to engage in physical activity are related to higher levels of physical activity participation. These data provide a preliminary empirical rationale for why interventions targeting these concepts should lead to improved physical activity participation in adults with RA. Copyright © 2011 by the American College of Rheumatology.

Identification of residues important for the activity of aldehyde-deformylating oxygenase through investigation into the structure-activity relationship.

Science.gov (United States)

Wang, Qing; Bao, Luyao; Jia, Chenjun; Li, Mei; Li, Jian-Jun; Lu, Xuefeng

2017-03-16

Aldehyde-deformylating oxygenase (ADO) is a key enzyme involved in the biosynthetic pathway of fatty alk(a/e)nes in cyanobacteria. However, cADO (cyanobacterial ADO) showed extreme low activity with the k cat value below 1 min -1 , which would limit its application in biofuel production. To identify the activity related key residues of cADO is urgently required. The amino acid residues which might affect cADO activity were identified based on the crystal structures and sequence alignment of cADOs, including the residues close to the di-iron center (Tyr39, Arg62, Gln110, Tyr122, Asp143 of cADO-1593), the protein surface (Trp 178 of cADO-1593), and those involved in two important hydrogen bonds (Gln49, Asn123 of cADO-1593, and Asp49, Asn123 of cADO-sll0208) and in the oligopeptide whose conformation changed in the absence of the di-iron center (Leu146, Asn149, Phe150 of cADO-1593, and Thr146, Leu148, Tyr150 of cADO-sll0208). The variants of cADO-1593 from Synechococcus elongatus PCC7942 and cADO-sll0208 from Synechocystis sp. PCC6803 were constructed, overexpressed, purified and kinetically characterized. The k cat values of L146T, Q49H/N123H/F150Y and W178R of cADO-1593 and L148R of cADO-sll0208 were increased by more than two-fold, whereas that of R62A dropped by 91.1%. N123H, Y39F and D143A of cADO-1593, and Y150F of cADO-sll0208 reduced activities by ≤ 20%. Some important amino acids, which exerted some effects on cADO activity, were identified. Several enzyme variants exhibited greatly reduced activity, while the k cat values of several mutants are more than two-fold higher than the wild type. This study presents the report on the relationship between amino acid residues and enzyme activity of cADOs, and the information will provide a guide for enhancement of cADO activity through protein engineering.

Structure-activity relationships of strychnine analogues at glycine receptors

DEFF Research Database (Denmark)

Mohsen, A.M.Y.; Heller, Eberhard; Holzgrabe, Ulrike

2014-01-01

Nine strychnine derivatives including neostrychnine, strychnidine, isostrychnine, 21,22-dihydro-21-hydroxy-22-oxo-strychnine, and several hydrogenated analogs were synthesized, and their antagonistic activities at human α1 and α1β glycine receptors were evaluated. Isostrychnine has shown the best...... pharmacological profile exhibiting an IC50 value of 1.6 μM at α1 glycine receptors and 3.7-fold preference towards the α1 subtype. SAR Analysis indicates that the lactam moiety and the C(21)[DOUBLE BOND]C(22) bond in strychnine are essential structural features for its high antagonistic potency at glycine...

Preliminary design of offshore wind turbine support structures : The importance of proper mode shape estimation

NARCIS (Netherlands)

Van der Male, P.

2013-01-01

Offshore wind turbines are highly exposed to timevarying loads. For support structures, estimation of the fatigue damage during the lifetime of the structure is an essential design aspect. This already applies for the preliminary design stage. In determining the dynamic amplification in the

Cell wall integrity, genotoxic injury and PCD dynamics in alfalfa saponin-treated white poplar cells highlight a complex link between molecule structure and activity.

Science.gov (United States)

Paparella, Stefania; Tava, Aldo; Avato, Pinarosa; Biazzi, Elisa; Macovei, Anca; Biggiogera, Marco; Carbonera, Daniela; Balestrazzi, Alma

2015-03-01

In the present work, eleven saponins and three sapogenins purified from Medicago sativa were tested for their cytotoxicity against highly proliferating white poplar (Populus alba L.) cell suspension cultures. After preliminary screening, four saponins with different structural features in terms of aglycone moieties and sugar chains (saponin 3, a bidesmoside of hederagenin; saponins 4 and 5, monodesmoside and bidesmoside of medicagenic acid respectively, and saponin 10, a bidesmoside of zanhic acid) and different cytotoxicity were selected and used for further investigation on their structure-activity relationship. Transmission Electron Microscopy (TEM) analyses provided for the first time evidence of the effects exerted by saponins on plant cell wall integrity. Exposure to saponin 3 and saponin 10 resulted into disorganization of the outer wall layer and the effect was even more pronounced in white poplar cells treated with the two medicagenic acid derivatives, saponins 4 and 5. Oxidative burst and nitric oxide accumulation were common hallmarks of the response of white poplar cells to saponins. When DNA damage accumulation and DNA repair profiles were evaluated by Single Cell Gel Electrophoresis, induction of single and double strand breaks followed by effective repair was observed within 24h. The reported data are discussed in view of the current issues dealing with saponin structure-activity relationship. Copyright © 2015 Elsevier Ltd. All rights reserved.

Structure activity relationships of quinoxalin-2-one derivatives as platelet-derived growth factor-beta receptor (PDGFbeta R) inhibitors, derived from molecular modeling.

Science.gov (United States)

Mori, Yoshikazu; Hirokawa, Takatsugu; Aoki, Katsuyuki; Satomi, Hisanori; Takeda, Shuichi; Aburada, Masaki; Miyamoto, Ken-ichi

2008-05-01

We previously reported a quinoxalin-2-one compound (Compound 1) that had inhibitory activity equivalent to existing platelet-derived growth factor-beta receptor (PDGFbeta R) inhibitors. Lead optimization of Compound 1 to increase its activity and selectivity, using structural information regarding PDGFbeta R-ligand interactions, is urgently needed. Here we present models of the PDGFbeta R kinase domain complexed with quinoxalin-2-one derivatives. The models were constructed using comparative modeling, molecular dynamics (MD) and ligand docking. In particular, conformations derived from MD, and ligand binding site information presented by alpha-spheres in the pre-docking processing, allowed us to identify optimal protein structures for docking of target ligands. By carrying out molecular modeling and MD of PDGFbeta R in its inactive state, we obtained two structural models having good Compound 1 binding potentials. In order to distinguish the optimal candidate, we evaluated the structural activity relationships (SAR) between the ligand-binding free energies and inhibitory activity values (IC50 values) for available quinoxalin-2-one derivatives. Consequently, a final model with a high SAR was identified. This model included a molecular interaction between the hydrophobic pocket behind the ATP binding site and the substitution region of the quinoxalin-2-one derivatives. These findings should prove useful in lead optimization of quinoxalin-2-one derivatives as PDGFb R inhibitors.

β-Glucans: Relationships between Modification, Conformation and Functional Activities

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Qiang Wang

2017-02-01

Full Text Available β-glucan is a type of polysaccharide which widely exists in bacteria, fungi, algae, and plants, and has been well known for its biological activities such as enhancing immunity, antitumor, antibacterial, antiviral, and wound healing activities. The conformation of β-glucan plays a crucial role on its biological activities. Therefore, β-glucans obtained from different sources, while sharing the same basic structures, often show different bioactivities. The basic structure and inter-molecular forces of polysaccharides can be changed by modification, which leads to the conformational transformation in solution that can directly affect bioactivity. In this review, we will first determine different ways to modify β-glucan molecules including physical methods, chemical methods, and biological methods, and then reveal the relationship of the flexible helix form of the molecule chain and the helix conformation to their bioactivities. Last, we summarize the scientific challenges to modifying β-glucan’s conformation and functional activity, and discuss its potential future development.

Lipid A structural modifications in extreme conditions and identification of unique modifying enzymes to define the Toll-like receptor 4 structure-activity relationship.

Science.gov (United States)

Scott, Alison J; Oyler, Benjamin L; Goodlett, David R; Ernst, Robert K

2017-11-01

Strategies utilizing Toll-like receptor 4 (TLR4) agonists for treatment of cancer, infectious diseases, and other targets report promising results. Potent TLR4 antagonists are also gaining attention as therapeutic leads. Though some principles for TLR4 modulation by lipid A have been described, a thorough understanding of the structure-activity relationship (SAR) is lacking. Only through a complete definition of lipid A-TLR4 SAR is it possible to predict TLR4 signaling effects of discrete lipid A structures, rendering them more pharmacologically relevant. A limited 'toolbox' of lipid A-modifying enzymes has been defined and is largely composed of enzymes from mesophile human and zoonotic pathogens. Expansion of this 'toolbox' will result from extending the search into lipid A biosynthesis and modification by bacteria living at the extremes. Here, we review the fundamentals of lipid A structure, advances in lipid A uses in TLR4 modulation, and the search for novel lipid A-modifying systems in extremophile bacteria. This article is part of a Special Issue entitled: Bacterial Lipids edited by Russell E. Bishop. Copyright © 2017 Elsevier B.V. All rights reserved.

Linking structure and activity in nonlinear spiking networks.

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Gabriel Koch Ocker

2017-06-01

Full Text Available Recent experimental advances are producing an avalanche of data on both neural connectivity and neural activity. To take full advantage of these two emerging datasets we need a framework that links them, revealing how collective neural activity arises from the structure of neural connectivity and intrinsic neural dynamics. This problem of structure-driven activity has drawn major interest in computational neuroscience. Existing methods for relating activity and architecture in spiking networks rely on linearizing activity around a central operating point and thus fail to capture the nonlinear responses of individual neurons that are the hallmark of neural information processing. Here, we overcome this limitation and present a new relationship between connectivity and activity in networks of nonlinear spiking neurons by developing a diagrammatic fluctuation expansion based on statistical field theory. We explicitly show how recurrent network structure produces pairwise and higher-order correlated activity, and how nonlinearities impact the networks' spiking activity. Our findings open new avenues to investigating how single-neuron nonlinearities-including those of different cell types-combine with connectivity to shape population activity and function.

Linking structure and activity in nonlinear spiking networks.

Science.gov (United States)

Ocker, Gabriel Koch; Josić, Krešimir; Shea-Brown, Eric; Buice, Michael A

2017-06-01

Recent experimental advances are producing an avalanche of data on both neural connectivity and neural activity. To take full advantage of these two emerging datasets we need a framework that links them, revealing how collective neural activity arises from the structure of neural connectivity and intrinsic neural dynamics. This problem of structure-driven activity has drawn major interest in computational neuroscience. Existing methods for relating activity and architecture in spiking networks rely on linearizing activity around a central operating point and thus fail to capture the nonlinear responses of individual neurons that are the hallmark of neural information processing. Here, we overcome this limitation and present a new relationship between connectivity and activity in networks of nonlinear spiking neurons by developing a diagrammatic fluctuation expansion based on statistical field theory. We explicitly show how recurrent network structure produces pairwise and higher-order correlated activity, and how nonlinearities impact the networks' spiking activity. Our findings open new avenues to investigating how single-neuron nonlinearities-including those of different cell types-combine with connectivity to shape population activity and function.

Preliminary Investigation of an Active PLZT Lens

Science.gov (United States)

Lightsey, W. D.; Peters, B. R.; Reardon, P. J.; Wong, J. K.

2001-01-01

The design, analysis and preliminary testing of a prototype Adjustable Focus Optical Correction Lens (AFOCL) is described. The AFOCL is an active optical component composed of solid state lead lanthanum-modified zirconate titanate (PLZT) ferroelectric ceramic with patterned indium tin oxide (ITO) transparent surface electrodes that modulate the refractive index of the PLZT to function as an electro-optic lens. The AFOCL was developed to perform optical re-alignment and wavefront correction to enhance the performance of Ultra-Lightweight Structures and Space Observatories (ULSSO). The AFOCL has potential application as an active optical component within a larger optical system. As such, information from a wavefront sensor would be processed to provide input to the AFOCL to drive the sensed wavefront to the desired shape and location. While offering variable and rapid focussing capability (controlled wavefront manipulation) similar to liquid crystal based spatial light modulators (SLM), the AFOCL offers some potential advantages because it is a solid-state, stationary, low-mass, rugged, and thin optical element that can produce wavefront quality comparable to the solid refractive lens it replaces. The AFOCL acts as a positive or negative lens by producing a parabolic phase-shift in the PLZT material through the application of a controlled voltage potential across the ITO electrodes. To demonstrate the technology, a 4 mm diameter lens was fabricated to produce 5-waves of optical power operating at 2.051 micrometer wavelength. Optical metrology was performed on the device to measure focal length, optical quality, and efficiency for a variety of test configurations. The data was analyzed and compared to theoretical data available from computer-based models of the AFOCL.

[Relationship between the anti-hemolysin activity and the structure of catechins and theaflavins].

Science.gov (United States)

Ikigai, H; Toda, M; Okubo, S; Hara, Y; Shimamura, T

1990-11-01

We examined the corresponding isomers of catechins and theaflavins for anti-hemolysin activities against Staphylococcus aureus alpha-toxin and Vibrio cholerae O1 hemolysin. Catechins and theaflavins showed anti-hemolysin activities in a dose-dependent manner. Among the catechins tested, (-)catechin gallate, (-)epicatechin gallate and (-)epigallocatechin gallate having galloyl groups in their molecules showed more potent anti-hemolysin activities against both toxins. On the other hand, free catechins, i. e. (-)catechin, (-)gallocatechin, (-) epicatechin and (-)epigallocatechin had low anti-hemolysin activities against alpha-toxin. Although (-)catechin or (-)gallocatechin had no effect on cholera hemolysin, (-) epicatechin and (-)epigallocatechin were slightly inhibitory. Among dextrocatechins, (+) epicatechin and (+)epigallocatechin proved to be more effective than (+)catechin and (+) gallocatechin. The anti-hemolysin activities of theaflavins against alpha-toxin and cholera hemolysin were dependent on the number of the galloyl group in their structure. These results suggest that the tertiary structure of the catechin or theaflavin and the active site of hemolysin, that affects the interaction between them, plays an important role in the anti-hemolysin activity.

Insights into the structure-activity relationship of the anticancer compound ZJ-101, a derivative of marine natural product superstolide A: A role played by the lactone moiety.

Science.gov (United States)

Qiu, Haibo; Qian, Shan; Head, Sarah A; Liu, Jun O; Jin, Zhendong

2016-10-01

Compound ZJ-101, a structurally simplified analog of the marine natural product superstolide A, was previously developed in our laboratory. In the subsequent structure-activity relationship study, a new analog ZJ-109 was designed and synthesized to probe the importance of the lactone moiety of the molecule by replacing the lactone in ZJ-101 with a lactam. The biological evaluation showed that ZJ-109 is about 8-12 times less active against cancer cells in vitro than ZJ-101, suggesting that the lactone moiety of the molecule is important for its anticancer activity. Copyright © 2016 Elsevier Ltd. All rights reserved.

Structure–Activity Relationship of Oligomeric Flavan-3-ols: Importance of the Upper-Unit B-ring Hydroxyl Groups in the Dimeric Structure for Strong Activities

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Yoshitomo Hamada

2015-10-01

Full Text Available Proanthocyanidins, which are composed of oligomeric flavan-3-ol units, are contained in various foodstuffs (e.g., fruits, vegetables, and drinks and are strongly biologically active compounds. We investigated which element of the proanthocyanidin structure is primarily responsible for this functionality. In this study, we elucidate the importance of the upper-unit of 4–8 condensed dimeric flavan-3-ols for antimicrobial activity against Saccharomyces cerevisiae (S. cerevisiae and cervical epithelioid carcinoma cell line HeLa S3 proliferation inhibitory activity. To clarify the important constituent unit of proanthocyanidin, we synthesized four dimeric compounds, (−-epigallocatechin-[4,8]-(+-catechin, (−-epigallocatechin-[4,8]-(−-epigallocatechin, (−-epigallocatechin-[4,8]-(−-epigallocatechin-3-O-gallate, and (+-catechin-[4,8]-(−-epigallocatechin and performed structure–activity relationship (SAR studies. In addition to antimicrobial activity against S. cerevisiae and proliferation inhibitory activity on HeLa S3 cells, the correlation of 2,2-diphenyl-l-picrylhydrazyl radical scavenging activity with the number of phenolic hydroxyl groups was low. On the basis of the results of our SAR studies, we concluded that B-ring hydroxyl groups of the upper-unit of the dimer are crucially important for strong and effective activity.

QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIP ANALYSIS (QSAR OF VINCADIFFORMINE ANALOGUES AS THE ANTIPLASMODIAL COMPOUNDS OF THE CHLOROQUINOSENSIBLE STRAIN

Directory of Open Access Journals (Sweden)

Iqmal Tahir

2010-06-01

Full Text Available Quantitative Structure-Activity Relationship (QSAR analysis of vincadifformine analogs as an antimalarial drug has been conducted using atomic net charges (q, moment dipole (, LUMO (Lowest Unoccupied Molecular Orbital and HOMO (Highest Occupied Molecular Orbital energies, molecular mass (m as well as surface area (A as the predictors to their activity. Data of predictors are obtained from computational chemistry method using semi-empirical molecular orbital AM1 calculation. Antimalarial activities were taken as the activity of the drugs against chloroquine-sensitive Plasmodium falciparum (Nigerian Cell strain and were presented as the value of ln(1/IC50 where IC50 is an effective concentration inhibiting 50% of the parasite growth. The best QSAR model has been determined by multiple linier regression analysis giving QSAR equation: Log (1/IC50 = 9.602.qC1 -17.012.qC2 +6.084.qC3 -19.758.qC5 -6.517.qC6 +2.746.qC7 -6.795.qN +6.59.qC8 -0.190. -0.974.ELUMO +0.515.EHOMO -0.274. +0.029.A -1.673 (n = 16; r = 0.995; SD = 0.099; F = 2.682   Keywords: QSAR analysis, antimalaria, vincadifformine.

Selective kappa-opioid agonists: synthesis and structure-activity relationships of piperidines incorporating on oxo-containing acyl group.

Science.gov (United States)

Giardina, G; Clarke, G D; Dondio, G; Petrone, G; Sbacchi, M; Vecchietti, V

1994-10-14

This study describes the synthesis and the structure-activity relationships (SARs) of the (S)-(-)-enantiomers of a novel class of 2-(aminomethyl)piperidine derivatives, using kappa-opioid binding affinity and antinociceptive potency as the indices of biological activity. Compounds incorporating the 1-tetralon-6-ylacetyl residue (30 and 34-45) demonstrated an in vivo antinociceptive activity greater than predicted on the basis of their kappa-binding affinities. In particular, (2S)-2-[(dimethylamino)methyl]-1-[(5,6,7,8-tetrahydro-5-oxo-2- naphthyl)acetyl]piperidine (34) was found to have a potency similar to spiradoline in animal models of antinociception after subcutaneous administration, with ED50s of 0.47 and 0.73 mumol/kg in the mouse and in the rat abdominal constriction tests, respectively. Further in vivo studies in mice and/or rats revealed that compound 34, compared to other selective kappa-agonists, has a reduced propensity to cause a number of kappa-related side effects, including locomotor impairment/sedation and diuresis, at antinociceptive doses. For example, it has an ED50 of 26.5 mumol/kg sc in the rat rotarod model, exhibiting a ratio of locomotor impairment/sedation vs analgesia of 36. Possible reasons for this differential activity and its clinical consequence are discussed.

Quantitative structure-cytotoxicity relationship of piperic acid amides.

Science.gov (United States)

Shimada, Chiyako; Uesawa, Yoshihiro; Ishihara, Mariko; Kagaya, Hajime; Kanamoto, Taisei; Terakubo, Shigemi; Nakashima, Hideki; Takao, Koichi; Miyashiro, Takaki; Sugita, Yoshiaki; Sakagami, Hiroshi

2014-09-01

A total of 12 piperic acid amides, including piperine, were subjected to quantitative structure-activity relationship (QSAR) analysis, based on their cytotoxicity, tumor selectivity and anti-HIV activity, in order to find new biological activities. Cytotoxicity against four human oral squamous cell carcinoma (OSCC) cell lines and three human oral normal cells was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. Tumor selectivity was evaluated by the ratio of the mean 50% cytotoxic concentration (CC50) against normal oral cells to that against OSCC cell lines. Anti-HIV activity was evaluated by the ratio of the CC50 to 50% HIV infection-cytoprotective concentration (EC50). Physicochemical, structural, and quantum-chemical parameters were calculated based on the conformations optimized by LowModeMD method followed by density functional theory method. All compounds showed low-to-moderate tumor selectivity, but no anti-HIV activity. N-Piperoyldopamine ( 8: ) which has a catechol moiety, showed the highest tumor selectivity, possibly due to its unique molecular shape and electrostatic interaction, especially its largest partial equalization of orbital electronegativities and vsurf descriptors. The present study suggests that molecular shape and ability for electrostatic interaction are useful parameters for estimating the tumor selectivity of piperic acid amides. Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

Recent Advances in Marine Algae Polysaccharides: Isolation, Structure, and Activities.

Science.gov (United States)

Xu, Shu-Ying; Huang, Xuesong; Cheong, Kit-Leong

2017-12-13

Marine algae have attracted a great deal of interest as excellent sources of nutrients. Polysaccharides are the main components in marine algae, hence a great deal of attention has been directed at isolation and characterization of marine algae polysaccharides because of their numerous health benefits. In this review, extraction and purification approaches and chemico-physical properties of marine algae polysaccharides (MAPs) are summarized. The biological activities, which include immunomodulatory, antitumor, antiviral, antioxidant, and hypolipidemic, are also discussed. Additionally, structure-function relationships are analyzed and summarized. MAPs' biological activities are closely correlated with their monosaccharide composition, molecular weights, linkage types, and chain conformation. In order to promote further exploitation and utilization of polysaccharides from marine algae for functional food and pharmaceutical areas, high efficiency, and low-cost polysaccharide extraction and purification methods, quality control, structure-function activity relationships, and specific mechanisms of MAPs activation need to be extensively investigated.

Preliminary Guideline for the High Temperature Structure Integrity Assessment Procedure Part II. High Temperature Structural Integrity Assessment

Energy Technology Data Exchange (ETDEWEB)

Lee, Jae Han; Kim, J. B.; Lee, H. Y.; Park, C. G.; Joo, Y. S.; Koo, G. H.; Kim, S. H

2007-02-15

A high temperature structural integrity assessment belongs to the Part II of a whole preliminary guideline for the high temperature structure. The main contents of this guideline are the evaluation procedures of the creep-fatigue crack initiation and growth in high temperature condition, the high temperature LBB evaluation procedure, and the inelastic evaluations of the welded joints in SFR structures. The methodologies for the proper inelastic analysis of an SFR structures in high temperatures are explained and the guidelines of inelastic analysis options using ANSYS and ABAQUS are suggested. In addition, user guidelines for the developed NONSTA code are included. This guidelines need to be continuously revised to improve the applicability to the design and analysis of the SFR structures.

Quantitative structure-property relationship (correlation analysis) of phosphonic acid-based chelates in design of MRI contrast agent.

Science.gov (United States)

Tiwari, Anjani K; Ojha, Himanshu; Kaul, Ankur; Dutta, Anupama; Srivastava, Pooja; Shukla, Gauri; Srivastava, Rakesh; Mishra, Anil K

2009-07-01

Nuclear magnetic resonance imaging is a very useful tool in modern medical diagnostics, especially when gadolinium (III)-based contrast agents are administered to the patient with the aim of increasing the image contrast between normal and diseased tissues. With the use of soft modelling techniques such as quantitative structure-activity relationship/quantitative structure-property relationship after a suitable description of their molecular structure, we have studied a series of phosphonic acid for designing new MRI contrast agent. Quantitative structure-property relationship studies with multiple linear regression analysis were applied to find correlation between different calculated molecular descriptors of the phosphonic acid-based chelating agent and their stability constants. The final quantitative structure-property relationship mathematical models were found as--quantitative structure-property relationship Model for phosphonic acid series (Model 1)--log K(ML) = {5.00243(+/-0.7102)}- MR {0.0263(+/-0.540)}n = 12 l r l = 0.942 s = 0.183 F = 99.165 quantitative structure-property relationship Model for phosphonic acid series (Model 2)--log K(ML) = {5.06280(+/-0.3418)}- MR {0.0252(+/- .198)}n = 12 l r l = 0.956 s = 0.186 F = 99.256.

A quantitative structure-activity relationship to predict efficacy of granular activated carbon adsorption to control emerging contaminants.

Science.gov (United States)

Kennicutt, A R; Morkowchuk, L; Krein, M; Breneman, C M; Kilduff, J E

2016-08-01

A quantitative structure-activity relationship was developed to predict the efficacy of carbon adsorption as a control technology for endocrine-disrupting compounds, pharmaceuticals, and components of personal care products, as a tool for water quality professionals to protect public health. Here, we expand previous work to investigate a broad spectrum of molecular descriptors including subdivided surface areas, adjacency and distance matrix descriptors, electrostatic partial charges, potential energy descriptors, conformation-dependent charge descriptors, and Transferable Atom Equivalent (TAE) descriptors that characterize the regional electronic properties of molecules. We compare the efficacy of linear (Partial Least Squares) and non-linear (Support Vector Machine) machine learning methods to describe a broad chemical space and produce a user-friendly model. We employ cross-validation, y-scrambling, and external validation for quality control. The recommended Support Vector Machine model trained on 95 compounds having 23 descriptors offered a good balance between good performance statistics, low error, and low probability of over-fitting while describing a wide range of chemical features. The cross-validated model using a log-uptake (qe) response calculated at an aqueous equilibrium concentration (Ce) of 1 μM described the training dataset with an r(2) of 0.932, had a cross-validated r(2) of 0.833, and an average residual of 0.14 log units.

Identification of Lilial as a fragrance sensitizer in a perfume by bioassay-guided chemical fractionation and structure-activity relationships

DEFF Research Database (Denmark)

Arnau, E G; Andersen, Klaus Ejner; Bruze, M

2000-01-01

Fragrance materials are among the most common causes of allergic contact dermatitis. The aim of this study was to identify in a perfume fragrance allergens not included in the fragrance mix, by use of bioassay-guided chemical fractionation and chemical analysis/structure-activity relationships...... (SARs). The basis for the investigation was a 45-year-old woman allergic to her own perfume. She had a negative patch test to the fragrance mix and agreed to participate in the study. Chemical fractionation of the perfume concentrate was used for repeated patch testing and/or repeated open application......" in their chemical structure, indicating an ability to modify skin proteins and thus behave as a skin sensitizer, were tested on the patient. The patient reacted positively to the synthetic fragrance p-t-butyl-alpha-methylhydrocinnamic aldehyde (Lilial), a widely used fragrance compound not present in the fragrance...

Structure-activity relationship of the inhibitory effects of flavonoids on nitric oxide production in RAW264.7 cells.

Science.gov (United States)

Jiang, Wen-Jun; Daikonya, Akihiro; Ohkawara, Mitsuyoshi; Nemoto, Takashi; Noritake, Ryusuke; Takamiya, Tomoko; Kitanaka, Susumu; Iijima, Hiroshi

2017-01-15

We isolated flavonoids from herbal specimens from the Tibetan region (Sophora yunnanensis and Rhodiola sacra) that suppress nitric oxide (NO) production in macrophages stimulated by lipopolysaccharide and interferon-γ. The isolated flavonoids carry symmetric substitutions in the B ring (R 3' =R 5' ). We analyzed the quantitative structure-activity relationship of the inhibitory activity by comparative molecular field analysis (CoMFA) using this series of flavonoids. Use of flavonoids with symmetrical substitutions in the B ring made it simpler to align molecules because it was not necessary to consider a huge number of combinations due to the B-ring conformation. The CoMFA model, whose cross-validated q 2 value was 0.705, suggested the existence of a hydroxy group at the 5-position, the choice of the A/C-ring scaffold (chromane or chromene) and electrostatic field around the B ring are important for NO inhibitory activity. Flavonoids synthesized based on the CoMFA model exhibited significant inhibitory potential against NO production, validating the predictive capability of the CoMFA model. Copyright © 2016 Elsevier Ltd. All rights reserved.

The insulin secretory action of novel polycyclic guanidines: discovery through open innovation phenotypic screening, and exploration of structure-activity relationships.

Science.gov (United States)

Shaghafi, Michael B; Barrett, David G; Willard, Francis S; Overman, Larry E

2014-02-15

We report the discovery of the glucose-dependent insulin secretogogue activity of a novel class of polycyclic guanidines through phenotypic screening as part of the Lilly Open Innovation Drug Discovery platform. Three compounds from the University of California, Irvine, 1-3, having the 3-arylhexahydropyrrolo[1,2-c]pyrimidin-1-amine scaffold acted as insulin secretagogues under high, but not low, glucose conditions. Exploration of the structure-activity relationship around the scaffold demonstrated the key role of the guanidine moiety, as well as the importance of two lipophilic regions, and led to the identification of 9h, which stimulated insulin secretion in isolated rat pancreatic islets in a glucose-dependent manner. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

Quantitative structure-activity relationship study of antioxidative peptide by using different sets of amino acids descriptors

Science.gov (United States)

Li, Yao-Wang; Li, Bo; He, Jiguo; Qian, Ping

2011-07-01

A database consisting of 214 tripeptides which contain either His or Tyr residue was applied to study quantitative structure-activity relationships (QSAR) of antioxidative tripeptides. Partial Least-Squares Regression analysis (PLSR) was conducted using parameters individually of each amino acid descriptor, including Divided Physico-chemical Property Scores (DPPS), Hydrophobic, Electronic, Steric, and Hydrogen (HESH), Vectors of Hydrophobic, Steric, and Electronic properties (VHSE), Molecular Surface-Weighted Holistic Invariant Molecular (MS-WHIM), isotropic surface area-electronic charge index (ISA-ECI) and Z-scale, to describe antioxidative tripeptides as X-variables and antioxidant activities measured with ferric thiocyanate methods were as Y-variable. After elimination of outliers by Hotelling's T 2 method and residual analysis, six significant models were obtained describing the entire data set. According to cumulative squared multiple correlation coefficients ( R2), cumulative cross-validation coefficients ( Q2) and relative standard deviation for calibration set (RSD c), the qualities of models using DPPS, HESH, ISA-ECI, and VHSE descriptors are better ( R2 > 0.6, Q2 > 0.5, RSD c 0.44). Furthermore, the predictive ability of models using DPPS descriptor is best among the six descriptors systems (cumulative multiple correlation coefficient for predict set ( Rext2) > 0.7). It was concluded that the DPPS is better to describe the amino acid of antioxidative tripeptides. The results of DPPS descriptor reveal that the importance of the center amino acid and the N-terminal amino acid are far more than the importance of the C-terminal amino acid for antioxidative tripeptides. The hydrophobic (positively to activity) and electronic (negatively to activity) properties of the N-terminal amino acid are suggested to play the most important significance to activity, followed by the hydrogen bond (positively to activity) of the center amino acid. The N-terminal amino acid

Activation analysis by filtered neutrons. Preliminary investigation

International Nuclear Information System (INIS)

Skarnemark, G.; Rodinson, T.; Skaalberg, M.; Tokay, R.K.

1986-01-01

In order to investigate if measuring sensibility and precision by epithermal neutron activation analysis may be improved, different types of geological and biologic test samples were radiated. The test samples were enclosed in an extra filter of tungsten or sodium in order to reduce the flux of those neutrons that otherwise would induce interfering activity in the sample. The geological test samples consist of granites containing lanthanides which had been crushed in tung- sten carbide grinder. Normally such test samples show a interferins 1 87W-activity. By use of a tungsten filter the activity was reduced by up to 60%, which resulted in a considerable improvement of sensibility and precision of the measurement. The biologic test samples consisted of evaporated urine from patients treated with the cell poison cis-platinol. A reliable method to measure the platinum content has not existed so far. This method, however, enables platinum contents as low as about 0.1 ppm to be determined which is quite adequate. To sum up this preliminary study has demonstrated that activation analysis using filtered neutrons, correctly applied, is a satisfactory method of reducing interferences without complicated and time-consuming chemical separation procedures. (O.S.)

Structure-Activity Relationships for Rates of Aromatic Amine Oxidation by Manganese Dioxide

International Nuclear Information System (INIS)

Salter-Blanc, Alexandra J.; Lyon, Molly A.; Science University, Portland, OR; Ness, Stuart C.; Science University, Portland, OR; Tratnyek, Paul G.; Science University, Portland, OR

2016-01-01

New energetic compounds are designed to minimize their potential environmental impacts, which includes their transformation and the fate and effects of their transformation products. The nitro groups of energetic compounds are readily reduced to amines, and the resulting aromatic amines are subject to oxidation and coupling reactions. Manganese dioxide (MnO 2 ) is a common environmental oxidant and model system for kinetic studies of aromatic amine oxidation. Here in this study, a training set of new and previously reported kinetic data for the oxidation of model and energetic-derived aromatic amines was assembled and subjected to correlation analysis against descriptor variables that ranged from general purpose [Hammett σ constants (σ − ), pK a s of the amines, and energies of the highest occupied molecular orbital (E HOMO )] to specific for the likely rate-limiting step [one-electron oxidation potentials (E ox )]. The selection of calculated descriptors (pK a ), E HOMO , and E ox ) was based on validation with experimental data. All of the correlations gave satisfactory quantitative structure-activity relationships (QSARs), but they improved with the specificity of the descriptor. The scope of correlation analysis was extended beyond MnO 2 to include literature data on aromatic amine oxidation by other environmentally relevant oxidants (ozone, chlorine dioxide, and phosphate and carbonate radicals) by correlating relative rate constants (normalized to 4-chloroaniline) to E HOMO (calculated with a modest level of theory).

Structurally-constrained relationships between cognitive states in the human brain.

Directory of Open Access Journals (Sweden)

Ann M Hermundstad

2014-05-01

Full Text Available The anatomical connectivity of the human brain supports diverse patterns of correlated neural activity that are thought to underlie cognitive function. In a manner sensitive to underlying structural brain architecture, we examine the extent to which such patterns of correlated activity systematically vary across cognitive states. Anatomical white matter connectivity is compared with functional correlations in neural activity measured via blood oxygen level dependent (BOLD signals. Functional connectivity is separately measured at rest, during an attention task, and during a memory task. We assess these structural and functional measures within previously-identified resting-state functional networks, denoted task-positive and task-negative networks, that have been independently shown to be strongly anticorrelated at rest but also involve regions of the brain that routinely increase and decrease in activity during task-driven processes. We find that the density of anatomical connections within and between task-positive and task-negative networks is differentially related to strong, task-dependent correlations in neural activity. The space mapped out by the observed structure-function relationships is used to define a quantitative measure of separation between resting, attention, and memory states. We find that the degree of separation between states is related to both general measures of behavioral performance and relative differences in task-specific measures of attention versus memory performance. These findings suggest that the observed separation between cognitive states reflects underlying organizational principles of human brain structure and function.

Modeling Chemical Interaction Profiles: I. Spectral Data-Activity Relationship and Structure-Activity Relationship Models for Inhibitors and Non-inhibitors of Cytochrome P450 CYP3A4 and CYP2D6 Isozymes

Directory of Open Access Journals (Sweden)

Richard D. Beger

2012-03-01

Full Text Available An interagency collaboration was established to model chemical interactions that may cause adverse health effects when an exposure to a mixture of chemicals occurs. Many of these chemicals—drugs, pesticides, and environmental pollutants—interact at the level of metabolic biotransformations mediated by cytochrome P450 (CYP enzymes. In the present work, spectral data-activity relationship (SDAR and structure-activity relationship (SAR approaches were used to develop machine-learning classifiers of inhibitors and non-inhibitors of the CYP3A4 and CYP2D6 isozymes. The models were built upon 602 reference pharmaceutical compounds whose interactions have been deduced from clinical data, and 100 additional chemicals that were used to evaluate model performance in an external validation (EV test. SDAR is an innovative modeling approach that relies on discriminant analysis applied to binned nuclear magnetic resonance (NMR spectral descriptors. In the present work, both 1D 13C and 1D 15N-NMR spectra were used together in a novel implementation of the SDAR technique. It was found that increasing the binning size of 1D 13C-NMR and 15N-NMR spectra caused an increase in the tenfold cross-validation (CV performance in terms of both the rate of correct classification and sensitivity. The results of SDAR modeling were verified using SAR. For SAR modeling, a decision forest approach involving from 6 to 17 Mold2 descriptors in a tree was used. Average rates of correct classification of SDAR and SAR models in a hundred CV tests were 60% and 61% for CYP3A4, and 62% and 70% for CYP2D6, respectively. The rates of correct classification of SDAR and SAR models in the EV test were 73% and 86% for CYP3A4, and 76% and 90% for CYP2D6, respectively. Thus, both SDAR and SAR methods demonstrated a comparable performance in modeling a large set of structurally diverse data. Based on unique NMR structural descriptors, the new SDAR modeling method complements the existing SAR

Extraction optimization, preliminary characterization and antioxidant activities of polysaccharides from Glycine soja.

Science.gov (United States)

Jing, Changliang; Yuan, Yuan; Tang, Qi; Zou, Ping; Li, Yiqiang; Zhang, Chengsheng

2017-10-01

Single-factor experiment and Central Composite Design (CCD) was applied to optimize the ultrasound-assisted extraction (UAE) conditions of polysaccharides from Glycine soja (CGPS), and a preliminary characterization of three polysaccharide fractions (CGPS, GPS-1, and GPS-2) and their antioxidant activities were investigated. Under the optimal conditions: ratio of liquid to solid 42.7mL/g, extraction power 293.7W, extraction temperature 68.9°C, and extraction time 34.7min, the experimental CGPS yield was 6.04mg/g. CGPS was further purified by DEAE-cellulose and Sephadex-100 chromatography to obtain two fractions (GPS-1 and GPS-2), and their monosaccharides compositions were characterized by HPLC. Fourier-transform infrared spectra (FT-IR) indicated the chemical structures of them. Moreover, they exhibited high antioxidant activities in a concentration-dependent manner in vitro. In summary, the present study suggested that UAE was a very effective method to extract polysaccharides from Glycine soja and the polysaccharides could be explored as potential antioxidant agents for medicine and function food. Copyright © 2017 Elsevier B.V. All rights reserved.

Preliminary design study of the TMT Telescope structure system: overview

Science.gov (United States)

Usuda, Tomonori; Ezaki, Yutaka; Kawaguchi, Noboru; Nagae, Kazuhiro; Kato, Atsushi; Takaki, Junji; Hirano, Masaki; Hattori, Tomoya; Tabata, Masaki; Horiuchi, Yasushi; Saruta, Yusuke; Sofuku, Satoru; Itoh, Noboru; Oshima, Takeharu; Takanezawa, Takashi; Endo, Makoto; Inatani, Junji; Iye, Masanori; Sadjadpour, Amir; Sirota, Mark; Roberts, Scott; Stepp, Larry

2014-07-01

We present an overview of the preliminary design of the Telescope Structure System (STR) of Thirty Meter Telescope (TMT). NAOJ was given responsibility for the TMT STR in early 2012 and engaged Mitsubishi Electric Corporation (MELCO) to take over the preliminary design work. MELCO performed a comprehensive preliminary design study in 2012 and 2013 and the design successfully passed its Preliminary Design Review (PDR) in November 2013 and April 2014. Design optimizations were pursued to better meet the design requirements and improvements were made in the designs of many of the telescope subsystems as follows: 1. 6-legged Top End configuration to support secondary mirror (M2) in order to reduce deformation of the Top End and to keep the same 4% blockage of the full aperture as the previous STR design. 2. "Double Lower Tube" of the elevation (EL) structure to reduce the required stroke of the primary mirror (M1) actuators to compensate the primary mirror cell (M1 Cell) deformation caused during the EL angle change in accordance with the requirements. 3. M1 Segment Handling System (SHS) to be able to make removing and installing 10 Mirror Segment Assemblies per day safely and with ease over M1 area where access of personnel is extremely difficult. This requires semi-automatic sequence operation and a robotic Segment Lifting Fixture (SLF) designed based on the Compliance Control System, developed for controlling industrial robots, with a mechanism to enable precise control within the six degrees of freedom of position control. 4. CO2 snow cleaning system to clean M1 every few weeks that is similar to the mechanical system that has been used at Subaru Telescope. 5. Seismic isolation and restraint systems with respect to safety; the maximum acceleration allowed for M1, M2, tertiary mirror (M3), LGSF, and science instruments in 1,000 year return period earthquakes are defined in the requirements. The Seismic requirements apply to any EL angle, regardless of the

Anti-leishmanial and structure-activity relationship of ring substituted 3-phenyl-1-(1,4-di-N-oxide quinoxalin-2-yl-2-propen-1-one derivatives

Directory of Open Access Journals (Sweden)

Asunción Burguete

2008-12-01

Full Text Available A series of ring substituted 3-phenyl-1-(1,4-di-N-oxide quinoxalin-2-yl-2-propen-1-one derivatives were synthesized and tested for in vitro leishmanicidal activity against amastigotes of Leishmania amazonensis in axenical cultures and murine infected macrophages. Structure-activity relationships demonstrated the importance of a radical methoxy at position R3', R4' and R5'. (2E-3-(3,4,5-trimethoxy-phenyl-1-(3,6,7-trimethyl-1,4-dioxy-quinoxalin-2-yl-propenone was the most active. Cytotoxicity on macrophages revealed that this product was almost six times more active than toxic.

Atomic-level structure and structure-property relationship in metallic glass

Science.gov (United States)

Cheng, Yongqiang

One of the key tasks in material science is to understand the structure and structure-property relationship. The recently emerging bulk metallic glasses (BMGs) have demonstrated unique properties, especially intriguing mechanical properties such as their high strength and high propensity to localize deformation in shear bands. However, a comprehensive understanding of the structure of BMGs has been hindered by the complexity of these amorphous materials. Even more challenging is the structure-property correlation, which has been well established in crystals but has been seriously lacking for BMGs. This thesis presents a systematic study of the atomic-level structures of two representative BMGs, Cu-Zr and Cu-Zr-Al. The interpenetrating Cu-centered icosahedral clusters have been identified to be the primary structural feature. The fraction of icosahedra increases with increasing Cu or Al contents, and with decreasing cooling rate. The effect of Al in improving the icosahedral order is two-fold: the geometric effect due to the atomic-size mismatch and the chemical effect originated from the Cu-Al bond shortening. The resolved structure is used to study the structure-property relationship. The full icosahedra are found to be responsible for the dynamical slowdown of the supercooled liquid, which underlies the non-Arrhenius behavior, and explains the composition dependence of glass transition temperature, glass forming ability, and the room temperature strength. By simulated deformation, the initiation of plasticity and tendency for strain localization are also investigated. The full icosahedra are found to be the most rigid and resistant cluster with solid-like character, while the unstable clusters with liquid-like character serve as the fertile sites for initiating shear transformations. In addition, the elastic moduli are calculated and analyzed, and the origins of the different configurational dependence of shear modulus (G) and bulk modulus ( B) are explained. The

Structure-activity relationship and mechanism of action studies of manzamine analogues for the control of neuroinflammation and cerebral infections.

Science.gov (United States)

Peng, Jiangnan; Kudrimoti, Sucheta; Prasanna, Sivaprakasam; Odde, Srinivas; Doerksen, Robert J; Pennaka, Hari K; Choo, Yeun-Mun; Rao, Karumanchi V; Tekwani, Babu L; Madgula, Vamsi; Khan, Shabana I; Wang, Bin; Mayer, Alejandro M S; Jacob, Melissa R; Tu, Lan Chun; Gertsch, Jürg; Hamann, Mark T

2010-01-14

Structure-activity relationship studies were carried out by chemical modification of manzamine A (1), 8-hydroxymanzamine A (2), manzamine F (14), and ircinal isolated from the sponge Acanthostrongylophora. The derived analogues were evaluated for antimalarial, antimicrobial, and antineuroinflammatory activities. Several modified products exhibited potent and improved in vitro antineuroinflammatory, antimicrobial, and antimalarial activity. 1 showed improved activity against malaria compared to chloroquine in both multi- and single-dose in vivo experiments. The significant antimalarial potential was revealed by a 100% cure rate of malaria in mice with one administration of 100 mg/kg of 1. The potent antineuroinflammatory activity of the manzamines will provide great benefit for the prevention and treatment of cerebral infections (e.g., Cryptococcus and Plasmodium). In addition, 1 was shown to permeate across the blood-brain barrier (BBB) in an in vitro model using a MDR-MDCK monolayer. Docking studies support that 2 binds to the ATP-noncompetitive pocket of glycogen synthesis kinase-3beta (GSK-3beta), which is a putative target of manzamines. On the basis of the results presented here, it will be possible to initiate rational drug design efforts around this natural product scaffold for the treatment of several different diseases.

Relationship between pore structure and compressive strength

Indian Academy of Sciences (India)

Properties of concrete are strongly dependent on its pore structure features, porosity being an important one among them. This study deals with developing an understanding of the pore structure-compressive strength relationship in concrete. Several concrete mixtures with different pore structures are proportioned and ...

Quantitative structure-cytotoxicity relationship of phenylpropanoid amides.

Science.gov (United States)

Shimada, Chiyako; Uesawa, Yoshihiro; Ishihara, Mariko; Kagaya, Hajime; Kanamoto, Taisei; Terakubo, Shigemi; Nakashima, Hideki; Takao, Koichi; Saito, Takayuki; Sugita, Yoshiaki; Sakagami, Hiroshi

2014-07-01

A total of 12 phenylpropanoid amides were subjected to quantitative structure-activity relationship (QSAR) analysis, based on their cytotoxicity, tumor selectivity and anti-HIV activity, in order to investigate on their biological activities. Cytotoxicity against four human oral squamous cell carcinoma (OSCC) cell lines and three human oral normal cells was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. Tumor selectivity was evaluated by the ratio of the mean CC50 (50% cytotoxic concentration) against normal oral cells to that against OSCC cell lines. Anti-HIV activity was evaluated by the ratio of CC50 to EC50 (50% cytoprotective concentration from HIV infection). Physicochemical, structural, and quantum-chemical parameters were calculated based on the conformations optimized by the LowModeMD method followed by density functional theory (DFT) method. Twelve phenylpropanoid amides showed moderate cytotoxicity against both normal and OSCC cell lines. N-Caffeoyl derivatives coupled with vanillylamine and tyramine exhibited relatively higher tumor selectivity. Cytotoxicity against normal cells was correlated with descriptors related to electrostatic interaction such as polar surface area and chemical hardness, whereas cytotoxicity against tumor cells correlated with free energy, surface area and ellipticity. The tumor-selective cytotoxicity correlated with molecular size (surface area) and electrostatic interaction (the maximum electrostatic potential). The molecular size, shape and ability for electrostatic interaction are useful parameters for estimating the tumor selectivity of phenylpropanoid amides. Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

Preliminary Results on the Experimental Investigation of the Structure Functions of Bound Nucleons

Energy Technology Data Exchange (ETDEWEB)

Bodek, Arie [Univ. of Rochester, NY (United States); Thomas Jefferson National Accelerator Facility (TJNAF), Newport News, VA (United States)

2016-08-01

We present preliminary results on an experimental study of the nuclear modification of the longitudinal ($\\sigma_L$) and transverse ($\\sigma_T$) structure functions of nucleons bound in nuclear targets. The origin of these modifications (commonly referred as as the EMC effect) is not fully understood. Our measurements of R= $\\sigma_L / \\sigma_T$ for nuclei ($R_A$) and for deuterium ($R_D$) indicate that nuclear modifications of the structure functions of bound nucleons are different for the longitudinal and transverse structure functions, and that contrary to expectation from several theoretical models, $R_A< R_D$.

A preliminary study on electromyographic analysis of the paraspinal musculature in idiopathic scoliosis

NARCIS (Netherlands)

Cheung, J.; Halbertsma, J.P.; Veldhuizen, A.G.; Sluiter, W.J.; Maurits, N.M.; Cool, J.C.; van Horn, J.R.

The paraspinal muscles have been implicated as a major causative factor in the progression of idiopathic scoliosis. Therefore, the objectives of this preliminary study were to measure the electromyographic activity (EMG) of the paraspinal muscles to determine its relationship to progression of the

Structure-activity relationship studies of 5,7-dihydroxyflavones as naturally occurring inhibitors of cell proliferation in human leukemia HL-60 cells.

Science.gov (United States)

Ninomiya, Masayuki; Nishida, Kyohei; Tanaka, Kaori; Watanabe, Kunitomo; Koketsu, Mamoru

2013-07-01

Flavonoids are widely occurring polyphenols that are found in plants. The aim of this study was to investigate the structure-activity relationships of 5,7-dihydroxyflavones, with a focus on the effect of B ring structure substitution on the antiproliferative effects of the compounds in human leukemia HL-60 cells. We prepared a series of 5,7-dihydroxyflavones and evaluated their ability to inhibit the proliferation of HL-60 cells by using the MTT assay. The apoptosis- and cell differentiation-inducing ability of the most potent flavones were investigated using staining and morphological analyses. This study explored the antileukemic and chemopreventive potency of 5,7-dihydroxyflavones, particularly diosmetin and chrysoeriol, which have both hydroxy and methoxy groups on the B ring.

Synthesis and structure-activity relationships of novel cationic lipids with anti-inflammatory and antimicrobial activities.

Science.gov (United States)

Myint, Melissa; Bucki, Robert; Janmey, Paul A; Diamond, Scott L

2015-07-15

Certain membrane-active cationic steroids are known to also possess both anti-inflammatory and antimicrobial properties. This combined functionality is particularly relevant for potential therapies of infections associated with elevated tissue damage, for example, cystic fibrosis airway disease, a condition characterized by chronic bacterial infections and ongoing inflammation. In this study, six novel cationic glucocorticoids were synthesized using beclomethasone, budesonide, and flumethasone. Products were either monosubstituted or disubstituted, containing one or two steroidal groups, respectively. In vitro evaluation of biological activities demonstrated dual anti-inflammatory and antimicrobial properties with limited cytotoxicity for all synthesized compounds. Budesonide-derived compounds showed the highest degree of both glucocorticoid and antimicrobial properties within their respective mono- and disubstituted categories. Structure-activity analyses revealed that activity was generally related to the potency of the parent glucocorticoid. Taken together, these data indicate that these types of dual acting cationic lipids can be synthesized with the appropriate starting steroid to tailor activities as desired. Copyright © 2015 Elsevier Ltd. All rights reserved.

Molecular Docking, Molecular Dynamics, and Structure-Activity Relationship Explorations of 14-Oxygenated N-Methylmorphinan-6-ones as Potent μ-Opioid Receptor Agonists.

Science.gov (United States)

Noha, Stefan M; Schmidhammer, Helmut; Spetea, Mariana

2017-06-21

Among opioids, morphinans are of major importance as the most effective analgesic drugs acting primarily via μ-opioid receptor (μ-OR) activation. Our long-standing efforts in the field of opioid analgesics from the class of morphinans led to N-methylmorphinan-6-ones differently substituted at positions 5 and 14 as μ-OR agonists inducing potent analgesia and fewer undesirable effects. Herein we present the first thorough molecular modeling study and structure-activity relationship (SAR) explorations aided by docking and molecular dynamics (MD) simulations of 14-oxygenated N-methylmorphinan-6-ones to gain insights into their mode of binding to the μ-OR and interaction mechanisms. The structure of activated μ-OR provides an essential model for how ligand/μ-OR binding is encoded within small chemical differences in otherwise structurally similar morphinans. We reveal important molecular interactions that these μ-agonists share and distinguish them. The molecular docking outcomes indicate the crucial role of the relative orientation of the ligand in the μ-OR binding site, influencing the propensity of critical non-covalent interactions that are required to facilitate ligand/μ-OR interactions and receptor activation. The MD simulations point out minor differences in the tendency to form hydrogen bonds by the 4,5α-epoxy group, along with the tendency to affect the 3-7 lock switch. The emerged SARs reveal the subtle interplay between the substituents at positions 5 and 14 in the morphinan scaffold by enabling the identification of key structural elements that determine the distinct pharmacological profiles. This study provides a significant structural basis for understanding ligand binding and μ-OR activation by the 14-oxygenated N-methylmorphinan-6-ones, which should be useful for guiding drug design.

Quantitative Structure-Activity Relationship Modeling Coupled with Molecular Docking Analysis in Screening of Angiotensin I-Converting Enzyme Inhibitory Peptides from Qula Casein Hydrolysates Obtained by Two-Enzyme Combination Hydrolysis.

Science.gov (United States)

Lin, Kai; Zhang, Lanwei; Han, Xue; Meng, Zhaoxu; Zhang, Jianming; Wu, Yifan; Cheng, Dayou

2018-03-28

In this study, Qula casein derived from yak milk casein was hydrolyzed using a two-enzyme combination approach, and high angiotensin I-converting enzyme (ACE) inhibitory activity peptides were screened by quantitative structure-activity relationship (QSAR) modeling integrated with molecular docking analysis. Hydrolysates (casein presents an excellent source to produce ACE inhibitory peptides.

Molecular Descriptors Family on Structure Activity Relationships 6. Octanol-Water Partition Coefficient of Polychlorinated Biphenyls

Directory of Open Access Journals (Sweden)

Lorentz JÄNTSCHI

2006-01-01

Full Text Available Octanol-water partition coefficient of two hundred and six polychlorinated biphenyls was model by the use of an original method based on complex information obtained from compounds structure. The regression analysis shows that best results are obtained in four-varied model (r2 = 0.9168. The prediction ability of the model was studied through leave-one-out analysis (r2cv(loo = 0.9093 and in training and test sets analysis. Modeling the octanol-water partition coefficient of polychlorinated biphenyls by integration of complex structural information provide a stable and performing four-varied model, allowing us to make remarks about relationship between structure of polychlorinated biphenyls and associated octanol-water partition coefficients.

Structure-Activity Relationship Study on the Ethyl p-Methoxycinnamate as an Anti-Inflammatory Agent

Directory of Open Access Journals (Sweden)

Ismiarni Komala

2018-02-01

Full Text Available Ethyl p-methoxycinnamate (EPMC (1 has been isolated as a major compound from the rhizome of Kaempferia galanga together with the other compound ethyl cinnamate (2. As reported in the literature, EPMC (1 exhibited a significant in vitro and in vivo anti-inflammatory activity. In this research, we investigated the anti-inflammatory activity of compounds 1 and 2 by using anti-denaturation of heat bovine serum albumin (BSA method. In order to analyze active sites that are responsible for the anti-inflammatory activity, therefore, it is necessary to conduct structural modification of EPMC (1. The structural modification was performed through re-esterification reaction by using conventional and assistance of the unmodified microwave oven. Evaluation of the results of the bioassay indicated that the ester and methoxy functional groups of EPMC (1 play an important role for the anti-inflammatory activity.

Synthesis, crystal structure and biological activity of n-(5-(o-tolyl)-1, 3, 4-thiadiazol-2-yl)cyclopropanecarboxamide

International Nuclear Information System (INIS)

Tong, J.Y.; Sun, N.B.; Wu, H.K.

2013-01-01

A new 1, 3, 4-thiadiazole compound, N-(5-(o-tolyl)-1,3,4-thiadiazol-2-yl) cyclopropanecarboxamide, was synthesized and its structure was confirmed by 1H NMR, MS and HRMS. The single crystal structure of the title compound was determined by X-ray diffraction. The preliminary biological test showed that the synthesized compound has moderate herbicidal activity against Brassica campestris and fungicidal activities against Sclerotinia sclerotiorum(Lib.) de Bary, Rhizoctonia solanii, Fusarium oxysporum, Corynespora cassiicola, and Botrytis cinerea. (author)

Structure-function relationships in reconstituted HDL: Focus on antioxidative activity and cholesterol efflux capacity.

Science.gov (United States)

Cukier, Alexandre M O; Therond, Patrice; Didichenko, Svetlana A; Guillas, Isabelle; Chapman, M John; Wright, Samuel D; Kontush, Anatol

2017-09-01

High-density lipoprotein (HDL) contains multiple components that endow it with biological activities. Apolipoprotein A-I (apoA-I) and surface phospholipids contribute to these activities; however, structure-function relationships in HDL particles remain incompletely characterised. Reconstituted HDLs (rHDLs) were prepared from apoA-I and soy phosphatidylcholine (PC) at molar ratios of 1:50, 1:100 and 1:150. Oxidative status of apoA-I was varied using controlled oxidation of Met112 residue. HDL-mediated inactivation of PC hydroperoxides (PCOOH) derived from mildly pre-oxidized low-density lipoprotein (LDL) was evaluated by HPLC with chemiluminescent detection in HDL+LDL mixtures and re-isolated LDL. Cellular cholesterol efflux was characterised in RAW264.7 macrophages. rHDL inactivated LDL-derived PCOOH in a dose- and time-dependent manner. The capacity of rHDL to both inactivate PCOOH and efflux cholesterol via ATP-binding cassette transporter A1 (ABCA1) increased with increasing apoA-I/PC ratio proportionally to the apoA-I content in rHDL. Controlled oxidation of apoA-I Met112 gradually decreased PCOOH-inactivating capacity of rHDL but increased ABCA1-mediated cellular cholesterol efflux. Increasing apoA-I content in rHDL enhanced its antioxidative activity towards oxidized LDL and cholesterol efflux capacity via ABCA1, whereas oxidation of apoA-I Met112 decreased the antioxidative activity but increased the cholesterol efflux. These findings provide important considerations in the design of future HDL therapeutics. Non-standard abbreviations and acronyms: AAPH, 2,2'-azobis(-amidinopropane) dihydrochloride; ABCA1, ATP-binding cassette transporter A1; apoA-I, apolipoprotein A-I; BHT, butylated hydroxytoluene; CV, cardiovascular; EDTA, ethylenediaminetetraacetic acid; HDL-C, high-density lipoprotein cholesterol; LOOH, lipid hydroperoxides; Met(O), methionine sulfoxide; Met112, methionine 112 residue; Met86, methionine 86 residue; oxLDL, oxidized low

Structure-activity relationships of lipopolysaccharide sequestration in guanylhydrazone-bearing lipopolyamines.

Science.gov (United States)

Wu, Wenyan; Sil, Diptesh; Szostak, Michal L; Malladi, Subbalakshmi S; Warshakoon, Hemamali J; Kimbrell, Matthew R; Cromer, Jens R; David, Sunil A

2009-01-15

The toxicity of gram-negative bacterial endotoxin (lipopolysaccharide, LPS) resides in its structurally highly conserved glycolipid component called lipid A. Our major goal has been to develop small-molecules that would sequester LPS by binding to the lipid A moiety, so that it could be useful for the prophylaxis or adjunctive therapy of gram-negative sepsis. We had previously identified in rapid-throughput screens several guanylhydrazones as potent LPS binders. We were desirous of examining if the presence of the guanylhydrazone (rather than an amine) functionality would afford greater LPS sequestration potency. In evaluating a congeneric set of guanylhydrazone analogues, we find that C(16) alkyl substitution is optimal in the N-alkylguanylhydrazone series; a homospermine analogue with the terminal amine N-alkylated with a C(16) chain with the other terminus of the molecule bearing an unsubstituted guanylhydrazone moiety is marginally more active, suggesting very slight, if any, steric effects. Neither C(16) analogue is significantly more active than the N-C(16)-alkyl or N-C(16)-acyl compounds that we had characterized earlier, indicating that basicity of the phosphate-recognizing cationic group, is not a determinant of LPS sequestration activity.

An examination of a reciprocal relationship between network governance and network structure

DEFF Research Database (Denmark)

Bergenholtz, Carsten; Goduscheit, René Chester

The present article examines the network structure and governance of inter-organisational innovation networks. Network governance refers to the issue of how to manage and coordinate the relational activities and processes in the network while research on network structure deals with the overall...... structural relations between the actors in the network. These streams of research do contain references to each other but mostly rely on a static conception of the relationship between network structure and the applied network governance. The paper is based on a primarily qualitative case study of a loosely...... coupled Danish inter-organisational innovation network. The proposition is that a reciprocal relation between network governance and network structure can be identified....

The relationship between energy consumption structure, economic structure and energy intensity in China

International Nuclear Information System (INIS)

Feng Taiwen; Sun Linyan; Zhang Ying

2009-01-01

This paper investigates the long-run equilibrium relationships, temporal dynamic relationships and causal relationships between energy consumption structure, economic structure and energy intensity in China. Time series variables over the periods from 1980 to 2006 are employed in empirical tests. Cointegration tests suggest that these three variables tend to move together in the long-run. In addition, Granger causality tests indicate that there is a unidirectional causality running from energy intensity to economic structure but not vice versa. Impulse response analysis provides reasonable evidences that one shock of the three variables will cause the periods of destabilized that followed. However, the impact of the energy consumption structure shock on energy intensity and the impact of the economic structure shock on energy consumption structure seem to be rather marginal. The findings have significant implications from the point of view of energy conservation and economic development. In order to decrease energy intensity, Chinese government must continue to reduce the proportion of coal in energy consumption, increase the utilization efficiency of coal and promote the upgrade of economic structure. Furthermore, a full analysis of factors that may relate to energy intensity (e.g. energy consumption structure, economic structure) should be conducted before making energy policies.

Effect of green tea catechins and hydrolyzable tannins on benzo[a]pyrene-induced DNA adducts and structure-activity relationship.

Science.gov (United States)

Cao, Pengxiao; Cai, Jian; Gupta, Ramesh C

2010-04-19

Green tea catechins and hydrolyzable tannins are gaining increasing attention as chemopreventive agents. However, their mechanism of action is poorly understood. We investigated the effects of four green tea catechins and two hydrolyzable tannins on microsome-induced benzo[a]pyrene (BP)-DNA adducts and the possible structure-activity relationship. BP (1 microM) was incubated with rat liver microsomes and DNA in the presence of the test compound (1-200 microM) or vehicle. The purified DNA was analyzed by (32)P-postlabeling. The inhibitory activity of the catechins was in the following descending order: epigallocatechin gallate (IC(50) = 16 microM) > epicatechin gallate (24 microM) > epigallocatechin (146 microM) > epicatechin (462 microM), suggesting a correlation between the number of adjacent aromatic hydroxyl groups in the molecular structure and their potencies. Tannic acid (IC(50) = 4 microM) and pentagalloglucose (IC(50) = 26 microM) elicited as much DNA adduct inhibitory activity as the catechins or higher presumably due to the presence of more functional hydroxyl groups. To determine if the activity of these compounds was due to direct interaction of phenolic groups with electrophilic metabolite(s) of BP, DNA was incubated with anti-benzo[a]pyrene-7,8-diol-9,10-epoxide (anti-BPDE) (0.5 microM) in the presence of test compounds (200 microM) or vehicle. Significant inhibition of DNA adduct formation was found (tannic acid > pentagalloglucose > epigallocatechin gallate > epicatechin gallate). This notion was confirmed by analysis of the reaction products of anti-BPDE with the catechins and pentagalloglucose by electrospray ionization mass spectrometry and liquid chromatography-mass spectrometry. In conclusion, our data demonstrate that green tea catechins and the hydrolyzable tannins are highly effective in inhibiting BP-DNA adduct formation at least, in part, due to direct interaction of adjacent hydroxyl groups in their structures and that the activity is

Molecular Vibration-Activity Relationship in the Agonism of Adenosine Receptors

OpenAIRE

Chee, Hyun Keun; Oh, S. June

2013-01-01

The molecular vibration-activity relationship in the receptor-ligand interaction of adenosine receptors was investigated by structure similarity, molecular vibration, and hierarchical clustering in a dataset of 46 ligands of adenosine receptors. The resulting dendrogram was compared with those of another kind of fingerprint or descriptor. The dendrogram result produced by corralled intensity of molecular vibrational frequency outperformed four other analyses in the current study of adenosine ...

Quantitative Structure--Activity Relationship (QSAR) for the Oxidation of Trace Organic Contaminants by Sulfate Radical.

Science.gov (United States)

Xiao, Ruiyang; Ye, Tiantian; Wei, Zongsu; Luo, Shuang; Yang, Zhihui; Spinney, Richard

2015-11-17

The sulfate radical anion (SO4•–) based oxidation of trace organic contaminants (TrOCs) has recently received great attention due to its high reactivity and low selectivity. In this study, a meta-analysis was conducted to better understand the role of functional groups on the reactivity between SO4•– and TrOCs. The results indicate that compounds in which electron transfer and addition channels dominate tend to exhibit a faster second-order rate constants (kSO4•–) than that of H–atom abstraction, corroborating the SO4•– reactivity and mechanisms observed in the individual studies. Then, a quantitative structure activity relationship (QSAR) model was developed using a sequential approach with constitutional, geometrical, electrostatic, and quantum chemical descriptors. Two descriptors, ELUMO and EHOMO energy gap (ELUMO–EHOMO) and the ratio of oxygen atoms to carbon atoms (#O:C), were found to mechanistically and statistically affect kSO4•– to a great extent with the standardized QSAR model: ln kSO4•– = 26.8–3.97 × #O:C – 0.746 × (ELUMO–EHOMO). In addition, the correlation analysis indicates that there is no dominant reaction channel for SO4•– reactions with various structurally diverse compounds. Our QSAR model provides a robust predictive tool for estimating emerging micropollutants removal using SO4•– during wastewater treatment processes.

Effects of synthetic and naturally occurring flavonoids on Na+, K+-ATPase: Aspects of the structure-activity relationship and action mechanism

International Nuclear Information System (INIS)

Hirano, T.; Oka, K.; Akiba, M.

1989-01-01

A comparative study was made of the effects of 15 synthetic and naturally occurring flavonoids on the hydrolytic activity of Na + , K + -adenosine triphosphatase (ATPase). Twelve of the flavonoids examined were mono-hydroxy or mono-methoxy derivatives. All inhibited Na + , K + -ATPase from dog kidney cortex when present at concentrations from 40-1000 μM. Flavones possessing cyclohexyl instead of the phenyl group were the most potent with IC 50 at 257-320 μM. Structure-activity relationships were observed among the following mono-substituted flavones as: (i) 2-cyclohexyl-benzopyran-4-one much-gt 2-phenyl-benzopyran-4-one; (ii) 2-cyclohexyl-7-hydroxybenzopyran-4-one > 2-cyclohexyl-6-hydroxy-benzopyran-4-one > 2-cyclohexyl-5-hydroxybenzopyran-4-one. Some flavonoids showing potent inhibitory activity were also examined for ouabain-displacement activity on human erythrocytes. Hardly and of the flavonoids were able to block [ 3 H] ouabain binding to erythrocytes. These results suggest that the mechanism by which flavonoid block Na + , K + -ATPase is not related to the cardiac glycoside-specific binding site(s) of this enzyme

Preliminary Experiment on Neutron-Induced Mn Activity in Mn-Cd Solutions

Energy Technology Data Exchange (ETDEWEB)

Broda, E.

1942-07-01

This report was written by E. Broda, J. Gueron and L. Kowarski at the Cavendish Laboratory (Cambridge) in June 1942 and is about a preliminary experiment on neutron-induced Mn activity in Mn-Cd solutions. The description of the experiment and the results can be found also in this report. (nowak)

ERC hazard classification matrices for above ground structures and groundwater and soil remediation activities

International Nuclear Information System (INIS)

Curry, L.R.

1997-01-01

This document provides the status of the preliminary hazard classification (PHC) process for the Environmental Restoration Contractor (ERC) above ground structures and groundwater and soil remediation activities currently underway for planned for fiscal year (FY) 1997. This classification process is based on current US Department of Energy (DOE), Richland Operations Office (RL) guidance for the classification of facilities and activities containing radionuclide and nonradiological hazardous material inventories. The above ground structures presented in the matrices were drawn from the Bechtel Hanford, Inc. (BHI) Decontamination and Decommissioning (D and D) Project Facility List (DOE 1996), which identifies the facilities in the RL-Environmental Restoration baseline contract in 1997. This document contains the following two appendices: (1) Appendix A, which consists of a matrix identifying PHC documents that have been issued for BHI's above ground structures and groundwater and soil remediation activities underway or planned for FY 1997, and (2) Appendix B, which consists of a matrix showing anticipated PHCs for above ground structures, and groundwater and soil remediation activities underway or planned for FY 1997. Appendix B also shows the schedule for finalization of PHCs for above ground structures with an anticipated classification of Nuclear

The antimicrobial efficacy and structure activity relationship of novel carbohydrate fatty acid derivatives against Listeria spp. and food spoilage microorganisms.

Science.gov (United States)

Nobmann, Patricia; Smith, Aoife; Dunne, Julie; Henehan, Gary; Bourke, Paula

2009-01-15

Novel mono-substituted carbohydrate fatty acid (CFA) esters and ethers were investigated for their antibacterial activity against a range of pathogenic and spoilage bacteria focussing on Listeria monocytogenes. Carbohydrate derivatives with structural differences enable comparative studies on the structure/activity relationship for antimicrobial efficacy and mechanism of action. The antimicrobial efficacy of the synthesized compounds was compared with commercially available compounds such as monolaurin and monocaprylin, as well as the pure free fatty acids, lauric acid and caprylic acid, which have proven antimicrobial activity. Compound efficacy was compared using an absorbance based broth microdilution assay to determine the minimum inhibitory concentration (MIC), increase in lag phase and decrease in maximum growth rate. Among the carbohydrate derivatives synthesized, lauric ether of methyl alpha-d-glucopyranoside and lauric ester of methyl alpha-d-mannopyranoside showed the highest growth-inhibitory effect with MIC values of 0.04 mM, comparable to monolaurin. CFA derivatives were generally more active against Gram positive bacteria than Gram negative bacteria. The analysis of both ester and ether fatty acid derivatives of the same carbohydrate, in tandem with alpha and beta configuration of the carbohydrate moiety suggest that the carbohydrate moiety is involved in the antimicrobial activity of the fatty acid derivatives and that the nature of the bond also has a significant effect on efficacy, which requires further investigation. This class of CFA derivatives has great potential for developing antibacterial agents relevant to the food industry, particularly for control of Listeria or other Gram-positive pathogens.

MS/MS fragmentation-guided search of TMG-chitooligomycins and their structure-activity relationship in specific β-N-acetylglucosaminidase inhibition.

Science.gov (United States)

Usuki, Hirokazu; Yamamoto, Yukihiro; Kumagai, Yuya; Nitoda, Teruhiko; Kanzaki, Hiroshi; Hatanaka, Tadashi

2011-04-21

The reducing tetrasaccharide TMG-chitotriomycin (1) is an inhibitor of β-N-acetylglucosaminidase (GlcNAcase), produced by the actinomycete Streptomyces anulatus NBRC13369. The inhibitor shows a unique inhibitory spectrum, that is, selectivity toward enzymes from chitin-containing organisms such as insects and fungi. Nevertheless, its structure-selectivity relationship remains to be clarified. In this study, we conducted a structure-guided search of analogues of 1 in order to obtain diverse N,N,N-trimethylglucosaminium (TMG)-containing chitooligosaccharides. In this approach, the specific fragmentation profile of 1 on ESI-MS/MS analysis was used for the selective detection of desired compounds. As a result, two new analogues, named TMG-chitomonomycin (3) and TMG-chitobiomycin (2), were obtained from a culture filtrate of 1-producing Streptomyces. Their enzyme-inhibiting activity revealed that the potency and selectivity depended on the degree of polymerization of the reducing end GlcNAc units. Furthermore, a computational modeling study inspired the inhibitory mechanism of TMG-related compounds as a mimic of the substrate in the Michaelis complex of the GH20 enzyme. This study is an example of the successful application of a MS/MS experiment for structure-guided isolation of natural products.

An investigation into the relationship between political activity levels and political market orientation

DEFF Research Database (Denmark)

Ormrod, Robert P.; Henneberg, Stephan C.

2010-01-01

Purpose - The key objective of this research is to investigate the relationship between party member activity-levels and perceptions of their party's political market orientation. Specifically, it aims to scrutinise the differences in the interplay of attitudinal and behavioural aspects of politi......Purpose - The key objective of this research is to investigate the relationship between party member activity-levels and perceptions of their party's political market orientation. Specifically, it aims to scrutinise the differences in the interplay of attitudinal and behavioural aspects...... of political market orientation. Design/methodology/approach - Using a wide variety of respondent groups within the party, the research draws on an existing conceptualisation of political market orientation and empirically test its relationship with party member activity levels. Three models, plus a baseline...... model, are developed and data from 1,156 questionnaires are used to investigate a structural equation model using the partial least square method. Findings - While the baseline model exhibits a robust pattern of positive relationships between the attitudinal and behavioural constructs, the comparative...

TPK preliminary activities in manufacturing nuclear equipment; Pripremne aktivnosti TPk za izradu komponenata u nuklearnoj energetici

Energy Technology Data Exchange (ETDEWEB)

Ivanov, D; Fister, D; Poljicanin, I [TPK, Zagreb, (Yugoslavia)

1984-07-01

This paper gives a look into the preliminary activities of domestic industry in the conquest nuclear power program in the designing, engineering, quality assurance and manufacturing. TPK experiences in the preliminary activities in this field are shown in this article. review is given on te problem of basic materials. The general procedures are given in the future common action of domestic industry, and some efforts are made to discuss these problems, but they have not been discussed as much as possible. (author)

Combining Theoretical Perspectives on the Organizational Structure-Performance Relationship

Directory of Open Access Journals (Sweden)

Starling David Hunter

2015-08-01

Full Text Available Much of the literature linking organization structure to performance falls into two broad research streams. One stream concerns formal structure – the hierarchy of authority or reporting relationships as well as the degree of standardization, formalization, specialization, etc. The impact of formal structure and other elements of organization design on performance is typically contingent on factors such as strategic orientation, task characteristics, and environmental conditions. The other research stream focuses on informal structure – a network of interpersonal and intra-organizational relationships. Properties of informal structure are typically shown to have a more direct (less contingent impact on organizational performance. Despite these pronounced differences in the conceptualization of organization structure, considerable overlap and complementarity exist between the two research streams. In this article, I compare and contrast a pair of exemplars from each stream – the information processing perspective and the social network perspective – with respect to their conceptualizations of organization structure and its relationship to performance. Several recommendations for future research that combines the two approaches are offered.

A structure-activity relationship study on antiosteoclastogenesis effect of triterpenoids from the leaves of loquat (Eriobotrya japonica).

Science.gov (United States)

Tan, Hui; Ashour, Ahmed; Katakura, Yoshinori; Shimizu, Kuniyoshi

2015-04-15

Our previous results elucidated that the leaves of Eriobotrya japonica possessed the potential to suppress ovariectomy-induced bone mineral density deterioration, and ursolic acid, the major bioactive component in these leaves, suppressed the osteoclast differentiation. The aim of this study was to discover more candidates for development of novel antiosteoclastogenesis agents from the leaves of E. japonica. Phytochemical analysis following a cell-based osteoclastic tartrate-resistant acid phosphatase (TRAP) activity assay revealed 11 more compounds with a potent antiosteoclastogenesis effect. The potency of ursane-type triterpenoids from the leaves of E. japonica prompted us to investigate the structure-activity relationships underlying their antiosteoclastogenesis. The results revealed that both the hydroxyl group at C-3 and the carboxylic group at C-17 played indispensable roles in the antiosteoclastogenesis activity of ursane-type triterpenoids. The configuration at C-3 (a beta-form of the hydroxyl group) was found to be important for this activity. While introducing a hydroxyl group at C-19 increased the inhibitory activity of ursane-type triterpenoids carrying an alpha-form hydroxyl group at C-3. The bioactivity analyses of ursolic acid and oleanolic acid demonstrated that the antiosteoclastogenesis effect of ursolic acid may be related to different positions of the C-29 and C-30 methyl groups on the E-ring, since oleanolic acid showed limited activity. The addition of a hydroxyl group at C-2 would dramatically improve the inhibition of oleanane-type triterpenoids. Collectively, these findings could provide important clues for the improvement of multi-targeted antiosteoclastogenesis agents from the leaves of E. japonica. Copyright © 2015 Elsevier GmbH. All rights reserved.

Biological and structure-activity evaluation of chalcone derivatives against bacteria and fungi

Energy Technology Data Exchange (ETDEWEB)

Silva, Wender A.; Andrade, Carlos Kleber Z.; Napolitano, Hamilton B., E-mail: wender@unb.br, E-mail: ckleber@unb.br [Universidade de Brasilia (LaQMOS/UnB), DF (Brazil). Inst. de Quimica; Vencato, Ivo; Castro, Miriam R.C. de; Camargo, Ademir J. [Universidade Estadual de Goias (UEG), Anapolis, GO (Brazil). Ciencias Exatas e Tecnologicas; Lariucci, Carlito [Universidade Estadual de Goias (UEG), Goiania, GO (Brazil). Inst. de Fisica

2013-01-15

The present work describes the antibacterial and antifungal activities of several chalcones obtained by a straight Claisen-Schmidt aldol condensation determined by the minimal inhibitory concentration against different microorganisms (Gram-positive and Gram-negative bacteria and fungi). Solid state crystal structures of seven chalcones were determined by X-ray diffraction (XRD) analysis. Chemometric studies were carried out in order to identify a potential structure activity relationship. (author)

Active structural acoustic control of noise transmission through double panel systems

Science.gov (United States)

Carneal, James P.; Fuller, Chris R.

1995-04-01

A preliminary parametric study of active control of sound transmission through double panel systems has been experimentally performed. The technique used is the active structural acoustic control (ASAC) approach where control inputs, in the form of piezoelectric actuators, were applied to the structure while the radiated pressure field was minimized. Results indicate the application of control inputs to the radiating panel resulted in greater transmission loss due to its direct effect on the nature of the structural-acoustic coupling between the radiating panel and the receiving chamber. Increased control performance was seen in a double panel system consisting of a stiffer radiating panel with a lower modal density. As expected, more effective control of a radiating panel excited on-resonance is achieved over one excited off-resonance. In general, the results validate the ASAC approach for double panel systems and demonstrate that it is possible to take advantage of double panel behavior to enhance control performance, although it is clear that further research must be done to understand the physics involved.

Structure-Activity Relationships of Pentacyclic Triterpenoids as Potent and Selective Inhibitors against Human Carboxylesterase 1

Directory of Open Access Journals (Sweden)

Li-Wei Zou

2017-06-01

Full Text Available Human carboxylesterase 1 (hCE1, one of the most important serine hydrolases distributed in liver and adipocytes, plays key roles in endobiotic homeostasis and xenobiotic metabolism. This study aimed to find potent and selective inhibitors against hCE1 from phytochemicals and their derivatives. To this end, a series of natural triterpenoids were collected and their inhibitory effects against human carboxylesterases (hCEs were assayed using D-Luciferin methyl ester (DME and 6,8-dichloro-9,9-dimethyl-7-oxo-7,9-dihydroacridin-2-yl benzoate (DDAB as specific optical substrate for hCE1, and hCE2, respectively. Following screening of a series of natural triterpenoids, oleanolic acid (OA, and ursolic acid (UA were found with strong inhibitory effects on hCE1 and relative high selectivity over hCE2. In order to get the highly selective and potent inhibitors of hCE1, a series of OA and UA derivatives were synthesized from OA and UA by chemical modifications including oxidation, reduction, esterification, and amidation. The inhibitory effects of these derivatives on hCEs were assayed and the structure-activity relationships of tested triterpenoids as hCE1 inhibitors were carefully investigated. The results demonstrated that the carbonyl group at the C-28 site is essential for hCE1 inhibition, the modifications of OA or UA at this site including esters, amides and alcohols are unbeneficial for hCE1 inhibition. In contrast, the structural modifications on OA and UA at other sites, such as converting the C-3 hydroxy group to 3-O-β-carboxypropionyl (compounds 20 and 22, led to a dramatically increase of the inhibitory effects against hCE1 and very high selectivity over hCE2. 3D-QSAR analysis of all tested triterpenoids including OA and UA derivatives provide new insights into the fine relationships linking between the inhibitory effects on hCE1 and the steric-electrostatic properties of triterpenoids. Furthermore, both inhibition kinetic analyses and docking

MRI-based brain structure volumes in temporal lobe epilepsy patients and their unaffected siblings: a preliminary study.

LENUS (Irish Health Repository)

Scanlon, Cathy

2013-01-01

Investigating the heritability of brain structure may be useful in simplifying complicated genetic studies in temporal lobe epilepsy (TLE). A preliminary study is presented to determine if volume deficits of candidate brain structures present at a higher rate in unaffected siblings than controls subjects.

Real-time Fatigue and Free-Living Physical Activity in Hematopoietic Stem Cell Transplantation Cancer Survivors and Healthy Controls: A Preliminary Examination of the Temporal, Dynamic Relationship.

Science.gov (United States)

Hacker, Eileen Danaher; Kim, Inah; Park, Chang; Peters, Tara

Fatigue and physical inactivity, critical problems facing cancer survivors, impact overall health and functioning. Our group designed a novel methodology to evaluate the temporal, dynamic patterns in real-world settings. Using real-time technology, the temporal, dynamic relationship between real-time fatigue and free-living is described and compared in cancer survivors who were treated with hematopoietic stem cell transplantation (n = 25) and age- and gender-matched healthy controls (n = 25). Subjects wore wrist actigraphs on their nondominant hand to assess free-living physical activity, measured in 1-minute epochs, over 7 days. Subjects entered real-time fatigue assessments directly into the subjective event marker of the actigraph 5 times per day. Running averages of mean 1-minute activity counts 30, 60, and 120 minutes before and after each real-time fatigue score were correlated with real-time fatigue using generalized estimating equations, RESULTS:: A strong inverse relationship exists between real-time fatigue and subsequent free-living physical activity. This inverse relationship suggests that increasing real-time fatigue limits subsequent physical activity (B range= -0.002 to -0.004; P < .001). No significant differences in the dynamic patterns of real-time fatigue and free-living physical activity were found between groups. To our knowledge, this is the first study to document the temporal and potentially causal relationship between real-time fatigue and free-living physical activity in real-world setting. These findings suggest that fatigue drives the subsequent physical activity and the relationship may not be bidirectional. Understanding the temporal, dynamic relationship may have important health implications for developing interventions to address fatigue in cancer survivors.

Urban Adolescents’ Physical Activity Experience, Physical Activity Levels, and Use of Screen-Based Media during Leisure Time: A Structural Model

Directory of Open Access Journals (Sweden)

Hui Xie

2018-01-01

Full Text Available There is limited understanding of the relationship between physical activity and use of screen-based media, two important behaviors associated with adolescents’ health outcomes. To understand this relationship, researchers may need to consider not only physical activity level but also physical activity experience (i.e., affective experience obtained from doing physical activity. Using a sample predominantly consisting of African and Latino American urban adolescents, this study examined the interrelationships between physical activity experience, physical activity level, and use of screen-based media during leisure time. Data collected using self-report, paper and pencil surveys was analyzed using structural equation modeling. Results showed that physical activity experience was positively associated with physical activity level and had a direct negative relationship with use of non-active video games for males and a direct negative relationship with use of computer/Internet for both genders, after controlling for physical activity level. Physical activity level did not have a direct relationship with use of non-active video games or computer/Internet. However, physical activity level had a direct negative association with use of TV/movies. This study suggests that physical activity experience may play an important role in promoting physical activity and thwarting use of screen-based media among adolescents.

Urban Adolescents’ Physical Activity Experience, Physical Activity Levels, and Use of Screen-Based Media during Leisure Time: A Structural Model

Science.gov (United States)

Xie, Hui; Scott, Jason L.; Caldwell, Linda L.

2018-01-01

There is limited understanding of the relationship between physical activity and use of screen-based media, two important behaviors associated with adolescents’ health outcomes. To understand this relationship, researchers may need to consider not only physical activity level but also physical activity experience (i.e., affective experience obtained from doing physical activity). Using a sample predominantly consisting of African and Latino American urban adolescents, this study examined the interrelationships between physical activity experience, physical activity level, and use of screen-based media during leisure time. Data collected using self-report, paper and pencil surveys was analyzed using structural equation modeling. Results showed that physical activity experience was positively associated with physical activity level and had a direct negative relationship with use of non-active video games for males and a direct negative relationship with use of computer/Internet for both genders, after controlling for physical activity level. Physical activity level did not have a direct relationship with use of non-active video games or computer/Internet. However, physical activity level had a direct negative association with use of TV/movies. This study suggests that physical activity experience may play an important role in promoting physical activity and thwarting use of screen-based media among adolescents. PMID:29410634

A preliminary design of interior structure and foundation of an inflatable lunar habitat

Science.gov (United States)

Yin, Paul K.

1989-01-01

A preliminary structural design and analysis of an inflatable habitat for installation on the moon was completed. The concept takes the shape of a sphere with a diameter of approximately 16 meters. The interior framing provides five floor levels and is enclosed by a spherical air-tight membrane holding an interior pressure of 14.7 psi (101.4kpa). The spherical habitat is to be erected on the lunar surface with the lower one third below grade and the upper two thirds covered with a layer of lunar regolith for thermal insulation and shielding against radiation and meteoroids. The total dead weight (earth weight) of the structural aluminum, which is of vital interest for the costly space transportation, is presented. This structural dead weight represents a preliminary estimate without including structural details. The design results in two versions: one supports the weight of the radiation shielding in case of deflation of the fabric enclosure and the other assumes that the radiation shielding is self supporting. To gain some indication of the amount of structural materials needed if the identical habitat were installed on Mars and Earth, three additional design versions were generated where the only difference is in gravity. These additional design versions are highly academic since the difference will be much more than in gravity alone. The lateral loading due to dust storms on Mars and wind loads on Earth are some examples. The designs under the lunar gravity are realistic. They may not be adequate for final material procurement and fabrication, however, as the connection details, among other reasons, may effect the sizes of the structural members.

Rare-earth transition-metal intermetallics: Structure-bonding-property relationships

Energy Technology Data Exchange (ETDEWEB)

Han, M. K. [Iowa State Univ., Ames, IA (United States)

2006-01-01

The explorations of rare-earth, transition metal intermetallics have resulted in the synthesis and characterization, and electronic structure investigation, as well as understanding the structure-bonding property relationships. The work has presented the following results: (1) Understanding the relationship between compositions and properties in LaFe_13-xSi_x system: A detailed structural and theoretical investigation provided the understanding of the role of a third element on stabilizing the structure and controlling the transformation of cubic NaZn{sub 13}-type structures to the tetragonal derivative, as well as the relationship between the structures and properties. (2) Synthesis of new ternary rare-earth iron silicides Re_2-xFe₄Si_14-y and proposed superstructure: This compound offers complex structural challenges such as fractional occupancies and their ordering in superstructure. (3) Electronic structure calculation of FeSi₂: This shows that the metal-semiconductor phase transition depends on the structure. The mechanism of band gap opening is described in terms of bonding and structural distortion. This result shows that the electronic structure calculations are an essential tool for understanding the relationship between structure and chemical bonding in these compounds. (4) Synthesis of new ternary rare-earth Zinc aluminides Tb₃Zn_3.6Al_7.4: Partially ordered structure of Tb₃Zn_3.6Al_7.4 compound provides new insights into the formation, composition and structure of rare-earth transition-metal intermetallics. Electronic structure calculations attribute the observed composition to optimizing metal-metal bonding in the electronegative (Zn, Al) framework, while the specific ordering is strongly influenced by specific orbital interactions. (5) Synthesis of new structure type of Zn₃₉(Cr_xAl_1-x)₈₁

Rare-Earth Transition-Metal Intermetallics: Structure-bonding-Property Relationships

Energy Technology Data Exchange (ETDEWEB)

Han, Mi-Kyung [Iowa State Univ., Ames, IA (United States)

2006-01-01

Our explorations of rare-earth, transition metal intermetallics have resulted in the synthesis and characterization, and electronic structure investigation, as well as understanding the structure-bonding-property relationships. Our work has presented the following results: (1) Understanding the relationship between compositions and properties in LaFe_13-xSi_x system: A detailed structural and theoretical investigation provided the understanding of the role of a third element on stabilizing the structure and controlling the transformation of cubic NaZn₁₃-type structures to the tetragonal derivative, as well as the relationship between the structures and properties. (2) Synthesis of new ternary rare-earth iron silicides RE_2-xFe₄Si_14-y and proposed superstructure: This compound offers complex structural challenges such as fractional occupancies and their ordering in superstructure. (3) Electronic structure calculation of FeSi₂: This shows that the metal-semiconductor phase transition depends on the structure. The mechanism of band gap opening is described in terms of bonding and structural distortion. This result shows that the electronic structure calculations are an essential tool for understanding the relationship between structure and chemical bonding in these compounds. (4) Synthesis of new ternary rare-earth Zinc aluminides Tb₃Zn_3.6Al_7.4: Partially ordered structure of Tb_3.6Zn_13-xAl_7.4 compound provides new insights into the formation, composition and structure of rare-earth transition-metal intermetallics. Electronic structure calculations attribute the observed composition to optimizing metal-metal bonding in the electronegative (Zn, Al) framework, while the specific ordering is strongly influenced by specific orbital interactions. (5) Synthesis of new structure type of Zn₃₉(Cr_xAl_1-x

Structure-activity relationships of amide-phosphonate derivatives as inhibitors of the human soluble epoxide hydrolase.

Science.gov (United States)

Kim, In-Hae; Park, Yong-Kyu; Nishiwaki, Hisashi; Hammock, Bruce D; Nishi, Kosuke

2015-11-15

Structure-activity relationships of amide-phosphonate derivatives as inhibitors of the human soluble epoxide hydrolase (sEH) were investigated. First, a series of alkyl or aryl groups were substituted on the carbon alpha to the phosphonate function in amide compounds to see whether substituted phosphonates can act as a secondary pharmacophore. A tert-butyl group (16) on the alpha carbon was found to yield most potent inhibition on the target enzyme. A 4-50-fold drop in inhibition was induced by other substituents such as aryls, substituted aryls, cycloalkyls, and alkyls. Then, the modification of the O-substituents on the phosphonate function revealed that diethyl groups (16 and 23) were preferable for inhibition to other longer alkyls or substituted alkyls. In amide compounds with the optimized diethylphosphonate moiety and an alkyl substitution such as adamantane (16), tetrahydronaphthalene (31), or adamantanemethane (36), highly potent inhibitions were gained. In addition, the resulting potent amide-phosphonate compounds had reasonable water solubility, suggesting that substituted phosphonates in amide inhibitors are effective for both inhibition potency on the human sEH and water solubility as a secondary pharmacophore. Copyright © 2015 Elsevier Ltd. All rights reserved.

Methanol oxidation reaction on core-shell structured Ruthenium-Palladium nanoparticles: Relationship between structure and electrochemical behavior

Science.gov (United States)

Kübler, Markus; Jurzinsky, Tilman; Ziegenbalg, Dirk; Cremers, Carsten

2018-01-01

In this work the relationship between structural composition and electrochemical characteristics of Palladium(Pd)-Ruthenium(Ru) nanoparticles during alkaline methanol oxidation reaction is investigated. The comparative study of a standard alloyed and a precisely Ru-core-Pd-shell structured catalyst allows for a distinct investigation of the electronic effect and the bifunctional mechanism. Core-shell catalysts benefit from a strong electronic effect and an efficient Pd utilization. It is found that core-shell nanoparticles are highly active towards methanol oxidation reaction for potentials ≥0.6 V, whereas alloyed catalysts show higher current outputs in the lower potential range. However, differential electrochemical mass spectrometry (DEMS) experiments reveal that the methanol oxidation reaction on core-shell structured catalysts proceeds via the incomplete oxidation pathway yielding formaldehyde, formic acid or methyl formate. Contrary, the alloyed catalyst benefits from the Ru atoms at its surface. Those are found to be responsible for high methanol oxidation activity at lower potentials as well as for complete oxidation of CH3OH to CO2 via the bifunctional mechanism. Based on these findings a new Ru-core-Pd-shell-Ru-terrace catalyst was synthesized, which combines the advantages of the core-shell structure and the alloy. This novel catalyst shows high methanol electrooxidation activity as well as excellent selectivity for the complete oxidation pathway.

Structural optimization and structure-functional selectivity relationship studies of G protein-biased EP2 receptor agonists.

Science.gov (United States)

Ogawa, Seiji; Watanabe, Toshihide; Moriyuki, Kazumi; Goto, Yoshikazu; Yamane, Shinsaku; Watanabe, Akio; Tsuboi, Kazuma; Kinoshita, Atsushi; Okada, Takuya; Takeda, Hiroyuki; Tani, Kousuke; Maruyama, Toru

2016-05-15

The modification of the novel G protein-biased EP2 agonist 1 has been investigated to improve its G protein activity and develop a better understanding of its structure-functional selectivity relationship (SFSR). The optimization of the substituents on the phenyl ring of 1, followed by the inversion of the hydroxyl group on the cyclopentane moiety led to compound 9, which showed a 100-fold increase in its G protein activity compared with 1 without any increase in β-arrestin recruitment. Furthermore, SFSR studies revealed that the combination of meta and para substituents on the phenyl moiety was crucial to the functional selectivity. Copyright © 2016 Elsevier Ltd. All rights reserved.

Quantitative Structure-Activity Relationship of Insecticidal Activity of Benzyl Ether Diamidine Derivatives

Science.gov (United States)

Zhai, Mengting; Chen, Yan; Li, Jing; Zhou, Jun

2017-12-01

The molecular electrongativity distance vector (MEDV-13) was used to describe the molecular structure of benzyl ether diamidine derivatives in this paper, Based on MEDV-13, The three-parameter (M 3, M 15, M 47) QSAR model of insecticidal activity (pIC 50) for 60 benzyl ether diamidine derivatives was constructed by leaps-and-bounds regression (LBR) . The traditional correlation coefficient (R) and the cross-validation correlation coefficient (R CV ) were 0.975 and 0.971, respectively. The robustness of the regression model was validated by Jackknife method, the correlation coefficient R were between 0.971 and 0.983. Meanwhile, the independent variables in the model were tested to be no autocorrelation. The regression results indicate that the model has good robust and predictive capabilities. The research would provide theoretical guidance for the development of new generation of anti African trypanosomiasis drugs with efficiency and low toxicity.

Active cooling for downhole instrumentation: Preliminary analysis and system selection

Energy Technology Data Exchange (ETDEWEB)

Bennett, G.A.

1988-03-01

A feasibility study and a series of preliminary designs and analyses were done to identify candidate processes or cycles for use in active cooling systems for downhole electronic instruments. A matrix of energy types and their possible combinations was developed and the energy conversion process for each pari was identified. The feasibility study revealed conventional as well as unconventional processes and possible refrigerants and identified parameters needing further clarifications. A conceptual design or series od oesigns for each system was formulated and a preliminary analysis of each design was completed. The resulting coefficient of performance for each system was compared with the Carnot COP and all systems were ranked by decreasing COP. The system showing the best combination of COP, exchangeability to other operating conditions, failure mode, and system serviceability is chosen for use as a downhole refrigerator. 85 refs., 48 figs., 33 tabs.

Discovery and structure-activity relationship of novel 4-hydroxy-thiazolidine-2-thione derivatives as tumor cell specific pyruvate kinase M2 activators.

Science.gov (United States)

Li, Ridong; Ning, Xianling; Zhou, Shuo; Lin, Zhiqiang; Wu, Xingyu; Chen, Hong; Bai, Xinyu; Wang, Xin; Ge, Zemei; Li, Runtao; Yin, Yuxin

2018-01-01

Pyruvate kinase M2 isoform (PKM2) is a crucial protein responsible for aerobic glycolysis of cancer cells. Activation of PKM2 may alter aberrant metabolism in cancer cells. In this study, we discovered a 4-hydroxy-thiazolidine-2-thione compound 2 as a novel PKM2 activator from a random screening of an in-house compound library. Then a series of novel 4-hydroxy-thiazolidine-2-thione derivatives were designed and synthesized for screening as potent PKM2 activators. Among these, some compounds showed higher PKM2 activation activity than lead compound 2 and also exhibited significant anti-proliferative activities on human cancer cell lines at nanomolar concentration. The compound 5w was identified as the most potent antitumor agent, which showed excellent anti-proliferative effects with IC 50 values from 0.46 μM to 0.81 μM against H1299, HCT116, Hela and PC3 cell lines. 5w also showed less cytotoxicity in non-tumor cell line HELF compared with cancer cells. In addition, Preliminary pharmacological studies revealed that 5w arrests the cell cycle at the G2/M phase in HCT116 cell line. The best PKM2 activation by compound 5t was rationalized through docking studies. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Preliminary findings radon daughter levels in structures constructed on reclaimed Florida phosphate land

International Nuclear Information System (INIS)

1975-09-01

Preliminary results are reported from a survey of the radon daughter levels in structures in Polk County, Florida, built on reclaimed phosphate tailings containing various amounts of 226 Ra. The structures surveyed consisted primarily of private dwellings although a few office buildings were also surveyed. Track-etch films and TLD air samplers were used to measure the levels of radon daughters within the structures and in structures built on non-phosphate land. Radiation levels were converted to WL units (the working level (WL) unit is defined as the potential α energy from the short-lived daughters of Rn which will produce 1.3 x 10 5 MeV in one liter of air). The highest observed level in any structure was 0.2 WL. Possible health hazards to long-time occupants are discussed

Structure Activity Relationships of α-L-LNA Modified Phosphorothioate Gapmer Antisense Oligonucleotides in Animals

Directory of Open Access Journals (Sweden)

Punit P Seth

2012-01-01

Full Text Available We report the structure activity relationships of short 14-mer phosphorothioate gapmer antisense oligonucleotides (ASOs modified with α-L-locked nucleic acid (LNA and related modifications targeting phosphatase and tensin homologue (PTEN messenger RNA in mice. α-L-LNA represents the α-anomer of enantio-LNA and modified oligonucleotides show LNA like binding affinity for complementary RNA. In contrast to sequence matched LNA gapmer ASOs which showed elevations in plasma alanine aminotransferase (ALT levels indicative of hepatotoxicity, gapmer ASOs modified with α-L-LNA and related analogs in the flanks showed potent downregulation of PTEN messenger RNA in liver tissue without producing elevations in plasma ALT levels. However, the α-L-LNA ASO showed a moderate dose-dependent increase in liver and spleen weights suggesting a higher propensity for immune stimulation. Interestingly, replacing α-L-LNA nucleotides in the 3′- and 5′-flanks with R-5′-Me-α-L-LNA but not R-6′-Me- or 3′-Me-α-L-LNA nucleotides, reversed the drug induced increase in organ weights. Examination of structural models of dinucleotide units suggested that the 5′-Me group increases steric bulk in close proximity to the phosphorothioate backbone or produces subtle changes in the backbone conformation which could interfere with recognition of the ASO by putative immune receptors. Our data suggests that introducing steric bulk at the 5′-position of the sugar-phosphate backbone could be a general strategy to mitigate the immunostimulatory profile of oligonucleotide drugs. In a clinical setting, proinflammatory effects manifest themselves as injection site reactions and flu-like symptoms. Thus, a mitigation of these effects could increase patient comfort and compliance when treated with ASOs.

Integrated optimization on aerodynamics-structure coupling and flight stability of a large airplane in preliminary design

Directory of Open Access Journals (Sweden)

Xiaozhe WANG

2018-06-01

Full Text Available The preliminary phase is significant during the whole design process of a large airplane because of its enormous potential in enhancing the overall performance. However, classical sequential designs can hardly adapt to modern airplanes, due to their repeated iterations, long periods, and massive computational burdens. Multidisciplinary analysis and optimization demonstrates the capability to tackle such complex design issues. In this paper, an integrated optimization method for the preliminary design of a large airplane is proposed, accounting for aerodynamics, structure, and stability. Aeroelastic responses are computed by a rapid three-dimensional flight load analysis method combining the high-order panel method and the structural elasticity correction. The flow field is determined by the viscous/inviscid iteration method, and the cruise stability is evaluated by the linear small-disturbance theory. Parametric optimization is carried out using genetic algorithm to seek the minimal weight of a simplified plate-beam wing structure in the cruise trim condition subject to aeroelastic, aerodynamic, and stability constraints, and the optimal wing geometry shape, front/rear spar positions, and structural sizes are obtained simultaneously. To reduce the computational burden of the static aeroelasticity analysis in the optimization process, the Kriging method is employed to predict aerodynamic influence coefficient matrices of different aerodynamic shapes. The multidisciplinary analyses guarantee computational accuracy and efficiency, and the integrated optimization considers the coupling effect sufficiently between different disciplines to improve the overall performance, avoiding the limitations of sequential approaches utilized currently. Keywords: Aeroelasticity, Integrated optimization, Multidisciplinary analysis, Large airplane, Preliminary design

Structure-activity relationship and role of oxygen in the potential antitumour activity of fluoroquinolones in human epithelial cancer cells.

Science.gov (United States)

Perucca, Paola; Savio, Monica; Cazzalini, Ornella; Mocchi, Roberto; Maccario, Cristina; Sommatis, Sabrina; Ferraro, Daniela; Pizzala, Roberto; Pretali, Luca; Fasani, Elisa; Albini, Angelo; Stivala, Lucia Anna

2014-11-01

The photobehavior of ciprofloxacin, lomefloxacin and ofloxacin fluoroquinolones was investigated using several in vitro methods to assess their cytotoxic, antiproliferative, and genotoxic potential against two human cancer cell lines. We focused our attention on the possible relationship between their chemical structure, O₂ partial pressure and photobiological activity on cancer cells. The three molecules share the main features of most fluoroquinolones, a fluorine in 6 and a piperazino group in 7, but differ at the key position 8, unsubstituted in ciprofloxacin, a fluorine in lomefloxacin and an alkoxy group in ofloxacin. Studies in solution show that ofloxacin has a low photoreactivity; lomefloxacin reacts via aryl cation, ciprofloxacin reacts but not via the cation. In our experiments, ciprofloxacin and lomefloxacin showed a high and comparable potential for photodamaging cells and DNA. Lomefloxacin appeared the most efficient molecule in hypoxia, acting mainly against tumour cell proliferation and generating DNA plasmid photocleavage. Although our results do not directly provide evidence that a carbocation is involved in photodamage induced by lomefloxacin, our data strongly support this hypothesis. This may lead to new and more efficient anti-tumour drugs involving a cation in their mechanism of action. This latter acting independently of oxygen, can target hypoxic tumour tissue. Copyright © 2014 Elsevier B.V. All rights reserved.

Cloning, expression, and preliminary structural characterization of RTN-1C

International Nuclear Information System (INIS)

Fazi, Barbara; Melino, Sonia; Sano, Federica Di; Cicero, Daniel O.; Piacentini, Mauro; Paci, Maurizio

2006-01-01

Reticulons (RTNs) are endoplasmic reticulum-associated proteins widely distributed in plants, yeast, and animals. They are characterized by unique N-terminal parts and a common 200 amino acid C-terminal domain containing two long hydrophobic sequences. Despite their implication in many cellular processes, their molecular structure and function are still largely unknown. In this study, the reticulon family member RTN-1C has been expressed and purified in Escherichia coli and its molecular structure has been analysed by fluorescence and CD spectroscopy in different detergents in order to obtain a good solubility and a relative stability. The isotopically enriched protein has been also produced to perform structural studies by NMR spectroscopy. The preliminary results obtained showed that RTN-1C protein possesses helical transmembrane segments when a membrane-like environment is produced by detergents. Moreover, fluorescence experiments indicated the exposure of tryptophan side chains as predicted by structure prediction programs. We also produced the isotopically labelled protein and the procedure adopted allowed us to plan future NMR studies to investigate the biochemical behaviour of reticulon-1C and of its peptides spanning out from the membrane

A preliminary investigation into the measurement of global thunderstorm incidence and electrosphere potential at Sanae, Antarctica

International Nuclear Information System (INIS)

Smart, C.A.

1980-01-01

One of the atmospheric parameters that may be affected by variations in the electrosphere potential is thunderstorm activity. The author made preliminary investigations into the simultaneous monitoring of global thunderstorm incidence and electrosphere potential. The author looked at the structure of the sun and the earth solar activity and solar emissions as well as the sun-weather relationships. Measurement were made by the author during 1978 at Sanae, Antarctica. The objective was to investigate the fluctuations of global thunderstorm activity and electrosphere potential and to establish some link between these and with solar activity. Potential gradient of the lower atmosphere was measured by means of a field mill and fluctuations taken to be representative of those of the electrosphere potential. Thunderstorm incidence was monitored by measurement of extra low frequency (ELF) electromagnetic noise radiated by lightning. A dipole or loop antenna was used for the recording of extra low frequency electromagnetic noise. A computer program was developed to facilitate the data analysis

A review of the global relationship among freshwater fish, autotrophic activity, and regional climate

Science.gov (United States)

Deines, Andrew M.; Bunnell, David B.; Rogers, Mark W.; Beard, T. Douglas; Taylor, William W.

2015-01-01

The relationship between autotrophic activity and freshwater fish populations is an important consideration for ecologists describing trophic structure in aquatic communities, fisheries managers tasked with increasing sustainable fisheries development, and fish farmers seeking to maximize production. Previous studies of the empirical relationships of autotrophic activity and freshwater fish yield have found positive relationships but were limited by small sample sizes, small geographic scopes, and the inability to compare patterns among many types of measurement techniques. Individual studies and reviews have also lacked consistent consideration of regional climate factors which may inform relationships between fisheries and autotrophic activity. We compiled data from over 700 freshwater systems worldwide and used meta-analysis and linear models to develop a comprehensive global synthesis between multiple metrics of autotrophic activity, fisheries, and climate indicators. Our results demonstrate that multiple metrics of fish (i.e., catch per unit effort, yield, and production) increase with autotrophic activity across a variety of fisheries. At the global scale additional variation in this positive relationship can be ascribed to regional climate differences (i.e., temperature and precipitation) across systems. Our results provide a method and proof-of-concept for assessing inland fisheries production at the global scale, where current estimates are highly uncertain, and may therefore inform the continued sustainable use of global inland fishery resources.

Preparation of Gc protein-derived macrophage activating factor (GcMAF) and its structural characterization and biological activities.

Science.gov (United States)

Mohamad, Saharuddin Bin; Nagasawa, Hideko; Uto, Yoshihiro; Hori, Hitoshi

2002-01-01

Gc protein has been reported to be a precursor of Gc protein-derived macrophage activation factor (GcMAF) in the inflammation-primed macrophage activation cascade. An inducible beta-galactosidase of B cells and neuraminidase of T cells convert Gc protein to GcMAF. Gc protein from human serum was purified using 25(OH)D3 affinity column chromatography and modified to GcMAF using immobilized glycosidases (beta-galactosidase and neuraminidase) The sugar moiety structure of GcMAF was characterized by lectin blotting by Helix pomatia agglutinin. The biological activities of GcMAF were evaluated by a superoxide generation assay and a phagocytosis assay. We successfully purified Gc protein from human serum. GcMAF was detected by lectin blotting and showed a high biological activity. Our results support the importance of the terminal N-acetylgalactosamine moiety in the GcMAF-mediated macrophage activation cascade, and the existence of constitutive GcMAF in human serum. These preliminary data are important for designing small molecular GcMAF mimics.

Brief Report: Activities in Heterosexual Romantic Relationships--Grade Differences and Associations with Relationship Satisfaction

Science.gov (United States)

Carlson, Wendy; Rose, Amanda J.

2012-01-01

Whereas much research addresses relations of youths' heterosexual romantic relationships with sexual and/or delinquent activities, less attention has been paid to youths' more normative, day-to-day activities with romantic partners. This gap in the literature is problematic given that these activities define the substance of the relationships and…

Quantitative Structure activity relationship and risk analysis of some pesticides in the cattle milk

Directory of Open Access Journals (Sweden)

Faqir Muhammad*, Ijaz Javed, Masood Akhtar1, Zia-ur-Rahman, Mian Muhammad Awais1, Muhammad Kashif Saleemi2 and Muhammad Irfan Anwar3

2012-10-01

Full Text Available Milk of cattle was collected from various localities of Faisalabad, Pakistan. Pesticides concentration was determined by HPLC using solid phase microextraction. The residue analysis revealed that about 40% milk samples were contaminated with pesticides. The mean±SE levels (ppm of cyhalothrin, endosulfan, chlorpyrifos and cypermethrin were 0.38±0.02, 0.26±0.02, 0.072±0.01 and 0.085±0.02, respectively. Quantitative structure activity relationship (QSAR models were used to predict the residues of unknown pesticides in the milk of cattle using their known physicochemical properties such as molecular weight (MW, melting point (MP, and log octanol to water partition coefficient (Ko/w as well as the milk characteristics such as pH, % fat, and specific gravity (SG in this species. The analysis revealed good correlation coefficients (R2 = 0.91 for cattle QSAR model. The coefficient for Ko/w for the studied pesticides was higher in cattle milk. Risk analysis was conducted based upon the determined pesticide residues and their provisional tolerable daily intakes. The daily intake levels of pesticide residues including cyhalothrin, chlorpyrifos and cypermethrin in present study were 3, 11, 2.5 times higher, respectively in cattle milk. This intake of pesticide contaminated milk might pose health hazards to humans in this locality.

Status report on preliminary design activities for solar heating and cooling systems

Energy Technology Data Exchange (ETDEWEB)

1978-05-01

Information presented provides status and progress on the development of solar heating and cooling systems. The major emphasis is placed on program organization, system size definition, site identification, system approaches, heat pump and equipment design, collector procurement, and other preliminary design activities as part of the contract requirements.

Brand relationships: A study of five relationship constructs

DEFF Research Database (Denmark)

Bergkvist, Lars; Bech-Larsen, Tino

This study investigates the relationships between the five brand relationship constructs sense of community, brand identification, brand love, brand loyalty, and active engagement. Structural equation modelling with partial least squares showed provided support for six relational hypotheses...

Structure-Activity Relationship Study of Ionotropic Glutamate Receptor Antagonist (2S,3R)-3-(3-Carboxyphenyl)pyrrolidine-2-carboxylic Acid

DEFF Research Database (Denmark)

Krogsgaard-Larsen, Niels; Storgaard, Morten; Møller, Charlotte

2015-01-01

Herein we describe the first structure-activity relationship study of the broad-range iGluR antagonist (2S,3R)-3-(3-carboxyphenyl)pyrrolidine-2-carboxylic acid (1) by exploring the pharmacological effect of substituents in the 4, 4', or 5' positions and the bioisosteric substitution of the distal...... carboxylic acid for a phosphonic acid moiety. Of particular interest is a hydroxyl group in the 4' position 2a which induced a preference in binding affinity for homomeric GluK3 over GluK1 (Ki = 0.87 and 4.8 μM, respectively). Two X-ray structures of ligand binding domains were obtained: 2e in GluA2-LBD...... and 2f in GluK1-LBD, both at 1.9 Å resolution. Compound 2e induces a D1-D2 domain opening in GluA2-LBD of 17.3-18.8° and 2f a domain opening in GluK1-LBD of 17.0-17.5° relative to the structures with glutamate. The pyrrolidine-2-carboxylate moiety of 2e and 2f shows a similar binding mode as kainate...

New Insights about Enzyme Evolution from Large Scale Studies of Sequence and Structure Relationships*

Science.gov (United States)

Brown, Shoshana D.; Babbitt, Patricia C.

2014-01-01

Understanding how enzymes have evolved offers clues about their structure-function relationships and mechanisms. Here, we describe evolution of functionally diverse enzyme superfamilies, each representing a large set of sequences that evolved from a common ancestor and that retain conserved features of their structures and active sites. Using several examples, we describe the different structural strategies nature has used to evolve new reaction and substrate specificities in each unique superfamily. The results provide insight about enzyme evolution that is not easily obtained from studies of one or only a few enzymes. PMID:25210038

Preliminary structural characterization of human SOUL, a haem-binding protein

International Nuclear Information System (INIS)

Freire, Filipe; Romão, Maria João; Macedo, Anjos L.; Aveiro, Susana S.; Goodfellow, Brian J.; Carvalho, Ana Luísa

2009-01-01

This manuscript describes the overexpression, purification and crystallization of human SOUL protein (hSOUL). hSOUL is a 23 kDa haem-binding protein that was first identified as the PP23 protein isolated from human full-term placenta. Human SOUL (hSOUL) is a 23 kDa haem-binding protein that was first identified as the PP 23 protein isolated from human full-term placentas. Here, the overexpression, purification and crystallization of hSOUL are reported. The crystals belonged to space group P6 4 22, with unit-cell parameters a = b = 145, c = 60 Å and one protein molecule in the asymmetric unit. X-ray diffraction data were collected to 3.5 Å resolution at the ESRF. A preliminary model of the three-dimensional structure of hSOUL was obtained by molecular replacement using the structures of murine p22HBP, obtained by solution NMR, as search models

Structure-activity relationships in a new series of insecticidally active dioxatricycloalkenes derived by structural comparison of the GABA [γ-aminobutyric acid] antagonists bicycloorthocarboxylates and endosulfan

International Nuclear Information System (INIS)

Ozoe, Yoshihisa; Sawada, Yoshihiro; Mochida, Kazuo; Nakamura, Toshiie; Matsumura, Fumio

1990-01-01

To study structural requirements for picrotoxinin-type GABA (γ-aminobutyric acid) antagonists to interact with the receptor site, 5-substituted 4,6-dioxatricyclo[7.2.1.0 2,8 ]dodec-10-enes and related compounds were prepared and examined for their insecticidal activity and potency in displacing [ 35 S]tert-butylbicyclophosphorothionate (TBPS) binding. Compounds with high insecticidal activity possessed a phenyl group with an electron-withdrawing para substituent, a cycloalkyl group, or a C 3 -C 5 straight-chain alkyl group at the 5-position. The effect of the 5-substituents on insecticidal activity was very similar to that of the 1-substituents of the bicyloorthocarboxylate GABA antagonists. Representative dioxatricycloalkenes displaced the binding of the GABA antagonist [ 35 S]TBPS to housefly head membranes by 29-53% at 10 μM. X-ray crystal structure analysis demonstrated that this class of compounds had structures superimposable on those of 4-tert-butylbicycloorthocarboxylates. These findings indicate that the dioxatricycloalkenes and some other analogues occupy the picrotoxinin binding site in such a way that the fourth interacting subsite of the receptor site accommodates the 5-substituent

Development of quantitative structure activity relationship (QSAR) model for disinfection byproduct (DBP) research: A review of methods and resources

Energy Technology Data Exchange (ETDEWEB)

Chen, Baiyang, E-mail: poplar_chen@hotmail.com [Harbin Institute of Technology Shenzhen Graduate School, Shenzhen Key Laboratory of Water Resource Utilization and Environmental Pollution Control, Shenzhen 518055 (China); Zhang, Tian [Harbin Institute of Technology Shenzhen Graduate School, Shenzhen Key Laboratory of Water Resource Utilization and Environmental Pollution Control, Shenzhen 518055 (China); Bond, Tom [Department of Civil and Environmental Engineering, Imperial College, London SW7 2AZ (United Kingdom); Gan, Yiqun [Harbin Institute of Technology Shenzhen Graduate School, Shenzhen Key Laboratory of Water Resource Utilization and Environmental Pollution Control, Shenzhen 518055 (China)

2015-12-15

Quantitative structure–activity relationship (QSAR) models are tools for linking chemical activities with molecular structures and compositions. Due to the concern about the proliferating number of disinfection byproducts (DBPs) in water and the associated financial and technical burden, researchers have recently begun to develop QSAR models to investigate the toxicity, formation, property, and removal of DBPs. However, there are no standard procedures or best practices regarding how to develop QSAR models, which potentially limit their wide acceptance. In order to facilitate more frequent use of QSAR models in future DBP research, this article reviews the processes required for QSAR model development, summarizes recent trends in QSAR-DBP studies, and shares some important resources for QSAR development (e.g., free databases and QSAR programs). The paper follows the four steps of QSAR model development, i.e., data collection, descriptor filtration, algorithm selection, and model validation; and finishes by highlighting several research needs. Because QSAR models may have an important role in progressing our understanding of DBP issues, it is hoped that this paper will encourage their future use for this application.

Kinetics and structure-activity relationship of dendritic bridged hindered phenol antioxidants to protect styrene against free radical induced peroxidation

Science.gov (United States)

Li, Cui-Qin; Guo, Su-Yue; Wang, Jun; Shi, Wei-Guang; Zhang, Zhi-Qiu; Wang, Peng-Xiang

2017-12-01

A series of dendritic poly(amido-amine) (PAMAM) bridged hindered phenols antioxidants were synthesized. The active antioxidant group (3-(3,5-di- tert-butyl-4-hydroxyphenyl)propionic acid) was attached to two generations of PAMAM dendrimers, and their structure was verified by nuclear magnetic resonance (NMR) and fourier transform infrared spectra (FT-IR). The antioxidant abilities of the dendritic phenols to inhibit the oxidation of styrene were evaluated and the relationships between the length of core, the generation of dendrimers and the antioxidant activities were established. The reaction kinetics of scavenging peroxyl radicals was followed by oxygen consumption. The inhibition time ( t inh) values showed the dendritic phenols had the ability of scavenging peroxyl radicals, and that the antioxidant ability increased with the increasing length of the core and the generation. The kinetic analysis demonstrated that dendritic phenols could slow the rate of styrene peroxidation induced by AIBN, as shown by the number of trapping ROO· ( n), and this role was in accordance with that of the t inh values.

Development of quantitative structure activity relationship (QSAR) model for disinfection byproduct (DBP) research: A review of methods and resources

International Nuclear Information System (INIS)

Chen, Baiyang; Zhang, Tian; Bond, Tom; Gan, Yiqun

2015-01-01

Quantitative structure–activity relationship (QSAR) models are tools for linking chemical activities with molecular structures and compositions. Due to the concern about the proliferating number of disinfection byproducts (DBPs) in water and the associated financial and technical burden, researchers have recently begun to develop QSAR models to investigate the toxicity, formation, property, and removal of DBPs. However, there are no standard procedures or best practices regarding how to develop QSAR models, which potentially limit their wide acceptance. In order to facilitate more frequent use of QSAR models in future DBP research, this article reviews the processes required for QSAR model development, summarizes recent trends in QSAR-DBP studies, and shares some important resources for QSAR development (e.g., free databases and QSAR programs). The paper follows the four steps of QSAR model development, i.e., data collection, descriptor filtration, algorithm selection, and model validation; and finishes by highlighting several research needs. Because QSAR models may have an important role in progressing our understanding of DBP issues, it is hoped that this paper will encourage their future use for this application.

Quantitative structure-activity relationships for predicting potential ecological hazard of organic chemicals for use in regulatory risk assessments.

Science.gov (United States)

Comber, Mike H I; Walker, John D; Watts, Chris; Hermens, Joop

2003-08-01

The use of quantitative structure-activity relationships (QSARs) for deriving the predicted no-effect concentration of discrete organic chemicals for the purposes of conducting a regulatory risk assessment in Europe and the United States is described. In the United States, under the Toxic Substances Control Act (TSCA), the TSCA Interagency Testing Committee and the U.S. Environmental Protection Agency (U.S. EPA) use SARs to estimate the hazards of existing and new chemicals. Within the Existing Substances Regulation in Europe, QSARs may be used for data evaluation, test strategy indications, and the identification and filling of data gaps. To illustrate where and when QSARs may be useful and when their use is more problematic, an example, methyl tertiary-butyl ether (MTBE), is given and the predicted and experimental data are compared. Improvements needed for new QSARs and tools for developing and using QSARs are discussed.

Cloning, purification, crystallization and preliminary structural studies of penicillin V acylase from Bacillus subtilis

International Nuclear Information System (INIS)

Rathinaswamy, Priya; Pundle, Archana V.; Prabhune, Asmita A.; SivaRaman, Hepzibah; Brannigan, James A.; Dodson, Guy G.; Suresh, C. G.

2005-01-01

An unannotated protein reported from B. subtilis has been expressed in E. coli and identified as possessing penicillin V acylase activity. The crystallization and preliminary crystallographic analysis of this penicillin V acylase is presented. Penicillin acylase proteins are amidohydrolase enzymes that cleave penicillins at the amide bond connecting the side chain to their β-lactam nucleus. An unannotated protein from Bacillus subtilis has been expressed in Escherichia coli, purified and confirmed to possess penicillin V acylase activity. The protein was crystallized using the hanging-drop vapour-diffusion method from a solution containing 4 M sodium formate in 100 mM Tris–HCl buffer pH 8.2. Diffraction data were collected under cryogenic conditions to a spacing of 2.5 Å. The crystals belonged to the orthorhombic space group C222 1 , with unit-cell parameters a = 111.0, b = 308.0, c = 56.0 Å. The estimated Matthews coefficient was 3.23 Å 3 Da −1 , corresponding to 62% solvent content. The structure has been solved using molecular-replacement methods with B. sphaericus penicillin V acylase (PDB code 2pva) as the search model

The relationship between ataque de nervios and unexplained neurological symptoms: a preliminary analysis.

Science.gov (United States)

Interian, Alejandro; Guarnaccia, Peter J; Vega, William A; Gara, Michael A; Like, Robert C; Escobar, Javier I; Díaz-Martínez, Angélica M

2005-01-01

Within somatization, unexplained neurological symptoms (UNSs) have been shown to mark a distinct subgroup with greater clinical severity. However, some UNSs resemble ataque de nervios somatic symptoms. This raises questions about cultural factors related to Hispanics with somatization characterized by UNSs. To examine cultural factors, preliminary analyses examined the relationship between Hispanic ethnicity, UNSs, and ataque de nervios. Data were obtained from 127 primary care patients (95 Hispanic, 32 European American) with somatization. The Composite International Diagnostic Interview provided somatization data, whereas the Primary Care Evaluation of Mental Disorders was used for data on Axis I disorders. Ataque de nervios was assessed via a proxy measure. Within each ethnic group, cross-tabs examined the relationship between ataque de nervios and multiple UNSs, and ataque de nervios and selected Axis I disorders. Only among Hispanics, a significant overlap was found between ataque de nervios and having four or more UNSs (p nervios and a diagnosis of panic disorder (p = .05). Although equal percentages of European Americans and Hispanics experience multiple UNSs, these results show that the presentation of UNSs among some Hispanics may be qualitatively different, because it may involve features related to ataque de nervios. A diagnosis of panic disorder also appears to interact with cultural factors.

Detailed Structural Analyses of KOH Activated Carbon from Waste Coffee Beans

Science.gov (United States)

Takahata, Tomokazu; Toda, Ikumi; Ono, Hiroki; Ohshio, Shigeo; Akasaka, Hiroki; Himeno, Syuji; Kokubu, Toshinori; Saitoh, Hidetoshi

2009-11-01

The relationship of the detailed structural change of KOH activated carbon and hydrogen storage ability was investigated in activated carbon materials fabricated from waste coffee beans. The specific surface area of porous carbon materials calculated from N2 adsorption isotherms stood at 2070 m2/g when the weight ratio of KOH to carbon materials was 5:1, and pore size was in the range of approximately 0.6 to 1.1 nm as micropores. In the structural analysis, X-ray diffraction analysis and Raman spectroscopy indicated structural change in these carbon materials through KOH activation. The order of the graphite structure changed to a smaller scale with this activation. It is theorized that specific surface area increased using micropores provided by carbon materials developed from the descent of the graphite structure. Hydrogen storage ability improved with these structural changes, and reached 0.6 wt % at 2070 m2/g. These results suggest that hydrogen storage ability is conferred by the chemical effect on graphite of carbon materials.

Probing structure-antifouling activity relationships of polyacrylamides and polyacrylates.

Science.gov (United States)

Zhao, Chao; Zhao, Jun; Li, Xiaosi; Wu, Jiang; Chen, Shenfu; Chen, Qiang; Wang, Qiuming; Gong, Xiong; Li, Lingyan; Zheng, Jie

2013-07-01

We have synthesized two different polyacrylamide polymers with amide groups (polySBAA and polyHEAA) and two corresponding polyacrylate polymers without amide groups (polySBMA and polyHEA), with particular attention to the evaluation of the effect of amide group on the hydration and antifouling ability of these systems using both computational and experimental approaches. The influence of polymer architectures of brushes, hydrogels, and nanogels, prepared by different polymerization methods, on antifouling performance is also studied. SPR and ELISA data reveal that all polymers exhibit excellent antifouling ability to repel proteins from undiluted human blood serum/plasma, and such antifouling ability can be further enhanced by presenting amide groups in polySBAA and polyHEAA as compared to polySBMA and polyHEA. The antifouling performance is positively correlated with the hydration properties. Simulations confirm that four polymers indeed have different hydration characteristics, while all presenting a strong hydration overall. Integration of amide group with pendant hydroxyl or sulfobetaine group in polymer backbones is found to increase their surface hydration of polymer chains and thus to improve their antifouling ability. Importantly, we present a proof-of-concept experiment to synthesize polySBAA nanogels, which show a switchable property between antifouling and pH-responsive functions driven by acid-base conditions, while still maintaining high stability in undiluted fetal bovine serum and minimal toxicity to cultured cells. This work provides important structural insights into how very subtle structural changes in polymers can yield great improvement in biological activity, specifically the inclusion of amide group in polymer backbone/sidechain enables to obtain antifouling materials with better performance for biomedical applications. Copyright © 2013 Elsevier Ltd. All rights reserved.

The preliminary results: Internal seismic velocity structure imaging beneath Mount Lokon

Energy Technology Data Exchange (ETDEWEB)

Firmansyah, Rizky, E-mail: rizkyfirmansyah@hotmail.com [Geophysical Engineering, Faculty of Mining and Petroleum Engineering, Institut Teknologi Bandung, Bandung, 40132 (Indonesia); Nugraha, Andri Dian, E-mail: nugraha@gf.itb.ac.id [Global Geophysical Group, Faculty of Mining and Petroleum Engineering, Institut Teknologi Bandung, Bandung, 40132 (Indonesia); Kristianto, E-mail: kris@vsi.esdm.go.id [Center for Volcanology and Geological Hazard Mitigation (CVGHM), Geological Agency, Bandung, 40122 (Indonesia)

2015-04-24

Historical records that before the 17{sup th} century, Mount Lokon had been dormant for approximately 400 years. In the years between 1350 and 1400, eruption ever recorded in Empung, came from Mount Lokon’s central crater. Subsequently, in 1750 to 1800, Mount Lokon continued to erupt again and caused soil damage and fall victim. After 1949, Mount Lokon dramatically increased in its frequency: the eruption interval varies between 1 – 5 years, with an average interval of 3 years and a rest interval ranged from 8 – 64 years. Then, on June 26{sup th}, 2011, standby alert set by the Center for Volcanology and Geological Hazard Mitigation. Peak activity happened on July 4{sup th}, 2011 that Mount Lokon erupted continuously until August 28{sup th}, 2011. In this study, we carefully analyzed micro-earthquakes waveform and determined hypocenter location of those events. We then conducted travel time seismic tomographic inversion using SIMULPS12 method to detemine Vp, Vs and Vp/Vs ratio structures beneath Lokon volcano in order to enhance our subsurface geological structure. During the tomographic inversion, we started from 1-D seismic velocities model obtained from VELEST33 method. Our preliminary results show low Vp, low Vs, and high Vp/Vs are observed beneath Mount Lokon-Empung which are may be associated with weak zone or hot material zones. However, in this study we used few station for recording of micro-earthquake events. So, we suggest in the future tomography study, the adding of some seismometers in order to improve ray coverage in the region is profoundly justified.

The relationship between structural and functional connectivity: graph theoretical analysis of an EEG neural mass model

NARCIS (Netherlands)

Ponten, S.C.; Daffertshofer, A.; Hillebrand, A.; Stam, C.J.

2010-01-01

We investigated the relationship between structural network properties and both synchronization strength and functional characteristics in a combined neural mass and graph theoretical model of the electroencephalogram (EEG). Thirty-two neural mass models (NMMs), each representing the lump activity

Relationship Between Resilience, Adjustment, and Psychological Functioning After Traumatic Brain Injury: A Preliminary Report.

Science.gov (United States)

Lukow, Herman R; Godwin, Emilie E; Marwitz, Jennifer H; Mills, Ana; Hsu, Nancy H; Kreutzer, Jeffrey S

2015-01-01

To examine the relationship between resilience, psychological distress, adjustment, and community participation after traumatic brain injury (TBI). Large university health system. Adult survivors of mild to severe TBI (N = 96). Descriptive, preliminary. The Connor-Davidson Resilience Scale (10-item version) was used to assess resilience, the Brief Symptom Inventory (BSI-18) was used to characterize psychological distress, and the Mayo-Portland Adaptability Index (MPAI-4) was used to measure ability, adjustment, and participation. Resilience scores were substantially lower than those of the general population. Significant relationships were found between resilience, psychological distress, and adjustment. Partial correlations (adjusting for the other MPAI-4 indices) showed significant correlation (P MPAI-4 Adjustment and resilience. Partial correlations (adjusting for the other BSI-18 scales) also showed significance for Depression (P < .01) and resilience. Resilience scores differed significantly (P < .001) between individuals meeting BSI-18 caseness criteria for psychological distress (n = 55) and those not meeting criteria (n = 41). Individuals with TBI are at risk for low resilience, which was found to correlate with psychological distress and psychosocial maladjustment. Developing interventions to strengthen resilience skills has the potential to improve postinjury psychosocial adjustment, an important area for future research.

Syntheses and absorption-structure relationships of some new ...

Indian Academy of Sciences (India)

New biheterocyclic compound was synthesized as starting material to prepare new photosensitizers mono-, tri-, substituted tri-, azadimethine and mixed cyanine dyes. Absorption-structure relationship of the synthesized cyanine dyes were determined by studying their electronic spectral behaviour in ethanol. The structure of ...

Parent-Child Relations and Peer Associations as Mediators of the Family Structure--Substance Use Relationship

Science.gov (United States)

Crawford, Lizabeth A.; Novak, Katherine B.

2008-01-01

Using data from the National Education Longitudinal Survey of 1988, the authors assess the extent to which adolescents' levels of parental attachment and opportunities for participating in delinquent activities mediate the family structure--substance use relationship. A series of hierarchical regressions supported the hypotheses that high levels…

Structure determination of glycogen synthase kinase-3 from Leishmania major and comparative inhibitor structure-activity relationships with Trypanosoma brucei GSK-3

Energy Technology Data Exchange (ETDEWEB)

Ojo, Kayode K; Arakaki, Tracy L; Napuli, Alberto J; Inampudi, Krishna K; Keyloun, Katelyn R; Zhang, Li; Hol, Wim G.J.; Verlind, Christophe L.M.J.; Merritt, Ethan A; Van Voorhis, Wesley C [UWASH

2012-04-24

Glycogen synthase kinase-3 (GSK-3) is a drug target under intense investigation in pharmaceutical companies and constitutes an attractive piggyback target for eukaryotic pathogens. Two different GSKs are found in trypanosomatids, one about 150 residues shorter than the other. GSK-3 short (GeneDB: Tb927.10.13780) has previously been validated genetically as a drug target in Trypanosoma brucei by RNAi induced growth retardation; and chemically by correlation between enzyme and in vitro growth inhibition. Here, we report investigation of the equivalent GSK-3 short enzymes of L. major (LmjF18.0270) and L. infantum (LinJ18_V3.0270, identical in amino acid sequences to LdonGSK-3 short) and a crystal structure of LmajGSK-3 short at 2 Å resolution. The inhibitor structure-activity relationships (SARs) of L. major and L. infantum are virtually identical, suggesting that inhibitors could be useful for both cutaneous and visceral leishmaniasis. Leishmania spp. GSK-3 short has different inhibitor SARs than TbruGSK-3 short, which can be explained mostly by two variant residues in the ATP-binding pocket. Indeed, mutating these residues in the ATP-binding site of LmajGSK-3 short to the TbruGSK-3 short equivalents results in a mutant LmajGSK-3 short enzyme with SAR more similar to that of TbruGSK-3 short. The differences between human GSK-3β (HsGSK-3β) and LmajGSK-3 short SAR suggest that compounds which selectively inhibit LmajGSK-3 short may be found.

Quantitative structure--property relationships for enhancing predictions of synthetic organic chemical removal from drinking water by granular activated carbon.

Science.gov (United States)

Magnuson, Matthew L; Speth, Thomas F

2005-10-01

Granular activated carbon is a frequently explored technology for removing synthetic organic contaminants from drinking water sources. The success of this technology relies on a number of factors based not only on the adsorptive properties of the contaminant but also on properties of the water itself, notably the presence of substances in the water which compete for adsorption sites. Because it is impractical to perform field-scale evaluations for all possible contaminants, the pore surface diffusion model (PSDM) has been developed and used to predict activated carbon column performance using single-solute isotherm data as inputs. Many assumptions are built into this model to account for kinetics of adsorption and competition for adsorption sites. This work further evaluates and expands this model, through the use of quantitative structure-property relationships (QSPRs) to predict the effect of natural organic matter fouling on activated carbon adsorption of specific contaminants. The QSPRs developed are based on a combination of calculated topographical indices and quantum chemical parameters. The QSPRs were evaluated in terms of their statistical predictive ability,the physical significance of the descriptors, and by comparison with field data. The QSPR-enhanced PSDM was judged to give results better than what could previously be obtained.

Biochemical interpretation of quantitative structure-activity relationships (QSAR) for biodegradation of N-heterocycles: a complementary approach to predict biodegradability.

Science.gov (United States)

Philipp, Bodo; Hoff, Malte; Germa, Florence; Schink, Bernhard; Beimborn, Dieter; Mersch-Sundermann, Volker

2007-02-15

Prediction of the biodegradability of organic compounds is an ecologically desirable and economically feasible tool for estimating the environmental fate of chemicals. We combined quantitative structure-activity relationships (QSAR) with the systematic collection of biochemical knowledge to establish rules for the prediction of aerobic biodegradation of N-heterocycles. Validated biodegradation data of 194 N-heterocyclic compounds were analyzed using the MULTICASE-method which delivered two QSAR models based on 17 activating (OSAR 1) and on 16 inactivating molecular fragments (GSAR 2), which were statistically significantly linked to efficient or poor biodegradability, respectively. The percentages of correct classifications were over 99% for both models, and cross-validation resulted in 67.9% (GSAR 1) and 70.4% (OSAR 2) correct predictions. Biochemical interpretation of the activating and inactivating characteristics of the molecular fragments delivered plausible mechanistic interpretations and enabled us to establish the following biodegradation rules: (1) Target sites for amidohydrolases and for cytochrome P450 monooxygenases enhance biodegradation of nonaromatic N-heterocycles. (2) Target sites for molybdenum hydroxylases enhance biodegradation of aromatic N-heterocycles. (3) Target sites for hydratation by an urocanase-like mechanism enhance biodegradation of imidazoles. Our complementary approach represents a feasible strategy for generating concrete rules for the prediction of biodegradability of organic compounds.

Structure-activity relationships in a new series of insecticidally active dioxatricycloalkenes derived by structural comparison of the GABA (. gamma. -aminobutyric acid) antagonists bicycloorthocarboxylates and endosulfan

Energy Technology Data Exchange (ETDEWEB)

Ozoe, Yoshihisa; Sawada, Yoshihiro; Mochida, Kazuo; Nakamura, Toshiie (Shimane Univ. (Japan)); Matsumura, Fumio (Univ. of California, Davis (USA))

1990-05-01

To study structural requirements for picrotoxinin-type GABA ({gamma}-aminobutyric acid) antagonists to interact with the receptor site, 5-substituted 4,6-dioxatricyclo(7.2.1.0{sup 2,8})dodec-10-enes and related compounds were prepared and examined for their insecticidal activity and potency in displacing ({sup 35}S)tert-butylbicyclophosphorothionate (TBPS) binding. Compounds with high insecticidal activity possessed a phenyl group with an electron-withdrawing para substituent, a cycloalkyl group, or a C{sub 3}-C{sub 5} straight-chain alkyl group at the 5-position. The effect of the 5-substituents on insecticidal activity was very similar to that of the 1-substituents of the bicyloorthocarboxylate GABA antagonists. Representative dioxatricycloalkenes displaced the binding of the GABA antagonist ({sup 35}S)TBPS to housefly head membranes by 29-53% at 10 {mu}M. X-ray crystal structure analysis demonstrated that this class of compounds had structures superimposable on those of 4-tert-butylbicycloorthocarboxylates. These findings indicate that the dioxatricycloalkenes and some other analogues occupy the picrotoxinin binding site in such a way that the fourth interacting subsite of the receptor site accommodates the 5-substituent.

Preliminary seismic design of dynamically coupled structural systems

International Nuclear Information System (INIS)

Pal, N.; Dalcher, A.W.; Gluck, R.

1977-01-01

In this paper, the analysis criteria for coupling and decoupling, which are most commonly used in nuclear design practice, are briefly reviewed and a procedure outlined and demonstrated with examples. Next, a criterion judged to be practical for preliminary seismic design purposes is defined. Subsequently, a technique compatible with this criterion is suggested. A few examples are presented to test the proposed procedure for preliminary seismic design purposes. Limitations of the procedure are also discussed and finally, the more important conclusions are summarized

Development of lutetium-labeled bombesin derivates: relationship between structure and diagnostic-therapeutic activity for prostate tumor

International Nuclear Information System (INIS)

Pujatti, Priscilla Brunelli

2009-01-01

Bombesin (BBN) receptors - in particular, the gastrin-releasing peptide (GRP) receptor peptide - have been shown to be massively over expressed in several human tumors types, including prostate cancer, and could be an alternative as target for its treatment by radionuclide therapy (RNT). A large number of BBN analogs had already been synthesized for this purpose and have shown to reduce tumor growth in mice. Nevertheless, most of the studied analogs exhibit high abdominal accumulation, especially in pancreas. This abdominal accumulation may represent a problem in clinical use of radiolabeled bombesin analogs probably due to serious side effects to patients. The goal of the present work was to radiolabel a novel series of bombesin derivatives with lutetium-177 and to evaluate the relationship between their structure and diagnostic-therapeutic activity for prostate tumor. The generic structure of studied peptides is DOTA-Phe-(Gly) n -BBN(6-14), where DOTA is the chelator, n is the number of glycine amino acids of Phe-(Gly) n spacer and BBN(6-14) is the bombesin sequence from the amino acid 6 to the amino acid 14. Preliminary studies were done to establish the ideal labeling conditions for obtaining the highest yield of labeled bombesin derivatives, determined by instant thin layer chromatography (ITLC-SG) and high performance liquid chromatography (HPLC). The stability of the preparations was evaluated either after storing at 2-8 degree C or incubation in human serum at 37 degree C and the partition coefficient was determined in n:octanol:water. In vivo studies were performed in both healthy Balb-c and Nude mice bearing PC-3 xenografts, in order to characterize the biological properties of labeled peptides. In vitro studies involved the evaluation of cold bombesin derivatives effect in PC-3 cells proliferation. Bombesin derivatives were successfully labeled with high yield at optimized conditions and exhibited high stability at 4 degree C. The analysis of the

Preliminary AD-Horn Thermomechanical and Electrodynamic Simulations

CERN Document Server

AUTHOR|(CDS)2095747; Horvath, David; Calviani, Marco

2016-01-01

As part of the Antiproton Decelerator (AD) target area consolidation activities planned for LS2, it has been necessary to perform a comprehensive study of the thermo-structural behaviour of the AD magnetic horn during operation, in order to detail specific requirements for the upgrade projects and testing procedures. The present work illustrates the preliminary results of the finite element analysis carried out to evaluate the thermal and structural behaviour of the device, as well as the methodology used to model and solve the thermomechanical and electrodynamic simulations performed in the AD magnetic horn.

The dynamic relationship between structural change and CO2 emissions in Malaysia: a cointegrating approach.

Science.gov (United States)

Ali, Wajahat; Abdullah, Azrai; Azam, Muhammad

2017-05-01

The current study investigates the dynamic relationship between structural changes, real GDP per capita, energy consumption, trade openness, population density, and carbon dioxide (CO 2 ) emissions within the EKC framework over a period 1971-2013. The study used the autoregressive distributed lagged (ARDL) approach to investigate the long-run relationship between the selected variables. The study also employed the dynamic ordinary least squared (DOLS) technique to obtain the robust long-run estimates. Moreover, the causal relationship between the variables is explored using the VECM Granger causality test. Empirical results reveal a negative relationship between structural change and CO 2 emissions in the long run. The results indicate a positive relationship between energy consumption, trade openness, and CO 2 emissions. The study applied the turning point formula of Itkonen (2012) rather than the conventional formula of the turning point. The empirical estimates of the study do not support the presence of the EKC relationship between income and CO 2 emissions. The Granger causality test indicates the presence of long-run bidirectional causality between energy consumption, structural change, and CO 2 emissions in the long run. Economic growth, openness to trade, and population density unidirectionally cause CO 2 emissions. These results suggest that the government should focus more on information-based services rather than energy-intensive manufacturing activities. The feedback relationship between energy consumption and CO 2 emissions suggests that there is an ominous need to refurbish the energy-related policy reforms to ensure the installations of some energy-efficient modern technologies.

Synthesis and Preliminary Antimicrobial Activities of New Arylideneamino-1,3,4-thiadiazole-(thio/dithio-acetamido Cephalosporanic Acids

Directory of Open Access Journals (Sweden)

Shakir Mahmood Alwan

2012-01-01

Full Text Available New derivatives of 7-aminocephalosporanic acid 1–8 were synthesized by acylation of the 7-amino group of the cephem nucleus with various arylidinimino-1,3,4-thiadiazole-thio(or dithio-acetic acid intermediates 3a–d and 5a–d, respectively, so the acyl side chains of these new cephalosporins contained a sulfide or disulfide bond. This unique combination of a Schiff base with the sulfide or disulfide bonds in the acyl side chain afforded new cephalosporins of reasonable potencies, some of which were found to possess moderate activities against the tested microorganisms. Their chemical structures were characterized by ¹H-NMR, IR spectroscopy and elemental microanalysis. Preliminary in vitro antimicrobial activities of the prepared cephalosporins were investigated using a panel of selected microorganisms. Results indicated that the newly synthesized cephalosporins containing disulfide bonds (compounds 5–8 exhibited better activities against Staphylococcus aureus and Escherichia coli. The cephalosporins cross-linked by a sulfide bond (compounds 1–4 showed a slight change in antimicrobial activities when compared with that of the reference cephalosporin (cephalexin.

Metric characteristics of Children-parents relationship questionnaire (VOS: a preliminary study

Directory of Open Access Journals (Sweden)

Ana Kozina

2010-11-01

Full Text Available The purpose of the article is to introduce the Children-parents relationship questionnaire (VOS and to present its metric characteristics. The questionnaire is based on parental styles of D. Baumrind (1967 and 3D model of parental styles developed by Milivojević and others (2004. The questionnaire was developed under assumption that relationship between children and their parents influences educational achievement of children. Results on convenience sample (N = 333 of seventh, eighth and ninth grade students in Slovenia show a three dimensional structure of the questionnaire: (a authoritative parental style and autonomy, (b authoritarian parental style and (c rewarding. Questionnaires' reliability in terms of internal consistency (,72 > α < ,95 as well as sensitivity (average r = ,67 proved to be sufficient. Our results show significant gender differences in perceived authoritative parental style and autonomy as well as low association between school grades and the perceived relationship.

Synthesis and evaluation of 8,4'-dideshydroxy-leinamycin revealing new insights into the structure-activity relationship of the anticancer natural product leinamycin.

Science.gov (United States)

Liu, Tao; Ma, Ming; Ge, Hui-Ming; Yang, Chunying; Cleveland, John; Shen, Ben

2015-11-01

Leinamycin (LNM, 1) is a novel antitumor antibiotic produced by Streptomyces atroolivaceus S-140 and features an unusual 1,3-dioxo-1,2-dithiolane moiety that is spiro-fused to a thiazole-containing 18-membered lactam ring. The 1,3-dioxo-1,2-dithiolane moiety of LNM is essential for its antitumor activity via an episulfonium ion-mediated DNA alkylation upon reductive activation in the presence of cellular thiols. We recently isolated leinamycin E1 (LNM E1, 2) from an engineered strain S. atroolivaceus SB3033, which lacks the 1,3-dioxo-1,2-dithiolane moiety. Here we report the chemical synthesis of 8,4'-dideshydroxy-LNM (5) from 2 and determination of the cytotoxicity of 5 against selected cancer cell lines in comparison with 1; 5 exhibits comparable activity as 1 with the EC50 values between 8.21 and 275 nM. This work reveals new insight into the structure-activity relationship of LNM and highlights the synergy between metabolic pathway engineering and medicinal chemistry for natural product drug discovery. Copyright © 2015 Elsevier Ltd. All rights reserved.

Investigating The Relationship Between Structural Geology and Wetland Loss Near Golden Meadow, Louisiana By Utilizing 3D Seismic Reflection and Well Log Data

Science.gov (United States)

Johnston, A. S.; Zhang, R.; Gottardi, R.; Dawers, N. H.

2017-12-01

Wetland loss is one of the greatest environmental and economic threats in the deltaic plain of the Gulf Coast. This loss is controlled by subsidence, sea level rise, decreased sediment supply rates, movement along normal faults, salt tectonics, fluid extraction related to oil, gas and water exploration, and compaction. However, the interplay and feedback between these different processes are still poorly understood. In this study, we investigate the role of active faulting and salt tectonics on wetland loss in an area located between Golden Meadow and Leeville, Louisiana. Using industry 3D seismic and well log data, we investigate key segments of the Golden Meadow fault zone and map shallow faults that overlie the Leeville salt dome, to compare those fault planes with areas of wetland loss and subsidence. Faults were mapped to a depth of 1200 m, and well logs were tied to the upper 180 m of the seismic data to make accurate projections of the faults to the surface. Preliminary results highlight a graben structure south of a segment of the Golden Meadow fault. Well log and published data from shallow borings reveal a thicker Holocene accumulation at the center of the graben, up to 45 m than on the flanks of the graben. The location of this graben spatially correlates with Catfish Lake, and part of it overlies salt adjacent to the main fault surface. Bayou Lafourche, the main distributary channel of the Lafourche lobe of the Mississippi River delta complex, appears to have its path controlled by faults. Bayou Lafourche changes orientation and flows parallel to, and on the downthrown side of, two radial faults associated with the Leeville salt dome. These preliminary results indicate that there is a relationship between surface geomorphology and subsurface structures that, at least in part, exert a control on wetland loss in southern Louisiana.

Antioxidant system of erythrocytes after γ-irradiation against the background of preliminary long-term overheating

International Nuclear Information System (INIS)

Melikhov, O.G.; Kozlov, N.B.

1991-01-01

A study was made of the influence of preliminary long-term heating on the state of the antioxidant system of erythrocytes after γ-irradiation. The activity of antioxidant protection enzymes (catalase, superoxide dismutase, and glutathione peroxidase) in erythrocytes varied in different directions depending on the preliminary long-term overheating schedule and perhaps on the structure and intracellular localization of the enzyme

New insights about enzyme evolution from large scale studies of sequence and structure relationships.

Science.gov (United States)

Brown, Shoshana D; Babbitt, Patricia C

2014-10-31

Understanding how enzymes have evolved offers clues about their structure-function relationships and mechanisms. Here, we describe evolution of functionally diverse enzyme superfamilies, each representing a large set of sequences that evolved from a common ancestor and that retain conserved features of their structures and active sites. Using several examples, we describe the different structural strategies nature has used to evolve new reaction and substrate specificities in each unique superfamily. The results provide insight about enzyme evolution that is not easily obtained from studies of one or only a few enzymes. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

Purity-activity relationships of natural products: the case of anti-TB active ursolic acid.

Science.gov (United States)

Jaki, Birgit U; Franzblau, Scott G; Chadwick, Lucas R; Lankin, David C; Zhang, Fangqiu; Wang, Yuehong; Pauli, Guido F

2008-10-01

The present study explores the variability of biological responses from the perspective of sample purity and introduces the concept of purity-activity relationships (PARs) in natural product research. The abundant plant triterpene ursolic acid (1) was selected as an exemplary natural product due to the overwhelming number yet inconsistent nature of its approximate 120 reported biological activities, which include anti-TB potential. Nine different samples of ursolic acid with purity certifications were obtained, and their purity was independently assessed by means of quantitative 1H NMR (qHNMR). Biological evaluation consisted of determining MICs against two strains of virulent Mycobacterium tuberculosis and IC50 values in Vero cells. Ab initio structure elucidation provided unequivocal structural confirmation and included an extensive 1H NMR spin system analysis, determination of nearly all J couplings and the complete NOE pattern, and led to the revision of earlier reports. As a net result, a sigmoid PAR profile of 1 was obtained, demonstrating the inverse correlation of purity and anti-TB bioactivity. The results imply that synergistic effects of 1 and its varying impurities are the likely cause of previously reported antimycobacterial potential. Generating PARs is a powerful extension of the routinely performed quantitative correlation of structure and activity ([Q]SAR). Advanced by the use of primary analytical methods such as qHNMR, PARs enable the elucidation of cases like 1 when increasing purity voids biological activity. This underlines the potential of PARs as a tool in drug discovery and synergy research and accentuates the need to routinely combine biological testing with purity assessment.

Quantitative Structure-Activity Relationships Predicting the Antioxidant Potency of 17β-Estradiol-Related Polycyclic Phenols to Inhibit Lipid Peroxidation

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Katalin Prokai-Tatrai

2013-01-01

Full Text Available The antioxidant potency of 17β-estradiol and related polycyclic phenols has been well established. This property is an important component of the complex events by which these types of agents are capable to protect neurons against the detrimental consequences of oxidative stress. In order to relate their molecular structure and properties with their capacity to inhibit lipid peroxidation, a marker of oxidative stress, quantitative structure-activity relationship (QSAR studies were conducted. The inhibition of Fe3+-induced lipid peroxidation in rat brain homogenate, measured through an assay detecting thiobarbituric acid reactive substances for about seventy compounds were correlated with various molecular descriptors. We found that lipophilicity (modeled by the logarithm of the n-octanol/water partition coefficient, logP was the property that influenced most profoundly the potency of these compounds to inhibit lipid peroxidation in the biological medium studied. Additionally, the important contribution of the bond dissociation enthalpy of the phenolic O-H group, a shape index, the solvent-accessible surface area and the energy required to remove an electron from the highest occupied molecular orbital were also confirmed. Several QSAR equations were validated as potentially useful exploratory tools for identifying or designing novel phenolic antioxidants incorporating the structural backbone of 17β-estradiol to assist therapy development against oxidative stress-associated neurodegeneration.

Preliminary results of MR imaging of lymphoma: Distinguishing active tumor from benign residue

International Nuclear Information System (INIS)

Drace, J.; Baker, L.L.; Chang, P.; Castellino, R.A.

1987-01-01

Distinguishing tumor from benign posttreatment tissue based on both morphologic and tissue characteristics is critically important. Patients are studied before, during, and after treatment; at the time of recurrence; and on long-term follow-up. Multisection spin-echo sequences in orthogonal planes and a special single-section tissue characterization matrix of 16 different repetition time/echo time combinations are used. These basic images are used for cluster analysis (approximate fuzzy C means), T1-T2 synthetic images, linear combinations, and comparison with internal standards. Preliminary results in 35 patients imaged before treatment and 12 patients with follow-up examinations consistently show lymphoma masses to have complex architecture with high T2-weighted signal and moderate T1-weighted signal, distinct from posttreatment fibrosis. Uncommon components of active tumor with low T2-weighted signal appear distinct from fibrosis on T1-weighted images. Preliminary cluster analysis results show distinct clustering of active lymphoma versus fibrosis and biopsy-proved cystic degeneration

Quantitative structure-activity relationships (QSAR) of 4-amino-2,6-diarylpyrimidine-5-carbonitriles with anti-inflammatory activity

Energy Technology Data Exchange (ETDEWEB)

Silva, Joao Bosco P. da; Ramos, Mozart N.; Barros Neto, Benicio de [Universidade Federal de Pernambuco (UFPE), Recife, PE (Brazil). Dept. de Quimica Fundamental]. E-mail: mramos@ufpe.br; Melo, Sebastiao Jose de [Universidade Federal de Pernambuco (UFPE), Recife, PE (Brazil). Dept. de Antibioticos]. E-mail: melosebastiao@yahoo.com.br; Falcao, Emerson Peter da Silva [Universidade Federal de Pernambuco (UFPE), Recife, PE (Brazil). Centro Academico de Vitoria de Santo Antao; Catanho, Maria Teresa J. de Almeida [Universidade Federal de Pernambuco (UFPE), Recife, PE (Brazil). Dept. de Biofisica e Radiobiologia

2008-07-01

The experimental anti-inflammatory activities of eight 4-amino-2,6-diarylpyrimidine-5- carbonitriles were subjected to a QSAR analysis based on results from B3LYP/6-31G(d,p) and AM1 electronic structure calculations. Principal component analyses and regressions based on these data indicate that potentially more active compounds should have low dipole moment and partition coefficient values and also be affected by the values of the charges of the carbon atoms through which the two aromatic rings are bonded to the pyrimidinic ring. Two new molecules were predicted to be at least as active as those with the highest activities used in the model building stage. One of them, having a methoxy group attached to one of the aromatic rings, was predicted to have an anti-inflammatory activity value of 52.3%. This molecule was synthesized and its experimental activity was found to be 52.8%, in agreement with the AM1 theoretical prediction. This value is 5% higher than the largest value used for modeling. (author)

Quantitative structure-activity relationships (QSAR) of 4-amino-2,6-diarylpyrimidine-5-carbonitriles with anti-inflammatory activity

International Nuclear Information System (INIS)

Silva, Joao Bosco P. da; Ramos, Mozart N.; Barros Neto, Benicio de; Melo, Sebastiao Jose de; Falcao, Emerson Peter da Silva; Catanho, Maria Teresa J. de Almeida

2008-01-01

The experimental anti-inflammatory activities of eight 4-amino-2,6-diarylpyrimidine-5- carbonitriles were subjected to a QSAR analysis based on results from B3LYP/6-31G(d,p) and AM1 electronic structure calculations. Principal component analyses and regressions based on these data indicate that potentially more active compounds should have low dipole moment and partition coefficient values and also be affected by the values of the charges of the carbon atoms through which the two aromatic rings are bonded to the pyrimidinic ring. Two new molecules were predicted to be at least as active as those with the highest activities used in the model building stage. One of them, having a methoxy group attached to one of the aromatic rings, was predicted to have an anti-inflammatory activity value of 52.3%. This molecule was synthesized and its experimental activity was found to be 52.8%, in agreement with the AM1 theoretical prediction. This value is 5% higher than the largest value used for modeling. (author)

Is Sexual Activity During Adolescence Good for Future Romantic Relationships?

Science.gov (United States)

Shulman, Shmuel; Seiffge-Krenke, Inge; Walsh, Sophie D

2017-09-01

Past research has consistently shown that romantic experiences during adolescence affect the nature and quality of romantic relationships during emerging adulthood. However, less is known about the role of adolescent sexual experiences in future sexual and romantic relationships. The current study examined the impact of different forms of sexual activity at age 16 (within a romantic relationship or casual encounters) on the nature and quality of sexual experiences in romantic relationships at age 23. One hundred and forty four (59.7% females) 16 year olds reported on their sexual activity within a romantic relationship or sexual encounters. In addition they reported on the quality of relationships they were involved in and their tendency to suppress emotions (included as an aspect of personality). At age 23 they reported on their romantic and sexual experiences during the past 2 years (number of short lived relationships, numbers of friends with benefits, casual sex encounters) and the quality of their romantic relationships (the duration of their longest relationship, partner support and feelings of certainty in the relationships). Findings showed that the tendency to suppress emotions was associated with lower likelihood to engage in casual sex at age 23. However, greater sexual experience in casual encounters during adolescence was consistently longitudinally associated with different forms of casual sexual encounters and short romantic involvements above and beyond the contribution of personality. In contrast, sexual activity within a romantic relationship predicted only a few indices of the quality of romantic involvement at age 23. The distinctive role of casual sexual activity and sexual activity within a romantic relationship for future sexual and romantic activities is discussed.

Relationship Structures and Semantic Type Assignments of the UMLS Enriched Semantic Network

Science.gov (United States)

Zhang, Li; Halper, Michael; Perl, Yehoshua; Geller, James; Cimino, James J.

2005-01-01

Objective: The Enriched Semantic Network (ESN) was introduced as an extension of the Unified Medical Language System (UMLS) Semantic Network (SN). Its multiple subsumption configuration and concomitant multiple inheritance make the ESN's relationship structures and semantic type assignments different from those of the SN. A technique for deriving the relationship structures of the ESN's semantic types and an automated technique for deriving the ESN's semantic type assignments from those of the SN are presented. Design: The technique to derive the ESN's relationship structures finds all newly inherited relationships in the ESN. All such relationships are audited for semantic validity, and the blocking mechanism is used to block invalid relationships. The mapping technique to derive the ESN's semantic type assignments uses current SN semantic type assignments and preserves nonredundant categorizations, while preventing new redundant categorizations. Results: Among the 426 newly inherited relationships, 326 are deemed valid. Seven blockings are applied to avoid inheritance of the 100 invalid relationships. Sixteen semantic types have different relationship structures in the ESN as compared to those in the SN. The mapping of semantic type assignments from the SN to the ESN avoids the generation of 26,950 redundant categorizations. The resulting ESN contains 138 semantic types, 149 IS-A links, 7,303 relationships, and 1,013,876 semantic type assignments. Conclusion: The ESN's multiple inheritance provides more complete relationship structures than in the SN. The ESN's semantic type assignments avoid the existing redundant categorizations appearing in the SN and prevent new ones that might arise due to multiple parents. Compared to the SN, the ESN provides a more accurate unifying semantic abstraction of the UMLS Metathesaurus. PMID:16049233

Crystallization of the glycogen-binding domain of the AMP-activated protein kinase β subunit and preliminary X-ray analysis

Energy Technology Data Exchange (ETDEWEB)

Polekhina, Galina, E-mail: gpolekhina@svi.edu.au; Feil, Susanne C.; Gupta, Abhilasha [St Vincent’s Institute of Medical Research, 9 Princes Street, Fitzroy, Victoria 3065 (Australia); O’Donnell, Paul [Department of Biochemistry and Molecular Biology, The University of Melbourne, Parkville 3010 (Australia); Stapleton, David; Parker, Michael W. [St Vincent’s Institute of Medical Research, 9 Princes Street, Fitzroy, Victoria 3065 (Australia)

2005-01-01

The glycogen-binding domain of the AMP-activated kinase β subunit has been crystallized in the presence of β-cyclodextrin. The structure has been determined by single isomorphous replacement and threefold averaging using in-house X-ray data collected from selenomethionine-substituted protein. AMP-activated protein kinase (AMPK) is an intracellular energy sensor that regulates metabolism in response to energy demand and supply by adjusting the ATP-generating and ATP-consuming pathways. AMPK potentially plays a critical role in diabetes and obesity as it is known to be activated by metforin and rosiglitazone, drugs used for the treatment of type II diabetes. AMPK is a heterotrimer composed of a catalytic α subunit and two regulatory subunits, β and γ. Mutations in the γ subunit are known to cause glycogen accumulation, leading to cardiac arrhythmias. Recently, a functional glycogen-binding domain (GBD) has been identified in the β subunit. Here, the crystallization of GBD in the presence of β-cyclodextrin is reported together with preliminary X-ray data analysis allowing the determination of the structure by single isomorphous replacement and threefold averaging using in-house X-ray data collected from a selenomethionine-substituted protein.

Crystallization of the glycogen-binding domain of the AMP-activated protein kinase β subunit and preliminary X-ray analysis

International Nuclear Information System (INIS)

Polekhina, Galina; Feil, Susanne C.; Gupta, Abhilasha; O’Donnell, Paul; Stapleton, David; Parker, Michael W.

2004-01-01

The glycogen-binding domain of the AMP-activated kinase β subunit has been crystallized in the presence of β-cyclodextrin. The structure has been determined by single isomorphous replacement and threefold averaging using in-house X-ray data collected from selenomethionine-substituted protein. AMP-activated protein kinase (AMPK) is an intracellular energy sensor that regulates metabolism in response to energy demand and supply by adjusting the ATP-generating and ATP-consuming pathways. AMPK potentially plays a critical role in diabetes and obesity as it is known to be activated by metforin and rosiglitazone, drugs used for the treatment of type II diabetes. AMPK is a heterotrimer composed of a catalytic α subunit and two regulatory subunits, β and γ. Mutations in the γ subunit are known to cause glycogen accumulation, leading to cardiac arrhythmias. Recently, a functional glycogen-binding domain (GBD) has been identified in the β subunit. Here, the crystallization of GBD in the presence of β-cyclodextrin is reported together with preliminary X-ray data analysis allowing the determination of the structure by single isomorphous replacement and threefold averaging using in-house X-ray data collected from a selenomethionine-substituted protein

Low-activation structural ceramic composites for fusion power reactors: materials development and main design issues

International Nuclear Information System (INIS)

Perez, A.S.; Le Bars, N.; Giancarli, L.; Proust, E.; Salavy, J.F.

1994-01-01

Development of advanced Low-Activation Materials (LAMs) with favourable short-term activation characteristics is discussed, for the use as structural materials in a fusion power reactor (in order to reduce the risk associated with a major accident, in particular those related with radio-isotopes release in the environment), and to try to approach the concept of an inherently safe reactor. LA Ceramics Composites (LACCs) are the most promising LAMs because of their relatively good thermo-mechanical properties. At present, SiC/SiC composite is the only LACC considered by the fusion community, and therefore is the one having the most complete data base. The preliminary design of a breeding blanket using SiC/SiC as structural material indicated that significant improvement of its thermal conductivity is required. (author) 11 refs.; 3 figs

Micro-, to nano-structural relationships in natural serpentines, derived from cationic substitutions.

Science.gov (United States)

Munoz, M.; Farges, F.; Andreani, M.; Ulrich, M.; Marcaillou, C.; Mathon, O.

2014-12-01

The understanding of the crystal chemistry of serpentine minerals (incl. antigorite, lizardite and chrysotile) is fundamental since serpentinization processes concern very large scientific domains: e.g., natural abiotic hydrogen production (Marcaillou et al., 2011), origins of life (Russell et al., 2010), fluid properties and mobility of metals in subduction zones (Kelley and Cottrell, 2009). This study aims at characterizing relations between the micro-, and nano-structures of the most abundant serpentine polytypes in the oceanic crust. Serpentine theoretical formula is Mg3Si2O5(OH)4 but several natural substitutions are possible and the formula may be written such as: (Mg,Fe2+,Fe3+,Al)3(Si,Al,Fe3+)2O5(OH)4; showing that Fe and Al may play an important role in the crystallization of serpentines. Preliminary crystal chemistry studies, suggest that, 1) the Al content alone cannot be directly correlated to serpentine polytypes (Andreani et al., 2008), 2) the amounts of tetrahedral iron can be significant in the presence of ferric iron (Marcaillou et al., 2011). Because magnetite is usually associated to serpentine, the Fe-speciation characterization of serpentine is delicate. Here, we provide the study of 33 magnetite-free serpentines containing various amounts of Fe and Al. The samples were characterized by SEM, Raman, XRF, as well as XANES, pre-edge, and EXAFS spectroscopy at the Fe K-edge. XANES experimental data were crosschecked and interpreted thanks to ab initio calculations and EXAFS shell-fitting. Also, preliminary 27Al-RMN data is presented. Results suggest relationships between the type and amount of substitution of trivalent cations in minerals, and the microstructures observed. Chrysotile incorporates less trivalent cations than other varieties, which tends to preserve the so-called misfit between the TO layers, and therefore the tubular structure of the mineral. Lizardites mainly involve Fe/Al Tschermak-type substitutions, while M-site vacancy charge

1-[(3-Aryloxy-3-aryl)propyl]-1H-imidazoles, new imidazoles with potent activity against Candida albicans and dermatophytes. Synthesis, structure-activity relationship, and molecular modeling studies.

Science.gov (United States)

La Regina, Giuseppe; D'Auria, Felicia Diodata; Tafi, Andrea; Piscitelli, Francesco; Olla, Stefania; Caporuscio, Fabiana; Nencioni, Lucia; Cirilli, Roberto; La Torre, Francesco; De Melo, Nadja Rodrigues; Kelly, Steven L; Lamb, David C; Artico, Marino; Botta, Maurizio; Palamara, Anna Teresa; Silvestri, Romano

2008-07-10

New 1-[(3-aryloxy-3-aryl)propyl]-1 H-imidazoles were synthesized and evaluated against Candida albicans and dermatophytes in order to develop structure-activity relationships (SARs). Against C. albicans the new imidazoles showed minimal inhibitory concentrations (MICs) comparable to those of ketoconazole, miconazole, and econazole, and were more potent than fluconazole. Several derivatives ( 10, 12, 14, 18- 20, 24, 28, 29, 30, and 34) turned out to be potent inhibitors of C. albicans strains resistant to fluconazole, with MIC values less than 10 microg/mL. Against dermatophytes strains, compounds 20, 25, and 33 (MIC

Molecular vibration-activity relationship in the agonism of adenosine receptors.

Science.gov (United States)

Chee, Hyun Keun; Oh, S June

2013-12-01

The molecular vibration-activity relationship in the receptor-ligand interaction of adenosine receptors was investigated by structure similarity, molecular vibration, and hierarchical clustering in a dataset of 46 ligands of adenosine receptors. The resulting dendrogram was compared with those of another kind of fingerprint or descriptor. The dendrogram result produced by corralled intensity of molecular vibrational frequency outperformed four other analyses in the current study of adenosine receptor agonism and antagonism. The tree that was produced by clustering analysis of molecular vibration patterns showed its potential for the functional classification of adenosine receptor ligands.

Inhibition of 2-Amino-1-methyl-6-phenylimidazo [4,5-b]pyridine (PhIP) Formation by Alkoxy Radical Scavenging of Flavonoids and Their Quantitative Structure-Activity Relationship in a Model System.

Science.gov (United States)

Yu, Chundi; Shao, Zeping; Liu, Bing; Zhang, Yan; Wang, Shuo

2016-08-01

The inhibitory effect of 10 flavonoids on the formation of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in a creatinine-phenylalanine model system was investigated through electronic spin resonance and a quantitative structure-activity relationship. Alkoxy radicals were observed during the heating process, providing evidence for a radical pathway in the formation of PhIP. The alkoxy radical scavenging capability of the flavonoids was proportional to their inhibition of PhIP formation (IC50 ). We deduced that flavonoid inhibition of PhIP generation occurs via scavenging of alkoxy radicals during the heating process. Multiple linear regression and partial least squares models were used to elucidate the relationship between PhIP inhibition activity and structure characteristics of the flavonoids. The lipo-hydro partition coefficient and molecular fractional polar surface area of the flavonoids were found to be predictive of the inhibition effect. © 2016 Institute of Food Technologists®

Characteristics of chemical binding to alpha 2u-globulin in vitro--evaluating structure-activity relationships

International Nuclear Information System (INIS)

Borghoff, S.J.; Miller, A.B.; Bowen, J.P.; Swenberg, J.A.

1991-01-01

alpha 2u-Globulin (alpha 2u) has been shown to accumulate in the kidneys of male rats treated with 2,2,4-trimethylpentane (TMP). 2,4,4-Trimethyl-2-pentanol (TMP-2-OH), a metabolite of TMP, is found reversibly bound to alpha 2u isolated from the kidneys of these treated rats. The objectives of the following study were to characterize the ability of [3H]TMP-2-OH to bind to alpha 2u in vitro and to determine whether other compounds that cause this protein to accumulate have the same binding characteristics. Although compounds that have been shown to cause the accumulation of alpha 2u in male rat kidneys compete in vitro with [3H]TMP-2-OH for binding to alpha 2u, they do so to varying degrees. The binding affinity (Kd) of the [3H]TMP-2-OH-alpha 2u complex was calculated to be on the order of 10(-7) M. The inhibition constant values (Ki) determined for d-limonene, 1,4-dichlorobenzene, and 2,5-dichlorophenol were all in the range 10(-4) M, whereas the Ki values for isophorone, 2,4,4- or 2,2,4-trimethyl-1-pentanol, and d-limonene oxide were determined to be in the range 10(-6) and 10(-7) M, respectively. TMP and 2,4,4- and 2,2,4-trimethylpentanoic acid did not compete for binding. This suggests that other factors, besides binding, are involved in the accumulation of alpha 2u. In this study the ability of a chemical to bind to alpha 2u was used as a measure of biological activity to assess structure-activity relationships among the chemicals tested and known to cause the accumulation of alpha 2u. The results so far suggest that binding is dependent on both hydrophobic interactions and hydrogen bonding

Structure-activity relationship of Trp-containing analogs of the antimicrobial peptide gomesin.

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Domingues, Tatiana M; Buri, Marcus V; Daffre, Sirlei; Campana, Patricia T; Riske, Karin A; Miranda, Antonio

2014-06-01

Gomesin (Gm) has a broad antimicrobial activity making it of great interest for development of drugs. In this study, we analyzed three Gm analogs, [Trp(1) ]-Gm, [Trp(7) ]-Gm, and [Trp(9) ]-Gm, in an attempt to gain insight into the contributions of different regions of the peptide sequence to its activity. The incorporation of the tryptophan residue in different positions has no effect on the antimicrobial and hemolytic activities of the Gm analogs in relation to Gm. Spectroscopic studies (circular dichroism, fluorescence and absorbance) of Gm and its analogs were performed in the presence of SDS, below and above its critical micelle concentration (CMC) (~8 mM), in order to monitor structural changes induced by the interaction with this anionic surfactant (0-15 mM). Interestingly, we found that the analogs interact more strongly with SDS at low concentrations (0.3-6.0 mM) than close to or above its CMC. This suggests that SDS monomers are able to cover the whole peptide, forming large detergent-peptide aggregates. On the other hand, the peptides interact differently with SDS micelles, inserting partially into the micelle core. Among the peptides, Trp in position 1 becomes more motionally-restricted in the presence of SDS, probably because this residue is located at the N-terminal region, which presents higher conformational freedom to interact stronger with SDS molecules. Trp residues in positions 7 and 9, close to and in the region of the turn of the molecule, respectively, induced a more constrained structure and the compounds cannot insert deeper into the micelle core or be completely buried by SDS monomers. Copyright © 2014 European Peptide Society and John Wiley & Sons, Ltd.

Relationship Between Dual Time Point FDG PET and Immunohistochemical Parameters in Preoperative Colorectal Cancer: Preliminary Study

International Nuclear Information System (INIS)

Lee, Jai Hyuen; Lee, Won Ae; Park, Seok Gun; Park, Dong Kook; Namgung, Hwan

2012-01-01

The clinical availability of 2 deoxy 2 [18F] fluoro D glucose (FDG) dual time point positron emission tomography/computerized tomography (DTPP) has been investigated in diverse oncologic fields. The aim of this preliminary study was to evaluate the relationship between various immunohistopathologic markers reflecting disease progression of colorectal cancer and parameters extracted from FDG DTPP in colorectal cancer patients. Forty seven patients with histologically confirmed colorectal cancer were analyzed in this preliminary study. FDG DTPP consisted of an early scan 1 h after FDG injection and a delayed scan 1.5 h after the early scan. Based on an analysis of FDG DTPP, we estimated the maximum standardized uptake value (SUV) of tumors on the early and delayed scans (SUV earlya nd SUV delayed, respectively). The retention index (RI) was calculated as follows: (SUV delayed- SUV early) x 100/ SUV early. The clinicopathological findings (size and T and N stages) and immunohistochemical factors [glucose transporter 1 (GLUT 1), hexokinase 2 (HK 2), p53, P504S, and β catenin] were analyzed by visual analysis. The RIs calculated from the SUVs ranged from -1.8 to 73.4 (31.8±15.5). The RIs were significantly higher in patients with high T stages (T3 and T4) than with low T stages (T1 and T2; P earlya nd SUV delayeda nd clinicopathologic parameters in this study. The RIs obtained from preoperative colorectal cancers had a significant relationship to tumor size, T staging, GLUT 1, and p53, in contrast to SUV earlyo r SUV delayed. Compared with previous reports, our results showed that RI can better predict GLUT 1 expression than HK 2 and other immunohistochemical markers. This study demonstrated that the RI might have the potential to be applied as a prognostic marked in preoperative colorectal cancer

[Volunteer satisfaction: Internal structure and relationship with permanence in organizations].

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Vecina Jiménez, M L; Chacón Fuertes, Fernando; Sueiro Abad, Manuel J

2009-02-01

Volunteer satisfaction: Internal structure and relationship with permanence in organizations. The concept of satisfaction is considered theoretically relevant in practically all the studies that have investigated the factors that influence the permanence of volunteer participation in organizations. However, the practical results are not conclusive, perhaps due to the wide range of ways in which the concept is understood and measured. The object of this study is: to analyse the internal structure of satisfaction and to verify its relationship with volunteer duration in organizations. The results of the factor analysis yield a three-factor structure: Satisfaction with the management of the organization, Satisfaction with the tasks, Satisfaction of motivations. The three factors allow us to differentiate between individuals who remain in the organization for a period of 12 consecutive months, and those who leave earlier. The results of structural equation model analysis show that the relationship between satisfaction and the length of time that volunteers stay with the organization is affected by the intention to remain.

Characterizing Nanoparticles Reactivity: Structure-Photocatalytic Activity Relationship

International Nuclear Information System (INIS)

Piella, J; Bastús, N G; Casals, E; Puntes, V

2013-01-01

Nanoparticles are reactive, and their final interactions with the surrounding media are ultimately determined by their reactivity, which in turns depends on the nanoparticles morphology, surface chemistry and environment in which they are embedded. One simple and informative approach for the study of the reactivity of nanoparticles is the determination of their photocatalytic activity. In the present work, we briefly summarize the importance of different parameters such as the size, shape and agglomeration state on the photocatalytic activity of colloidal inorganic nanoparticles. The study of the use of nanoparticles as photocatalyts is relevant not only for its potential applications in environmental remediation issues but also it can provide relevant information about the role of these parameters at the nanoscale.

Quantitative structure activity relationship and risk analysis of some pesticides in the goat milk.

Science.gov (United States)

Muhammad, Faqir; Awais, Mian Muhammad; Akhtar, Masood; Anwar, Muhammad Irfan

2013-01-04

The detection and quantification of different pesticides in the goat milk samples collected from different localities of Faisalabad, Pakistan was performed by HPLC using solid phase microextraction. The analysis showed that about 50% milk samples were contaminated with pesticides. The mean±SEM levels (ppm) of cyhalothrin, endosulfan, chlorpyrifos and cypermethrin were 0.34±0.007, 0.063±0.002, 0.034±0.002 and 0.092±0.002, respectively; whereas, methyl parathion was not detected in any of the analyzed samples. Quantitative structure activity relationship (QSAR) models were suggested to predict the residues of unknown pesticides in the goat milk using their known physicochemical characteristics including molecular weight (MW), melting point (MP), and log octanol to water partition coefficient (Ko/w) in relation to the characteristics such as pH, % fat, specific gravity and refractive index of goat milk. The analysis revealed good correlation coefficient (R2 = 0.985) for goat QSAR model. The coefficients for Ko/w and refractive index for the studied pesticides were higher in goat milk. This suggests that these are better determinants for pesticide residue prediction in the milk of these animals. Based upon the determined pesticide residues and their provisional tolerable daily intakes, risk analysis was also conducted which showed that daily intake levels of pesticide residues including cyhalothrin, chlorpyrifos and cypermethrin in present study are 2.68, 5.19 and 2.71 times higher, respectively in the goat milk. This intake of pesticide contaminated milk might pose health hazards to humans in this locality.

Quantitative Structure Activity Relationship and Risk Analysis of Some Pesticides in the Goat milk

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Faqir Muhammad

2013-01-01

Full Text Available The detection and quantification of different pesticides in the goat milk samples collected from different localities of Faisalabad, Pakistan was performed by HPLC using solid phase microextraction. The analysis showed that about 50% milk samples were contaminated with pesticides. The mean+/-SEM levels (ppm of cyhalothrin, endosulfan, chlorpyrifos and cypermethrin were 0.34+/-0.007, 0.063+/-0.002, 0.034+/-0.002 and 0.092+/-0.002, respectively; whereas, methyl parathion was not detected in any of the analyzed samples. Quantitative structure activity relationship (QSAR models were suggested to predict the residues of unknown pesticides in the goat milk using their known physicochemical characteristics including molecular weight (MW, melting point (MP, and log octanol to water partition coefficient (Ko/w in relation to the characteristics such as pH, % fat, specific gravity and refractive index of goat milk. The analysis revealed good correlation coefficient (R2 = 0.985 for goat QSAR model. The coefficients for Ko/w and refractive index for the studied pesticides were higher in goat milk. This suggests that these are better determinants for pesticide residue prediction in the milk of these animals. Based upon the determined pesticide residues and their provisional tolerable daily intakes, risk analysis was also conducted which showed that daily intake levels of pesticide residues including cyhalothrin, chlorpyrifos and cypermethrin in present study are 2.68, 5.19 and 2.71 times higher, respectively in the goat milk. This intake of pesticide contaminated milk might pose health hazards to humans in this locality.

Cucurbitane Glycosides Derived from Mogroside IIE: Structure-Taste Relationships, Antioxidant Activity, and Acute Toxicity

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Lei Wang

2014-08-01

Full Text Available Mogroside IIE is a bitter triterpenoid saponin which is the main component of unripe Luo Han Guo fruit and a precursor of the commercially available sweetener mogroside V. In this study, we developed an enzymatic glycosyl transfer method, by which bitter mogroside IIE could be converted into a sweet triterpenoid saponin mixture. The reactant concentration, temperature, pH and buffer system were studied. New saponins with the α-glucose group were isolated from the resulting mixtures, and the structures of three components of the extract were determined. The structure-taste relationships of these derivatives were also studied together with those of the natural mogrosides. The number and stereoconfiguration of glucose groups present in the mogroside molecules were found to be the main factor to determine the sweet or bitter taste of a compound. The antioxidant and food safety properties were initially evaluated by their radical scavenging ability and via 7 day mice survival tests, respectively. The results showed that the sweet triterpenoid saponin mixture has the same favorable physiological and safety characteristics as the natural mogrosides.

Relationship between smartphone addiction and physical activity in Chinese international students in Korea.

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Kim, Sung-Eun; Kim, Jin-Woo; Jee, Yong-Seok

2015-09-01

Excessive usage of smartphones may induce social problems, such as depression and impairment of social and emotional functioning. Moreover, its usage can impede physical activity, but the relationship between smartphone addiction and physical activity is obscure. Therefore, we examined the relationship and the impact of excessive smartphone use on physical activity. This study collected data through the structured questionnaire consisting of general characteristics, the number and hours of smartphone usage, and the Smartphone Addiction Proneness Scale (SAPS) from 110 Chinese international students in Korea. The body composition and physical activity, such as the total daily number of steps and consumed calories, were measured. In this study, high-risk smartphone users showed less physical activity, such as the total number of steps taken and the average consumed calories per day. Moreover, their body composition, such as muscle mass and fat mass, was significantly different. Among these factors, the hours of smartphone use revealed the proportional relationship with smartphone addiction (β = 0.209, p = 0.026), while the average number of walking steps per day showed a significant reverse proportional tendency in participants with smartphone addiction (β = -0.883, p smartphone addiction were less likely to walk for each day. Namely, smartphone addiction may negatively influence physical health by reducing the amount of physical activity, such as walking, resulting in an increase of fat mass and a decrease of muscle mass associated with adverse health consequences.

Insights into the structure-activity relationship of the anticancer compound ZJ-101, a derivative of marine natural product superstolide A: A critical role played by the conjugated trienyl lactone moiety.

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Qian, Shan; Shah, Aashay K; Head, Sarah A; Liu, Jun O; Jin, Zhendong

2016-08-01

Compound ZJ-101, a structurally simplified analog of the marine natural product superstolide A, was previously developed in our laboratory. In the subsequent structure-activity relationship study, two new analogs, ZJ-105 and ZJ-106, were designed and synthesized to probe the importance of the conjugated trienyl lactone moiety of the molecule by replacing the C2-C3 double bond in ZJ-101 with a single bond and switching the geometry of the C4-C5 double bond in ZJ-101 from Z to E, respectively. Biological evaluation showed that ZJ-105 completely loses antiproliferative activity whereas ZJ-106 is significantly less active against cancer cells in vitro than ZJ-101, suggesting that the conjugated trienyl lactone moiety of the molecule is critical for its anticancer activity. Copyright © 2016 Elsevier Ltd. All rights reserved.

A new structure-activity relationship (SAR model for predicting drug-induced liver injury, based on statistical and expert-basedstructural alerts.

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Fabiola Pizzo

2016-11-01

Full Text Available The prompt identification of chemical molecules with potential effects on liver may help in drug discovery and in raising the levels of protection for human health. Besides in vitro approaches, computational methods in toxicology are drawing attention. We built a structure-activity relationship (SAR model for evaluating hepatotoxicity. After compiling a data set of 950 compounds using data from the literature, we randomly split it into training (80% and test sets (20%. We also compiled an external validation set (101 compounds for evaluating the performance of the model. To extract structural alerts (SAs related to hepatotoxicity and non-hepatotoxicity we used SARpy, a statistical application that automatically identifies and extracts chemical fragments related to a specific activity. We also applied the chemical grouping approach for manually identifying other SAs. We calculated accuracy, specificity, sensitivity and Matthews correlation coefficient (MCC on the training, test and external validation sets. Considering the complexity of the endpoint, the model performed well. In the training, test and external validation sets the accuracy was respectively 81%, 63% and 68%, specificity 89%, 33% and 33%, sensitivity 93%, 88% and 80% and MCC 0.63, 0.27 and 0.13. Since it is preferable to overestimate hepatotoxicity rather than not to recognize unsafe compounds, the model’s architecture followed a conservative approach. As it was built using human data, it might be applied without any need for extrapolation from other species. This model will be freely available in the VEGA platform.

Electrochemical activity of thiahelicenes: Structure effects and electrooligomerization ability

International Nuclear Information System (INIS)

Bossi, Alberto; Falciola, Luigi; Graiff, Claudia; Maiorana, Stefano; Rigamonti, Clara; Tiripicchio, Antonio; Licandro, Emanuela; Mussini, Patrizia Romana

2009-01-01

Thiahelicenes are polycondensed heteroaromatic molecules characterized by a chiral helix-like structure including multiple thiophene units, with a lowering effect on the oxidation potentials and a shrinking effect on the band gaps. As a consequence they can be regarded as electrochemically and optically active conducting materials, exhibiting interesting properties under electrical or magnetic polarization, and are under study for non-linear optics (NLO) applications. The present extensive investigation on 11 thiahelicenes with different chain length and functionalization (including the first example of a thiahelicene with perfluorinated alkyl chains) together with the precursor benzodithiophene provides a deep insight on the structure vs. electrochemical activity relationship within this attractive compound class, focusing on both electron transfer (ET) properties and oligomerization ability (hinging on free α positions on terminal thiophene groups).

Relationships between non-pathological dream-enactment and mirror behaviors.

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Nielsen, Tore; Kuiken, Don

2013-09-01

Dream-enacting behaviors (DEBs) are behavioral expressions of forceful dream images often occurring during sleep-to-wakefulness transitions. We propose that DEBs reflect brain activity underlying social cognition, in particular, motor-affective resonance generated by the mirror neuron system. We developed a Mirror Behavior Questionnaire (MBQ) to assess some dimensions of mirror behaviors and investigated relationships between MBQ scores and DEBs in a large of university undergraduate cohort. MBQ scores were normally distributed and described by a four-factor structure (Empathy/Emotional Contagion, Behavioral Imitation, Sleepiness/Anger Contagion, Motor Skill Imitation). DEB scores correlated positively with MBQ total and factor scores even with social desirability, somnambulism and somniloquy controlled. Emotion-specific DEB items correlated with corresponding emotion-specific MBQ items, especially crying and smiling. Results provide preliminary evidence for cross-state relationships between propensities for dream-enacting and mirror behaviors--especially behaviors involving motor-affective resonance--and our suggestion that motor-affective resonance mediates dream-enactment imagery during sleep and emotional empathy during waking. Copyright © 2013 Elsevier Inc. All rights reserved.

Modeling the relationship between physical activity and quality of life in menopausal-aged women: a cross-sectional study.

Science.gov (United States)

Javadivala, Zeinab; Kousha, Ahmad; Allahverdipour, Hamid; Asghari Jafarabadi, Mohammad; Tallebian, Hossein

2013-09-17

The purpose of the present study was (a) to assess the relationship between physical activity and the intensity and duration of menopausal symptoms, (b) to investigate the relationship between physical activity and the four domains of health-related quality of life (HRQOL) and (c) to assess the relationship between physical activity and chronic diseases. This descriptive-analytical study that was conducted in Tabriz City, Iran. Data were collected in 2012 by personal home-based interviews, using structured questionnaires. All participants (n= 273), who were middle-aged (age range of 40-60 yr) were recruited from two of the 25 urban health service centers' clients, by clustered random sampling allocation. There was a positive significant relationship between Psychological, Social, and Environmental domains of HRQOL with physical activity (Pphysical activity. Diabetic (Pphysical activity would be effective in decreasing menopausal symptoms as well as improving healthy aging and also physical activity promotion as a part of healthy life style promotion programs needs to be improved in communities where women are physically inactive. In addition, women need to be informed about importance of physical activity on their life which it leads to feel healthy aging and pre and post- menopausal stages.

Effects of synthetic and naturally occurring flavonoids on Na sup + , K sup + -ATPase: Aspects of the structure-activity relationship and action mechanism

Energy Technology Data Exchange (ETDEWEB)

Hirano, T.; Oka, K.; Akiba, M. (Tokyo College of Pharmacy (Japan))

1989-01-01

A comparative study was made of the effects of 15 synthetic and naturally occurring flavonoids on the hydrolytic activity of Na{sup +}, K{sup +} -adenosine triphosphatase (ATPase). Twelve of the flavonoids examined were mono-hydroxy or mono-methoxy derivatives. All inhibited Na{sup +}, K{sup +} -ATPase from dog kidney cortex when present at concentrations from 40-1000 {mu}M. Flavones possessing cyclohexyl instead of the phenyl group were the most potent with IC{sub 50} at 257-320 {mu}M. Structure-activity relationships were observed among the following mono-substituted flavones as: (i) 2-cyclohexyl-benzopyran-4-one {much gt} 2-phenyl-benzopyran-4-one; (ii) 2-cyclohexyl-7-hydroxybenzopyran-4-one {gt} 2-cyclohexyl-6-hydroxy-benzopyran-4-one {gt} 2-cyclohexyl-5-hydroxybenzopyran-4-one. Some flavonoids showing potent inhibitory activity were also examined for ouabain-displacement activity on human erythrocytes. Hardly and of the flavonoids were able to block ({sup 3}H) ouabain binding to erythrocytes. These results suggest that the mechanism by which flavonoid block Na{sup +}, K{sup +} -ATPase is not related to the cardiac glycoside-specific binding site(s) of this enzyme.