These are representative sample records from Science.gov related to your search topic.
For comprehensive and current results, perform a real-time search at Science.gov.
1

Ecological Structure Activity Relationships  

EPA Science Inventory

Ecological Structure Activity Relationships, v1.00a, February 2009 ECOSAR (Ecological Structure Activity Relationships) is a personal computer software program that is used to estimate the toxicity of chemicals used in industry and discharged into water. The program predicts...

2

Structural relationships and vasorelaxant activity of monoterpenes  

PubMed Central

Background and purpose of the study The hypotensive activity of the essential oil of Mentha x villosa and its main constituent, the monoterpene rotundifolone, have been reported. Therefore, our objective was to evaluate the vasorelaxant effect of monoterpenes found in medicinal plants and establish the structure-activity relationship of rotundifolone and its structural analogues on the rat superior mesenteric artery. Methods Contractions of the vessels were induced with 10??M of phenylephine (Phe) in rings with endothelium. During the tonic phase of the contraction, the monoterpenes (10-8 - 10-3, cumulatively) were added to the organ bath. The extent of relaxation was expressed as the percentage of Phe-induced contraction. Results The results from the present study showed that both oxygenated terpenes (rotundifolone, (+)-limonene epoxide, pulegone epoxide, carvone epoxide, and (+)-pulegone) and non-oxygenated terpene ((+)-limonene) exhibit relaxation activity. The absence of an oxygenated molecular structure was not a critical requirement for the molecule to be bioactive. Also it was found that the position of ketone and epoxide groups in the monoterpene structures influence the vasorelaxant potency and efficacy. Major conclusion The results suggest that the presence of functional groups in the chemical structure of rotundifolone is not essential for its vasorelaxant activity. PMID:23351149

2012-01-01

3

Cationic phospholipids: structure?transfection activity relationships  

SciTech Connect

Synthetic cationic lipids are presently the most widely used non-viral gene carriers. Examined here is a particularly attractive cationic lipid class, triester phosphatidylcholines (PCs) exhibiting low toxicities and good transfection efficiency. Similarly to other cationic lipids, they form stable complexes (lipoplexes) with the polyanionic nucleic acids. A summary of studies on a set of {approx}30 cationic PCs reveals the existence of a strong, systematic dependence of their transfection efficiency on the lipid hydrocarbon chain structure: transfection activity increases with increase of chain unsaturation from 0 to 2 double bonds per lipid and decreases with increase of chain length in the range {approx}30-50 total number of chain carbon atoms. Maximum transfection was observed for ethyl phosphate PCs (EPCs) with monounsaturated 14:1 chains (total of 2 double bonds and 30 chain carbon atoms). Lipid phase behavior is known to depend strongly on the chain molecular structure and the above relationships thus substantiate a view that cationic PC phase propensities are an important determinant of their activity. Indeed, X-ray structural studies show that the rate of DNA release from lipoplexes as well as transfection activity well correlate with non-lamellar phase progressions observed in cationic PC mixtures with membrane lipids. These findings appear to be of considerable interest because, according to current views, key processes in lipid-mediated transfection such as lipoplex disassembly and DNA release within the cells are believed to take place upon cationic lipid mixing with cellular lipids.

Koynova, Rumiana; Tenchov, Boris; (NWU)

2010-01-18

4

Structure-activity relationships in aquatic toxicology.  

PubMed

Relationships among chemical structure, aquatic toxicity, and bioconcentration potential were examined for several classes of organic compounds. Structure-toxicity correlations were based largely on median lethal concentrations (LC50) and toxicant threshold concentrations (LC1) determined in mini-chronic tests with early life stages of fish and amphibians. Exposure was initiated at fertilization and maintained through 4 days posthatching. Bioconcentration potential was assessed using n-octanol/water partition coefficients (log P). In tests with polychlorinated biphenyls (PCB), acute and chronic toxicity generally increased with percent chlorination. In addition, toxicity of specific PCB's appeared to be affected by the ratio of less chlorinated to more highly chlorinated isomers. The toxicity of chlorinated methanes (i.e., methylene chloride, chloroform, carbon tetrachloride) also increased with chlorination. Concerning single ring aromatic compounds, pyridine was much less toxic than benzene and benzene was less toxic than its mono-substituted derivatives, including chlorobenzene, nitrobenzene, toluene, and phenol. However, no consistent order of toxicity was observed for the substituted compounds. Acute toxicity also increased with the number of aromatic rings in a series of nitrogen heterocyclic compounds, and the latter were less toxic than corresponding alicyclic compounds. Within most classes of compounds, a direct correlation was observed between acute toxicity and bioconcentration potential. As observed with PCB compounds, the mini-chronic test described in this study permitted evaluations of structure-activity relationships using both LC50 and LC1 values determined with early life stages. The LC1's compared well with results obtained in life-cycle studies, thus providing an economical and reliable means of estimating chronic values for reproductive impairment. PMID:6416914

Birge, W J; Cassidy, R A

1983-01-01

5

Structure activity relationships of novel antiepileptic drugs.  

PubMed

Despite notable success over years in the discovery and development of new antiepileptic drugs (AEDs), about 30-40% of the patients are resistant to drug treatment. There is a still significant need to develop novel AEDs that demonstrate superior efficacy, broad spectrum of activities and good safety profile. The synaptic vesicle glycoprotein 2A (SV2A), ?-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA-R) and voltage-gated potassium channels (KCNQ2/Q3) are clinically validated as new molecular targets for epilepsy. The discovery of SV2A as a target for levetiracetam, 2,3-benzodiazepine GYKI 52466 as a non-competitive AMPA-R antagonist and retigabine as a KCNQ2/Q3 channels activator provided a rational basis to develop novel AEDs. The optimization of SV2A binding affinity of levetiracetam led to the discovery of novel high affinity SV2A ligands that displayed superior efficacy and protective index in animal models of epilepsy. The high-throughput screening (HTS) and medicinal chemistry efforts yielded many non-competitive AMPA-R antagonists of which perampanel was recently approved as a first-in-a new class. The efficacy and lack of sub-type selectivity of retigabine prompted many research efforts to discover several potent and selective KCNQ2/Q3 channel activators of distinct chemical scaffolds that are at various stages of clinical development. Despite the known role of galanin and galanin receptor (Gal-R) in epilepsy over a decade, development of potent and brainpenetrant Gal-R agonists is very challenging. The discovery of selective Gal-R2 positive allosteric modulator, CYM 2503, offers a valuable and an alternative approach. The review focuses on the available structure-activity relationships and preclinical efficacy of novel antiepileptic compounds that are distinct from most of the approved AEDs, specifically SV2A ligands, non-competitive AMPA-R antagonists, KCNQ2/Q3 channels activators and Gal-R modulators. PMID:24251563

Mittapalli, G K; Roberts, E

2014-01-01

6

THE PRACTICE OF STRUCTURE ACTIVITY RELATIONSHIPS (SAR) IN TOXICOLOGY  

EPA Science Inventory

Both qualitative and quantitative modeling methods relating chemical structure to biological activity, called structure-activity relationship analyses or SAR, are applied to the prediction and characterization of chemical toxicity. This minireview will discuss some generic issue...

7

Semisynthetic Coumermycins: Structure-Activity Relationships  

PubMed Central

The relative antimicrobial activity of a large series of semisynthetic coumermycins has been determined. Most of the derivatives, which were 3-substituted-4-hydroxy-8-methyl-7-[3-O-(5-methyl-2-pyrrolylcarbonyl) noviosyloxy] coumarins, had an in vitro antibacterial spectrum similar to that of the parent compound, coumermycin A1, but were generally less potent in minimal inhibitory concentration (MIC) tests. Derivatives with an alkylcarboxamido, arylcarboxamido, or arylsulfonamido group in the 3 position had considerably greater in vitro activity than those possessing an amino-, aryl-, or alkyureido substituent. Efficacy in Staphylcoccous aureus Smith infections of mice was greater for those compounds with branched-chain alkylcarboxamido, unsubstituted, mono- or disubstituted aryl- and heteroaryl-carboxamido groups than for derivatives having an n-alkylcarboxamido, aralkyl-carboxamido, arylsulfonamido, or trisubstituted arylcarboxamido substituent. Significant in vitro activity against Klebsiella pneumoniae and other gram-negative species was restricted to those compounds having a 3-(3-n-alkyl-4-hydroxy-phenyl-carboxamido) group. Only the n-hexyl homologue demonstrated in vivo activity in a K. pneumoniae infection. Many derivatives were two- to threefold more active than coumermycin A1 in orally treated mouse infections, despite the fact that their MIC values were considerably higher. This result was undoubtedly a reflection of the markedly greater oral absorbability possessed by many of the derivatives. Although peak oral mouse blood levels of some compounds were > 25 times higher than those of coumermycin A1, their toxicity for the host was no greater. In addition, the semisynthetic coumermycins caused much less local irritation than coumermycin A1 when administered parenterally. PMID:5415210

Price, K. E.; Chisholm, D. R.; Godfrey, J. C.; Misiek, M.; Gourevitch, A.

1970-01-01

8

Partitioning and lipophilicity in quantitative structure-activity relationships.  

PubMed Central

The history of the relationship of biological activity to partition coefficient and related properties is briefly reviewed. The dominance of partition coefficient in quantitation of structure-activity relationships is emphasized, although the importance of other factors is also demonstrated. Various mathematical models of in vivo transport and binding are discussed; most of these involve partitioning as the primary mechanism of transport. The models describe observed quantitative structure-activity relationships (QSARs) well on the whole, confirming that partitioning is of key importance in in vivo behavior of a xenobiotic. The partition coefficient is shown to correlate with numerous other parameters representing bulk, such as molecular weight, volume and surface area, parachor and calculated indices such as molecular connectivity; this is especially so for apolar molecules, because for polar molecules lipophilicity factors into both bulk and polar or hydrogen bonding components. The relationship of partition coefficient to chromatographic parameters is discussed, and it is shown that such parameters, which are often readily obtainable experimentally, can successfully supplant partition coefficient in QSARs. The relationship of aqueous solubility with partition coefficient is examined in detail. Correlations are observed, even with solid compounds, and these can be used to predict solubility. The additive/constitutive nature of partition coefficient is discussed extensively, as are the available schemes for the calculation of partition coefficient. Finally the use of partition coefficient to provide structural information is considered. It is shown that partition coefficient can be a valuable structural tool, especially if the enthalpy and entropy of partitioning are available. PMID:3905374

Dearden, J C

1985-01-01

9

Antioxidant and Prooxidant Behavior of Flavonoids: StructureActivity Relationships  

Microsoft Academic Search

The antioxidant and prooxidant behavior of flavonoids and the related activity-structure relationships were investigated in this study using the oxygen radical absorbance capacity assay. Three different reactive species were used in the assay: 2,2?-azobis(2-amidino-propane) dihydrochloride, a peroxyl radical generator; Cu2+-H2O2, mainly a hydroxyl radical generator; and Cu2+, a transition metal. Flavonoids including flavones, isoflavones, and flavanones acted as antioxidants against

Guohua Cao; Emin Sofic; Ronald L. Prior

1997-01-01

10

Quantitative analysis of structure-activity relationships in engineered proteins by linear free-energy relationships  

Microsoft Academic Search

Protein engineering is being used increasingly to study the fine details of the structure and activity of enzymes. How can small effects of mutation on activity be reliably quantified and systematized, and artefacts be recognized? A traditional means of doing this in organic chemistry is the use of linear free-energy relationships that link changes in rate constant for a reaction

Alan R. Fersht; Robin J. Leatherbarrow; Tim N. C. Wells

1986-01-01

11

CONSIDERATION OF REACTION INTERMEDIATES IN STRUCTURE-ACTIVITY RELATIONSHIPS: A KEY TO UNDERSTANDING AND PREDICTION  

EPA Science Inventory

Consideration of Reaction Intermediates in Structure- Activity Relationships: A Key to Understanding and Prediction A structure-activity relationship (SAR) represents an empirical means for generalizing chemical information relative to biological activity, and is frequent...

12

Structure activity relationships: their function in biological prediction  

SciTech Connect

Quantitative structure activity relationships provide a means of ranking or predicting biological effects based on chemical structure. For each compound used to formulate a structure activity model two kinds of quantitative information are required: (1) biological activity and (2) molecular properties. Molecular properties are of three types: (1) molecular shape, (2) physiochemical parameters, and (3) abstract quantitations of molecular structure. Currently the two best descriptors are the hydrophobic parameter, log 1-octanol/water partition coefficient (log P), and the /sup 1/X/sup v/(one-chi-v) molecular connectivity index. Biological responses can be divided into three main categories: (1) non-specific effects due to membrane perturbation, (2) non-specific effects due to interaction with functional groups of proteins, and (3) specific effects due to interaction with receptors. Twenty-six synthetic fossil fuel-related nitrogen-containing aromatic compounds were examined to determine the quantitative correlation between log P and /sup 1/X/sup v/ and population growth impairment of Tetrahymena pyriformis. Nitro-containing compounds are the most active, followed by amino-containing compounds and azaarenes. Within each analog series activity increases with alkyl substitution and ring addition. The planar model log BR = 0.5564 log P + 0.3000 /sup 1/X/sup v/ -2.0138 was determined using mono-nitrogen substituted compounds. Attempts to extrapolate this model to dinitrogen-containing molecules were, for the most part, unsuccessful because of a change in mode of action from membrane perturbation to uncoupling of oxidative phosphoralation.

Schultz, T.W.

1982-01-01

13

Autotaxin Structure Activity Relationships Revealed through Lysophosphatidylcholine Analogs  

PubMed Central

Autotaxin (ATX) catalyzes the hydrolysis of lysophosphatidylcholine (LPC) to form the bioactive lipid lysophosphatidic acid (LPA). LPA stimulates cell proliferation, cell survival, and cell migration and is involved in obesity, rheumatoid arthritis, neuropathic pain, atherosclerosis and various cancers, suggesting that ATX inhibitors have broad therapeutic potential. Product feedback inhibition of ATX by LPA has stimulated structure activity studies focused on LPA analogs. However, LPA displays mixed mode inhibition, indicating it can bind to both the enzyme and the enzyme-substrate complex. This suggests that LPA may not interact solely with the catalytic site. In this report we have prepared LPC analogs to help map out substrate structure activity relationships. The structural variances include length and unsaturation of the fatty tail, choline and polar linker presence, acyl versus ether linkage of the hydrocarbon chain, and methylene and nitrogen replacement of the choline oxygen. All LPC analogs were assayed in competition with the synthetic substrate, FS-3, to show the preference ATX has for each alteration. Choline presence and methylene replacement of the choline oxygen were detrimental to ATX recognition. These findings provide insights into the structure of the enzyme in the vicinity of the catalytic site as well as suggesting that ATX produces rate enhancement, at least in part, by substrate destabilization. PMID:19345587

North, E. Jeffrey; Osborne, Daniel A.; Bridson, Peter K.; Baker, Daniel L.; Parrill, Abby L.

2009-01-01

14

Quantitative structure-activity relationship of some pesticides.  

PubMed

Herbicides (benzodiazepinediones), insecticides (dioxatricyclododecenes) and larvicides (N-oxalyl derivatives of tebufenozide) have been quantitatively investigated to explore the relationship between the molecular structure and their biological activity using molecular operating environment (MOE) software. The study provides good predictive models, cross-validated by leave-out-one method (Loo). The positive contribution of the descriptor n-O (count of oxygen atom) suggests the additional oxygen atom substitution at R1 position, in addition to benzodiazepine moiety is favorable for herbicidal activity, whereas the negative contribution of y component of dipole moment (Dip(y)) indicates that electronic interactions are also crucial for the activity. The negative correlation of V(SA)2 and globularity (Glo) descriptors clearly indicates that the volume, shape, and rigidity of tebufenozide derivatives determine their larvicidal activity. The biparametric model for insecticides shows that the indicator variable l(CH-CH3) and R(PC) (negative partial charge) are detrimental for its activity. Most of the active compounds in the series have shown less value for these descriptors. The derived QSAR models also provide valuable insights to optimize their toxicity, which remains a major concern for environment safety. PMID:18320846

Praba, G Om; Velmurugan, D

2007-12-01

15

The structure?activity relationship in herbicidal monosubstituted sulfonylureas  

SciTech Connect

The herbicide sulfonylurea (SU) belongs to one of the most important class of herbicides worldwide. It is well known for its ecofriendly, extreme low toxicity towards mammals and ultralow dosage application. The original inventor, G Levitt, set out structure-activity relationship (SAR) guidelines for SU structural design to attain superhigh bioactivity. A new approach to SU molecular design has been developed. After the analysis of scores of SU products by X-ray diffraction methodology and after greenhouse herbicidal screening of 900 novel SU structures synthesized in the authors laboratory, it was found that several SU structures containing a monosubstituted pyrimidine moiety retain excellent herbicidal characteristics, which has led to partial revision of the Levitt guidelines. Among the novel SU molecules, monosulfuron and monosulfuron-ester have been developed into two new herbicides that have been officially approved for field application and applied in millet and wheat fields in China. A systematic structural study of the new substrate-target complex and the relative mode of action in comparison with conventional SU has been carried out. A new mode of action has been postulated.

Li, Zheng-Ming; Ma, Yi; Guddat, Luke; Cheng, Pei-Quan; Wang, Jian-Guo; Pang, Siew S; Dong, Yu-Hui; Lai, Cheng-Ming; Wang, Ling-Xiu; Jia, Guo-Feng; Li, Yong-Hong; Wang, Su-Hua; Liu, Jie; Zhao, Wei-Guang; Wang, Bao-Lei (Nankai); (Queens); (Chinese Aca. Sci.)

2012-05-24

16

Structure-activity relationship of cytoplasmic 5'-nucleotidase substrate sites.  

PubMed Central

Various 5'-nucleotidases (EC 3.1.3.5) exist in vertebrate tissues. The sequence and cDNA cloning of the membrane-bound ecto-5'-nucleotidase (e-N) and one of the cytosolic isoenzymes, IMP-preferring (c-N-II), but not the cytosolic AMP-preferring form (c-N-I), have been reported. While c-N-II has a broad tissue distribution, c-N-I is found only in vertebrate heart. The published data on substrate specificity involve mainly the naturally occurring nucleoside monophosphates, without a systematic structure-activity relationship study. In the present study we have used a series of AMP and IMP analogues to examine the structure-activity relationship for c-N-I and c-N-II in detail. The rank order of activity of the test compounds differed substantially between c-N-I and c-N-II. c-N-I and c-N-II varied with respect to the following interactions with substrate: (1) hydrogen-bond formation with the substituent in the 6-position of the purine ring (a donor-type with c-N-I and an acceptor-type with c-N-II); and (2) hydrophobic attraction of the 6-position unsubstituted purine ring (more pronounced with c-N-I than with c-N-II). No better substrate than 5'-AMP was found for c-N-I. We propose that c-N-I functions as an AMP-binding protein in the myocardial cell with an important role during ischaemic ATP breakdown when AMP accumulates rapidly. PMID:8615751

Skladanowski, A C; Hoffmann, C; Krass, J; Jastorff, B; Makarewicz, W

1996-01-01

17

Interpretable correlation descriptors for quantitative structure-activity relationships  

PubMed Central

Background The topological maximum cross correlation (TMACC) descriptors are alignment-independent 2D descriptors for the derivation of QSARs. TMACC descriptors are generated using atomic properties determined by molecular topology. Previous validation (J Chem Inf Model 2007, 47: 626-634) of the TMACC descriptor suggests it is competitive with the current state of the art. Results Here, we illustrate the interpretability of the TMACC descriptors, through the analysis of the QSARs of inhibitors of angiotensin converting enzyme (ACE) and dihydrofolate reductase (DHFR). In the case of the ACE inhibitors, the TMACC interpretation shows features specific to C-domain inhibition, which have not been explicitly identified in previous QSAR studies. Conclusions The TMACC interpretation can provide new insight into the structure-activity relationships studied. Freely available, open source software for generating the TMACC descriptors can be downloaded from http://comp.chem.nottingham.ac.uk. PMID:20151000

2009-01-01

18

Discovery and structure-activity relationships of a novel class of quinazoline glucokinase activators.  

PubMed

We describe design, syntheses and structure-activity relationships of a novel class of 4,6-disubstituted quinazoline glucokinase activators. Prototype quinazoline leads (4 and 5) were designed based on the X-ray analyses of the previous 2-aminobenzamide lead classes. Modifications of the quinazoline leads led to the identification of a potent GK activator (21d). PMID:19726182

Iino, Tomoharu; Sasaki, Yasuhiro; Bamba, Makoto; Mitsuya, Morihiro; Ohno, Akio; Kamata, Kenji; Hosaka, Hideka; Maruki, Hiroko; Futamura, Mayumi; Yoshimoto, Riki; Ohyama, Sumika; Sasaki, Kaori; Chiba, Masato; Ohtake, Norikazu; Nagata, Yasufumi; Eiki, Jun-Ichi; Nishimura, Teruyuki

2009-10-01

19

Cytotoxic triosmium carbonyl clusters: a structure-activity relationship study.  

PubMed

A structure-activity relationship (SAR) study of the triosmium carbonyl cluster Os3 (CO)10 (NCCH3 )2 was carried out with a series of clusters of the general formula Os3 (CO)12-n Ln , cationic osmium clusters and a hemi-labile maltolato-Os cluster. The SAR results showed that good solubility in DMSO and at least one vacant site are required for cytotoxicity. In vitro evaluation of these new compounds showed that some are selectively active against estrogen receptor (ER)-independent MDA-MB-231 breast cancer cell lines relative to ER-dependent MCF-7 breast cancer cells, suggesting that the compounds have a different biological target specific to MDA-MB-231 cells. In particular, the maltolato cluster exhibits strong antiproliferative activity, with an IC50 value of 3??M after only 24?h incubation. Additionally, biochemical assays conducted with the cationic cluster show that it induces apoptosis, although a biological target has not yet been identified. Further research to establish the molecular targets of these compounds and to develop improved organometallic clusters as potential breast cancer therapeutics is underway. PMID:24446332

Lee, Hui Zhi Shirley; Leong, Weng Kee; Top, Siden; Vessières, Anne

2014-07-01

20

Polyploidy-Induction by Dihydroxylated Monochlorobiphenyls: Structure-Activity-Relationships  

PubMed Central

Recently semivolatile lower chlorinated biphenyls have been identified in inner city air, in public buildings like schools, and at many other sites. Inhalation exposure to these compounds, which are readily metabolized to mono- and dihydroxy-biphenyls and further to quinones, is of great concern in light of new studies revealing that at least one such compound, 4-monochlorobiphenyl (PCB3), has tumor initiating and mutagenic activity in rats. In vitro the quinone metabolites of PCB3 induced gene mutations, whereas its mono-and di-hydroxylated metabolites increased micronuclei frequency. To gain further insight into the genotoxicity and possible structure-activity relationships of the dihydroxy-metabolites, we measured the effects of the 2-chloro-, 3-chloro, and 4-chloro-2?,5?-dihydroxybiphenyl (PCB1-HQ, PCB2-HQ, and PCB3-HQ, respectively), and of 4-chloro-3?,4?-dihydroxybiphenyl (PCB3-Cat) on cytotoxicity, sister chromatid exchange (SCE), cellular proliferation and chromosome number. Notably only PCB3-Cat caused a significant increase in SCE levels. Cell cycle progression during exposure, which is indicated indirectly in this assay by the occurrence of metaphases with Harlequin stained chromosomes (cell underwent 2 S-phases) or uniformly dark stained chromosomes (underwent less than 2 S-phases) was inhibited by PCB2-HQ and PCB3-HQ. Most surprising was the finding that up to 96% of metaphases from cells treated with PCB2- or PCB3-HQ were tetraploid, some of which had dark and some Harlequin stained chromosomes. Neither PCB1-HQ nor PCB3-Cat or the negative (solvent) or positive control (ethylmethane sulfonate, EMS) induced this effect. The mechanism of this polyploidization is unknown. Nearly all cancer cells are hyperdiploid and polyploidization, followed by uneven chromosome loss, is hypothesized as one possible underlying mechanism of carcinogenesis. Thus different PCB metabolites may induce carcinogenesis by different mechanisms, including SCE induction or polyploidization. Understanding the mechanism(s) and structure-activity-relationships of these unexpected effects is needed before we can perform fully data-driven risk assessment of these compounds. PMID:20471090

Flor, Susanne; Ludewig, Gabriele

2010-01-01

21

TMACC: interpretable correlation descriptors for quantitative structure-activity relationships.  

PubMed

Highly predictive topological maximum cross correlation (TMACC) descriptors for the derivation of quantitative structure-activity relationships (QSARs) are presented, based on the widely used autocorrelation method. They require neither the calculation of three-dimensional conformations nor an alignment of structures. We have validated the TMACC descriptors across eight literature data sets, ranging in size from 66 to 361 molecules. In combination with partial least-squares regression, they perform competitively with a current state-of-the-art 2D QSAR methodology, hologram QSAR (HQSAR), yielding larger leave-one-out cross-validated coefficient of determination values (LOO q2) for five data sets. Like HQSAR, these descriptors are also interpretable but do not require hashing. The interpretation both enables the automated extraction of SARs and can give a description in qualitative agreement with more time-consuming 3D and 4D QSAR methods. Open source software for generating the TMACC descriptors is freely available from our Web site. PMID:17381177

Melville, James L; Hirst, Jonathan D

2007-01-01

22

Hydrolysis reactions of the taccalonolides reveal structure-activity relationships.  

PubMed

The taccalonolides are microtubule stabilizers isolated from plants of the genus Tacca that show potent in vivo antitumor activity and the ability to overcome multiple mechanisms of drug resistance. The most potent taccalonolide identified to date, AJ, is a semisynthetic product generated from the major plant metabolite taccalonolide A in a two-step reaction. The first step involves hydrolysis of taccalonolide A to generate taccalonolide B, and then this product is oxidized to generate an epoxide group at C-22-C-23. To generate sufficient taccalonolide AJ for in vivo antitumor efficacy studies, the hydrolysis conditions for the conversion of taccalonolide A to B were optimized. During purification of the hydrolysis products, we identified the new taccalonolide AO (1) along with taccalonolide I. When the same hydrolysis reaction was performed on a taccalonolide E-enriched fraction, four new taccalonolides, assigned as AK, AL, AM, and AN (2-5), were obtained in addition to the expected product taccalonolide N. Biological assays were performed on each of the purified taccalonolides, which allowed for increased refinement of the structure-activity relationship of this class of compounds. PMID:23855953

Li, Jing; Peng, Jiangnan; Risinger, April L; Mooberry, Susan L

2013-07-26

23

Structure activity relationships to assess new chemicals under TSCA  

SciTech Connect

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.

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

1990-12-31

24

Nonparametric regression applied to quantitative structure-activity relationships  

PubMed

Several nonparametric regressors have been applied to modeling quantitative structure-activity relationship (QSAR) data. The simplest regressor, the Nadaraya-Watson, was assessed in a genuine multivariate setting. Other regressors, the local linear and the shifted Nadaraya-Watson, were implemented within additive models--a computationally more expedient approach, better suited for low-density designs. Performances were benchmarked against the nonlinear method of smoothing splines. A linear reference point was provided by multilinear regression (MLR). Variable selection was explored using systematic combinations of different variables and combinations of principal components. For the data set examined, 47 inhibitors of dopamine beta-hydroxylase, the additive nonparametric regressors have greater predictive accuracy (as measured by the mean absolute error of the predictions or the Pearson correlation in cross-validation trails) than MLR. The use of principal components did not improve the performance of the nonparametric regressors over use of the original descriptors, since the original descriptors are not strongly correlated. It remains to be seen if the nonparametric regressors can be successfully coupled with better variable selection and dimensionality reduction in the context of high-dimensional QSARs. PMID:10761152

Constans; Hirst

2000-03-01

25

Structure activity relationship of synaptic and junctional neurotransmission  

PubMed Central

Chemical neurotransmission may include transmission to local or remote sites. Locally, contact between ‘bare’ portions of the bulbous nerve terminal termed a varicosity and the effector cell may be in the form of either synapse or non-synaptic contact. Traditionally, all local transmissions between nerves and effector cells are considered synaptic in nature. This is particularly true for communication between neurons. However, communication between nerves and other effectors such as smooth muscles has been described as nonsynaptic or junctional in nature. Nonsynaptic neurotransmission is now also increasing recognized in the CNS. This review focuses on the relationship between structure and function that orchestrate synaptic and junctional neurotransmissions. A synapse is a specialized focal contact between the presynaptic active zone capable for ultrafast release of soluble transmitters and the postsynaptic density that cluster ionotropic receptors. The presynaptic and the postsynaptic areas are separated by the ‘closed’ synaptic cavity. The physiological hallmark of the synapse is ultrafast postsynaptic potentials lasting in milliseconds. In contrast, junctions are juxtapositions of nerve terminals and the effector cells without clear synaptic specializations and the junctional space is ‘open’ to the extracellular space. Based on the nature of the transmitters, postjunctional receptors and their separation from the release sites, the junctions can be divided into ‘close’ and ‘wide’ junctions. Functionally, the ‘close’ and the ‘wide’ junctions can be distinguished by postjunctional potentials lasting ~1 second and 10s of seconds, respectively. Both synaptic and junctional communications are common between neurons; however, junctional transmission is the rule at many neuro-non-neural effectors. PMID:23535140

Goyal, Raj K; Chaudhury, Arun

2013-01-01

26

Using Theoretical Descriptors in Structural Activity Relationships: 4. Molecular Orbital Basicity and Electrostatic Basicity.  

National Technical Information Service (NTIS)

Quantitative Structure Activity Relationships (QSAR) have been used to develop predictive equations for numerous biological and physicocochemical properties. Linear Solvation Energy Relationship (LSER), a sub-set of QSAR have been used by Kamlet and Taft ...

G. R. Famini

1988-01-01

27

Cryptocaryol A and B: Total Syntheses, Stereochemical Revision, Structure Elucidation and Structure-Activity Relationship  

PubMed Central

The first total syntheses and structural elucidation of cryptocaryol A and cryptocaryol B were achieved in 23 and 25 linear steps, respectively. The synthesis relied on the use of a key pseudo-Cs symmetric pentaol intermediate, which in a stereo-chemically divergent manner was converted into either enantiomer as well as diastereomers. This synthetic effort enabled the first structure-activity relationships of this class of PDCD4 stabilizing natural products. PMID:23750754

Wang, Yanping; O'Doherty, George A.

2013-01-01

28

Music in minor activates limbic structures: a relationship with dissonance?  

PubMed

Using functional magnetic resonance imaging, we contrasted major and minor mode melodies controlled for liking to study the neural basis of musical mode perception. To examine the influence of the larger dissonance in minor melodies on neural activation differences, we further introduced a strongly dissonant stimulus, in the form of a chromatic scale. Minor mode melodies were evaluated as sadder than major melodies, and in comparison they caused increased activity in limbic structures, namely left parahippocampal gyrus, bilateral ventral anterior cingulate, and in left medial prefrontal cortex. Dissonance explained some, but not all, of the heightened activity in the limbic structures when listening to minor mode music. PMID:18418244

Green, Anders C; Baerentsen, Klaus B; Stødkilde-Jørgensen, Hans; Wallentin, Mikkel; Roepstorff, Andreas; Vuust, Peter

2008-05-01

29

Initial Insights into Structure-Activity Relationships of Avian Defensins*  

PubMed Central

Numerous ?-defensins have been identified in birds, and the potential use of these peptides as alternatives to antibiotics has been proposed, in particular to fight antibiotic-resistant and zoonotic bacterial species. Little is known about the mechanism of antibacterial activity of avian ?-defensins, and this study was carried out to obtain initial insights into the involvement of structural features or specific residues in the antimicrobial activity of chicken AvBD2. Chicken AvBD2 and its enantiomeric counterpart were chemically synthesized. Peptide elongation and oxidative folding were both optimized. The similar antimicrobial activity measured for both l- and d-proteins clearly indicates that there is no chiral partner. Therefore, the bacterial membrane is in all likelihood the primary target. Moreover, this work indicates that the three-dimensional fold is required for an optimal antimicrobial activity, in particular for Gram-positive bacterial strains. The three-dimensional NMR structure of chicken AvBD2 defensin displays the structural three-stranded antiparallel ?-sheet characteristic of ?-defensins. The surface of the molecule does not display any amphipathic character. In light of this new structure and of the king penguin AvBD103b defensin structure, the consensus sequence of the avian ?-defensin family was analyzed. Well conserved residues were highlighted, and the potential strategic role of the lysine 31 residue of AvBD2 was emphasized. The synthetic AvBD2-K31A variant displayed substantial N-terminal structural modifications and a dramatic decrease in activity. Taken together, these results demonstrate the structural as well as the functional role of the critical lysine 31 residue in antimicrobial activity. PMID:22205704

Derache, Chrystelle; Meudal, Herve; Aucagne, Vincent; Mark, Kevin J.; Cadene, Martine; Delmas, Agnes F.; Lalmanach, Anne-Christine; Landon, Celine

2012-01-01

30

Antioxidant, prooxidant and cytotoxic activity of hydroxylated resveratrol analogues: structure–activity relationship  

Microsoft Academic Search

Resveratrol (trans-3,4?,5-trihydroxystilbene), a naturally occurring hydroxystilbene, is considered an essential antioxidative constituent of red wine possessing chemopreventive properties. However, resveratrol and even more its metabolite piceatannol were reported to have also cytostatic activities. In order to find out whether this is related to antioxidative properties of those compounds, we synthesized five other polyhydroxylated resveratrol analogues and studied structure–activity relationships between

Marek Murias; Walter Jäger; Norbert Handler; Thomas Erker; Zsuzsanna Horvath; Thomas Szekeres; Hans Nohl; Lars Gille

2005-01-01

31

Synthesis, Antifungal Activity, and Structure Activity Relationships of Coruscanone A Analogs  

PubMed Central

Coruscanone A, a plant derived cyclopentenedione derivative, showed potent in vitro antifungal activity against Candida albicans and Cryptococcus neoformans, comparable to amphotericin B and fluconazole. A series of analogs have been synthesized by modification of the cyclopentenedione ring, the enolic methoxy functionality, and the side chain styryl moiety of this natural product lead. A structurally close 1,4-benzoquinone analog was also prepared. All the compounds were examined for their in vitro activity against major opportunistic fungal pathogens including C. albicans, C. neoformans and Aspergillus fumigatus, and fluconazole-resistant C. albicans strains, with several analogs demonstrating potent antifungal activity. Structure activity relationship studies indicate that the 2-methoxymethylene-cyclopent-4-ene-1,3-dione structural moiety is the pharmacophore responsible for the antifungal activity of this class of compounds, while the side chain styryl-like moiety plays an important complementary role, presumably contributing to target binding. PMID:17181171

Babu, K. Suresh; Li, Xing-Cong; Jacob, Melissa R.; Zhang, Qifeng; Khan, Shabana I.; Ferreira, Daneel; Clark, Alice M.

2008-01-01

32

COMPUTER-ASSISTED STUDIES OF MOLECULAR STRUCTURE-BIOLOGICAL ACTIVITY RELATIONSHIPS  

EPA Science Inventory

Computer-assisted methods can be used to investigate the relationships between the molecular structures of compounds and their biological activity. A number of approaches have been reported in the literature, including correlations of activity with substituent constants, conforma...

33

Cytotoxic and antifungal activities of melleolide antibiotics follow dissimilar structure-activity relationships.  

PubMed

The fungal genus Armillaria is unique in that it is the only natural source of melleolide antibiotics, i.e., protoilludene alcohols esterified with orsellinic acid or its derivatives. This class of natural products is known to exert antimicrobial and cytotoxic effects. Here, we present a refined relationship between the structure and the antimicrobial activity of the melleolides. Using both agar diffusion and broth dilution assays, we identified the ?(2,4)-double bond of the protoilludene moiety as a key structural feature for antifungal activity against Aspergillus nidulans, Aspergillus flavus, and Penicillium notatum. These findings contrast former reports on cytotoxic activities and may indicate a different mode of action towards susceptible fungi. We also report the isolation and structure elucidation of five melleolides (6'-dechloroarnamial, 6'-chloromelleolide F, 10-hydroxy-5'-methoxy-6'-chloroarmillane, and 13-deoxyarmellides A and B), along with the finding that treatment with an antifungal melleolide impacts transcription of A. nidulans natural product genes. PMID:24906293

Bohnert, Markus; Nützmann, Hans-Wilhelm; Schroeckh, Volker; Horn, Fabian; Dahse, Hans-Martin; Brakhage, Axel A; Hoffmeister, Dirk

2014-09-01

34

Structure-activity relationships of polybiguanides with activity against human immunodeficiency virus type 1.  

PubMed

Previous investigations showing that polydisperse biguanide (PDBG) molecules have activity against human immunodeficiency virus type 1 (HIV-1) also suggested a relationship between PDBG biologic activity and the lengths of hydrocarbon linkers surrounding the positively charged biguanide unit. To better define structure-activity relationships, PDBG molecules with select linker lengths were evaluated for cytotoxicity, anti-HIV-1 activity, and in vivo toxicity. Results of the in vitro experiments demonstrated that increases in linker length (and, therefore, increases in compound lipophilicity) were generally associated with increases in cytotoxicity and antiviral activity against HIV-1. However, a relationship between linker length asymmetry and in vitro therapeutic index (TI) suggested structural specificity in the mechanism of action against HIV-1. Polyethylene hexamethylene biguanide (PEHMB; biguanide units spaced between alternating ethylene and hexamethylene linkers) was found to have the highest in vitro TI (CC??/IC??) among the compounds examined. Recent improvements in PEHMB synthesis and purification have yielded preparations of PEHMB with in vitro TI values of 266 and 7000 against HIV-1 strains BaL and IIIB, respectively. The minimal toxicity of PEHMB relative to polyhexamethylene biguanide (PHMB; biguanide units alternating with hexamethylene linkers) in a murine model of cervicovaginal microbicide toxicity was consistent with considerable differences in cytotoxicity between PEHMB and PHMB observed during in vitro experiments. These structure-activity investigations increase our understanding of PDBG molecules as agents with activity against HIV-1 and provide the foundation for further preclinical studies of PEHMB and other biguanide-based compounds as antiviral and microbicidal agents. PMID:21106331

Passic, Shendra R; Ferguson, Mary Lee; Catalone, Bradley J; Kish-Catalone, Tina; Kholodovych, Vladyslav; Zhu, Wei; Welsh, William; Rando, Robert; Howett, Mary K; Wigdahl, Brian; Labib, Mohamed; Krebs, Fred C

2010-12-01

35

Current trends in the structure-activity relationships of sialyltransferases.  

PubMed

Sialyltransferases (STs) represent an important group of enzymes that transfer N-acetylneuraminic acid (Neu5Ac) from cytidine monophosphate-Neu5Ac to various acceptor substrates. In higher animals, sialylated oligosaccharide structures play crucial roles in many biological processes but also in diseases, notably in microbial infection and cancer. Cell surface sialic acids have also been found in a few microorganisms, mainly pathogenic bacteria, and their presence is often associated with virulence. STs are distributed into five different families in the CAZy database (http://www.cazy.org/). On the basis of crystallographic data available for three ST families and fold recognition analysis for the two other families, STs can be grouped into two structural superfamilies that represent variations of the canonical glycosyltransferase (GT-A and GT-B) folds. These two superfamilies differ in the nature of their active site residues, notably the catalytic base (a histidine or an aspartate residue). The observed structural and functional differences strongly suggest that these two structural superfamilies have evolved independently. PMID:21098518

Audry, Magali; Jeanneau, Charlotte; Imberty, Anne; Harduin-Lepers, Anne; Delannoy, Philippe; Breton, Christelle

2011-06-01

36

Antibacterial activity of xanthones from Garcinia mangostana (L.) and their structure-activity relationship studies.  

PubMed

Antibacterial activities of prenylated xanthones from Garcinia mangostana and their synthetic analogues were investigated, and their structure-activity relationships have been studied. ?-Mangostin has shown antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA), methicillin sensitive Staphylococcus aureus (MSSA), vancomycin-resistant Enterococcus (VRE) and vancomycin-sensitive Enterococcus (VSE) strains at MICs 3.13, 6.25, 6.25 and 6.25 µg mL(-1), respectively. In these experiments, gentamicin was used as the positive control. Further, some analogues of ?-mangostin and ?-mangostin were synthesised and their activity was tested against MRSA and VRE strains. The analysis of the bioassay results above indicated that, the combination of C-6 and C-3 hydroxyl groups along with the prenyl side chain at C-2 in the 1,3,6,7-tetraoxygenated xanthones from G. mangostana is essential to have a high antibacterial activity. PMID:22494050

Dharmaratne, H R W; Sakagami, Yoshikazu; Piyasena, K G P; Thevanesam, Vasanthi

2013-01-01

37

[Study on structure-activity relationship of flavonoids' multidrug resistance-associated protein inhibitory activity].  

PubMed

To study the quantitative structure-activity relationship (QSAR) between the stuctures of 29 flavonoids and the inhibitory activity of their multidrug resistance-associated protein (MRP) 1 and 2 by using the comparative molecular similarity index analysis (CoMSIA). By studying the impact of the combination of different molecular force fields, researchers obtained the molecular force fields that played an important role in inhibiting the activity of MRP1 and MRP2, built the optimized QSAR model, and discussed the structural modification method for flavonoids' multidrug resistance-associated protein inhibitor. The results of the study could not only provide the guidance for new drug R&D, but also help partially discuss the synergy mechanism between MRP1 and MRP2 receptors and traditional Chinese medicines containing flavonoids. PMID:25204184

Qiao, Lian-Sheng; He, Yu-Su; Zhang, Yan-Ling

2014-03-01

38

SIMPLIFYING COMPLEX QSAR'S (QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIPS) IN TOXICITY STUDIES WITH MULTIVARIATE STATISTICS  

EPA Science Inventory

During the past several decades many quantitative structure-activity relationships (QSAR's) have been derived from relatively small data sets of chemicals in a homologous series and selected empirical observations. An alternative approach is to analyze large data sets consisting ...

39

Inhibition of Angiotensin-Converting Enzyme Activity by Flavonoids: Structure-Activity Relationship Studies  

PubMed Central

Previous studies have demonstrated that certain flavonoids can have an inhibitory effect on angiotensin-converting enzyme (ACE) activity, which plays a key role in the regulation of arterial blood pressure. In the present study, 17 flavonoids belonging to five structural subtypes were evaluated in vitro for their ability to inhibit ACE in order to establish the structural basis of their bioactivity. The ACE inhibitory (ACEI) activity of these 17 flavonoids was determined by fluorimetric method at two concentrations (500 µM and 100 µM). Their inhibitory potencies ranged from 17 to 95% at 500 µM and from 0 to 57% at 100 µM. In both cases, the highest ACEI activity was obtained for luteolin. Following the determination of ACEI activity, the flavonoids with higher ACEI activity (i.e., ACEI >60% at 500 µM) were selected for further IC50 determination. The IC50 values for luteolin, quercetin, rutin, kaempferol, rhoifolin and apigenin K were 23, 43, 64, 178, 183 and 196 µM, respectively. Our results suggest that flavonoids are an excellent source of functional antihypertensive products. Furthermore, our structure-activity relationship studies show that the combination of sub-structures on the flavonoid skeleton that increase ACEI activity is made up of the following elements: (a) the catechol group in the B-ring, (b) the double bond between C2 and C3 at the C-ring, and (c) the cetone group in C4 at the C-ring. Protein-ligand docking studies are used to understand the molecular basis for these results. PMID:23185345

Guerrero, Ligia; Castillo, Julian; Quinones, Mar; Garcia-Vallve, Santiago; Arola, Lluis; Pujadas, Gerard; Muguerza, Begona

2012-01-01

40

Structure-activity relationships of 44 halogenated compounds for iodotyrosine deiodinase-inhibitory activity.  

PubMed

The aim of this study was to investigate the possible influence of halogenated compounds on thyroid hormone metabolism via inhibition of iodotyrosine deiodinase (IYD) activity. The structure-activity relationships of 44 halogenated compounds for IYD-inhibitory activity were examined in vitro using microsomes of HEK-293 T cells expressing recombinant human IYD. The compounds examined were 17 polychlorinated biphenyls (PCBs), 15 polybrominated diphenyl ethers (PBDEs), two agrichemicals, five antiparasitics, two pharmaceuticals and three food colorants. Among them, 25 halogenated phenolic compounds inhibited IYD activity at the concentration of 1×10(-4)M or 6×10(-4)M. Rose bengal was the most potent inhibitor, followed by erythrosine B, phloxine B, benzbromarone, 4'-hydroxy-2,2',4-tribromodiphenyl ether, 4-hydroxy-2,3',3,4'-tetrabromodiphenyl ether, 4-hydroxy-2',3,4',5,6'-pentachlorobiphenyl, 4'-hydroxy-2,2',4,5'-tetrabromodiphenyl ether, triclosan, and 4-hydroxy-2,2',3,4',5-pentabromodiphenyl ether. However, among PCBs and PBDEs without a hydroxyl group, including their methoxylated metabolites, none inhibited IYD activity. These results suggest that halogenated compounds may disturb thyroid hormone homeostasis via inhibition of IYD, and that the structural requirements for IYD-inhibitory activity include halogen atom and hydroxyl group substitution on a phenyl ring. PMID:24012475

Shimizu, Ryo; Yamaguchi, Masafumi; Uramaru, Naoto; Kuroki, Hiroaki; Ohta, Shigeru; Kitamura, Shigeyuki; Sugihara, Kazumi

2013-12-01

41

Structural relationship of epipolythiodioxopiperazines and their immunomodulating activity.  

PubMed

Epipolythiodioxopiperazines were tested for their immunoregulatory activity in vitro. Using the macrophage adherence test as a measure of inhibition of phagocytosis, their effect on stimulator cells in mixed lymphocyte cultures and their ability to inhibit mitogen stimulation of T lymphocytes, a hierarchy of activity was observed, with sporidesmin being the most active, followed by gliotoxin and 1,4-dimethyl-3,6-epidithio-2,5-dioxopiperazine. Derivatives of gliotoxin such as dehydro-, trisulfide and tetrasulfide gliotoxin have activities comparable to gliotoxin. The dimethylthioether derivative of gliotoxin was devoid of activity. The presence of reducing agents abrogated the activity of epipolythiodioxopiperazines. This suggests that the bridged disulfide moiety is the single most important chemical entity for their activity. The differential activities of the active compounds may be attributable to their variations in lipophilic properties. PMID:2422547

Müllbacher, A; Waring, P; Tiwari-Palni, U; Eichner, R D

1986-02-01

42

The cytotoxic activities of cardiac glycosides from Streptocaulon juventas and the structure-activity relationships.  

PubMed

A series of cardiac glycosides were isolated and identified from the anti-tumor fraction of the root of Streptocaulon juventas in previous studies. In the present research, the cytotoxic activities of the 43 cardiac glycosides on three cell lines, human lung A549 adenocarcinoma cell, large cell lung cancer NCI-H460 cell and normal human fetal lung fibroblast MRC-5 cell, were evaluated in vitro. Most of the tested compounds showed potent inhibitory activities toward the three cell lines. Then, the structure-activity relationships were discussed in detail. It was indicated that hydroxyl and acetyl groups at C-16 increased the activity, whereas hydroxyl group at C-1 and C-5 can both increase and decrease the activity. Two glucosyl groups which were connected by C1'?C6' showed better inhibitory activity against cancer cell lines, while the C1'?C4' connection showed stronger inhibitory activity against the normal cell line. Also, this is the first report that the activities of these compounds exhibited different variation trends between A549 and NCI-H460 cell lines, which indicated that these compounds could selectively inhibit the cell growth. The results would lay a foundation for further research on new anti-tumor drug development. PMID:25128424

Xue, Rui; Han, Na; Ye, Chun; Wang, Lihui; Yang, Jingyu; Wang, Yu; Yin, Jun

2014-10-01

43

ESTIMATION OF ELECTRON AFFINITY BASED ON STRUCTURE ACTIVITY RELATIONSHIPS  

EPA Science Inventory

Electron affinity for a wide range of organic molecules was calculated from molecular structure using the chemical reactivity models developed in SPARC. hese models are based on fundamental chemical structure theory applied to the prediction of chemical reactivities for organic m...

44

Benzofuranones as potential antinociceptive agents: structure-activity relationships.  

PubMed

This work evaluates the antinociceptive properties of benzofuranones using chemically induced models of pain and the hot plate test. All the compounds exhibited significant antinociceptive activity, with 3-[2-(4-chlorophenyl)-2-oxoetil]-2-benzofuran-1(3H)-one (3d) being the most active. According to the application of the Topliss method, the 2?-?(2) parameter was the preponderant one, indicating that the hydrophobicity (?) seems to be more involved in the antinociceptive activity. Based on the table of other possible substituents proposed by Topliss, three derived from compound 3d were tested. 3-[2-(3-methoxyphenyl)-2-oxoetil]-2-benzofuran-1(3H)-one (3g) showed greater antinociceptive activity with better pharmacokinetic properties predicted. These results show the efficiency of the Topliss Method as a research tool for the discovery of potential candidate molecules for a new antinociceptive drug. PMID:22960698

Gonçalves, Cleiton José; Lenoir, Andrey Sávio; Padaratz, Pâmela; Corrêa, Rogério; Niero, Rivaldo; Cechinel-Filho, Valdir; Campos Buzzi, Fátima de

2012-10-01

45

Flavonoid antioxidants: chemistry, metabolism and structure-activity relationships  

Microsoft Academic Search

Flavonoids are a class of secondary plant phenolics with significant antioxidant and chelating properties. In the human diet, they are most concentrated in fruits, vegetables, wines, teas and cocoa. Their cardioprotective effects stem from the ability to inhibit lipid peroxidation, chelate redox-active metals, and attenuate other processes involving reactive oxygen species. Flavonoids occur in foods primarily as glycosides and polymers

Kelly E Heim; Anthony R Tagliaferro; Dennis J Bobilya

2002-01-01

46

Structure-activity relationship of benzophenanthridine alkaloids from Zanthoxylum rhoifolium having antimicrobial activity.  

PubMed

Zanthoxylum rhoifolium (Rutaceae) is a plant alkaloid that grows in South America and has been used in Brazilian traditional medicine for the treatment of different health problems. The present study was designed to evaluate the antimicrobial activity of the steam bark crude methanol extract, fractions, and pure alkaloids of Z. rhoifolium. Its stem bark extracts exhibited a broad spectrum of antimicrobial activity, ranging from 12.5 to 100 µg/mL using bioautography method, and from 125 to 500 µg/mL in the microdilution bioassay. From the dichloromethane basic fraction, three furoquinoline alkaloids (1-3), and nine benzophenanthridine alkaloids (4-12) were isolated and the antimicrobial activity of the benzophenanthridine alkaloids is discussed in terms of structure-activity relationships. The alkaloid with the widest spectrum of activity was chelerythrine (10), followed by avicine (12) and dihydrochelerythrine (4). The minimal inhibitory concentrations of chelerythrine, of 1.50 µg/mL for all bacteria tested, and between 3.12 and 6.25 µg/mL for the yeast tested, show this compound to be a more powerful antimicrobial agent when compared with the other active alkaloids isolated from Z. rhoifolium. To verify the potential importance of the methylenedioxy group (ring A) of these alkaloids, chelerythrine was selected to represent the remainder of the benzophenanthridine alkaloids isolated in this work and was subjected to a demethylation reaction giving derivative 14. Compared to chelerythrine, the derivative (14) was less active against the tested bacteria and fungi. Kinetic measurements of the bacteriolytic activities of chelerythrine against the bacteria Bacillus subtilis (Gram-positive) and Escherichia coli (Gram-negative) were determined by optical density based on real time assay, suggesting that its mechanism of action is not bacteriolytic. The present study did not detect hemolytic effects of chelerythrine on erythrocytes and found a protective effect considering the decrease in TBARS and AOPP (advanced oxidized protein products) levels when compared to the control group. PMID:24824737

Tavares, Luciana de C; Zanon, Graciane; Weber, Andréia D; Neto, Alexandre T; Mostardeiro, Clarice P; Da Cruz, Ivana B M; Oliveira, Raul M; Ilha, Vinicius; Dalcol, Ionara I; Morel, Ademir F

2014-01-01

47

Structure-Activity Relationship of Benzophenanthridine Alkaloids from Zanthoxylum rhoifolium Having Antimicrobial Activity  

PubMed Central

Zanthoxylum rhoifolium (Rutaceae) is a plant alkaloid that grows in South America and has been used in Brazilian traditional medicine for the treatment of different health problems. The present study was designed to evaluate the antimicrobial activity of the steam bark crude methanol extract, fractions, and pure alkaloids of Z. rhoifolium. Its stem bark extracts exhibited a broad spectrum of antimicrobial activity, ranging from 12.5 to 100 µg/mL using bioautography method, and from 125 to 500 µg/mL in the microdilution bioassay. From the dichloromethane basic fraction, three furoquinoline alkaloids (1–3), and nine benzophenanthridine alkaloids (4–12) were isolated and the antimicrobial activity of the benzophenanthridine alkaloids is discussed in terms of structure-activity relationships. The alkaloid with the widest spectrum of activity was chelerythrine (10), followed by avicine (12) and dihydrochelerythrine (4). The minimal inhibitory concentrations of chelerythrine, of 1.50 µg/mL for all bacteria tested, and between 3.12 and 6.25 µg/mL for the yeast tested, show this compound to be a more powerful antimicrobial agent when compared with the other active alkaloids isolated from Z. rhoifolium. To verify the potential importance of the methylenedioxy group (ring A) of these alkaloids, chelerythrine was selected to represent the remainder of the benzophenanthridine alkaloids isolated in this work and was subjected to a demethylation reaction giving derivative 14. Compared to chelerythrine, the derivative (14) was less active against the tested bacteria and fungi. Kinetic measurements of the bacteriolytic activities of chelerythrine against the bacteria Bacillus subtilis (Gram-positive) and Escherichia coli (Gram-negative) were determined by optical density based on real time assay, suggesting that its mechanism of action is not bacteriolytic. The present study did not detect hemolytic effects of chelerythrine on erythrocytes and found a protective effect considering the decrease in TBARS and AOPP (advanced oxidized protein products) levels when compared to the control group. PMID:24824737

Tavares, Luciana de C.; Zanon, Graciane; Weber, Andreia D.; Neto, Alexandre T.; Mostardeiro, Clarice P.; Da Cruz, Ivana B. M.; Oliveira, Raul M.; Ilha, Vinicius; Dalcol, Ionara I.; Morel, Ademir F.

2014-01-01

48

Derivatives of Ergot-alkaloids: Molecular structure, physical properties, and structure-activity relationships  

NASA Astrophysics Data System (ADS)

A comprehensive screening of fifteen functionalized Ergot-alkaloids, containing bulk aliphatic cyclic substituents at D-ring of the ergoline molecular skeleton was performed, studying their structure-active relationships and model interactions with ?2A-adreno-, serotonin (5HT2A) and dopamine D3 (D3A) receptors. The accounted high affinity to the receptors binding loops and unusual bonding situations, joined with the molecular flexibility of the substituents and the presence of proton accepting/donating functional groups in the studied alkaloids, may contribute to further understanding the mechanisms of biological activity in vivo and in predicting their therapeutic potential in central nervous system (CNS), including those related the Schizophrenia. Since the presented correlation between the molecular structure and properties, was based on the comprehensively theoretical computational and experimental physical study on the successfully isolated derivatives, through using routine synthetic pathways in a relatively high yields, marked these derivatives as 'treasure' for further experimental and theoretical studied in areas such as: (a) pharmacological and clinical testing; (b) molecular-drugs design of novel psychoactive substances; (c) development of the analytical protocols for determination of Ergot-alkaloids through a functionalization of the ergoline-skeleton, and more.

Ivanova, Bojidarka B.; Spiteller, Michael

2012-09-01

49

Synthesis and structure activity relationship studies of novel Staphylococcus aureus Sortase A inhibitors  

Microsoft Academic Search

Synthetic methods have been developed for lead Sortase A inhibitors identified from previous studies. Several derivatives of the lead inhibitor were synthesized to derive preliminary structure activity relationships (SAR). Different regions of the lead inhibitor that are critical for the enzyme activity have been determined by systematic SAR studies. The E stereochemistry of the lead compound was found to be

Bala Chandra Chenna; Jason R. King; Bidhan A. Shinkre; Amanda L. Glover; Aaron L. Lucius; Sadanandan E. Velu

2010-01-01

50

Structural Relationships between Social Activities and Longitudinal Trajectories of Depression among Older Adults  

ERIC Educational Resources Information Center

Purpose: This study examines the structural relationships between social activities and trajectories of late-life depression. Design and Methods: Latent class analysis was used with a nationally representative sample of older adults (N = 5,294) from the Longitudinal Study on Aging II to classify patterns of social activities. A latent growth curve…

Hong, Song-Iee; Hasche, Leslie; Bowland, Sharon

2009-01-01

51

Quantitative structure-activity relationships for gammadelta T cell activation by bisphosphonates.  

PubMed

gammadelta T cells are the first line of defense against many infectious organisms and are also involved in tumor cell surveillance and killing. They are stimulated by a broad range of small, phosphorus-containing antigens (phosphoantigens) as well as by the bisphosphonates commonly used in bone resorption therapy, such as pamidronate and risedronate. Here, we report the activation of gammadelta T cells by a broad range of bisphosphonates and develop a pharmacophore model for gammadelta T cell activation, in addition to using a comparative molecular similarity index analysis (CoMSIA) approach to make quantitative relationships between gammadelta T cell activation by bisphosphonates and their three-dimensional structures. The CoMSIA analyses yielded R(2) values of approximately 0.8-0.9 and q(2) values of approximately 0.5-0.6 for a training set of 45 compounds. Using an external test set, the activities (IC(50) values) of 16 compounds were predicted within a factor of 4.5, on average. The CoMSIA fields consisted of approximately 40% hydrophobic, approximately 40% electrostatic, and approximately 20% steric interactions. Since bisphosphonates are known to be potent, nanomolar inhibitors of the mevalonate/isoprene pathway enzyme farnesyl pyrophosphate synthase (FPPS), we also compared the pharmacophores for gammadelta T cell activation with those for FPPS inhibition, using the Catalyst program. The pharmacophores for gammadelta T cell activation and FPPS inhibition both consisted of two negative ionizable groups, a positive charge feature and an endocyclic carbon feature, all having very similar spatial dispositions. In addition, the CoMSIA fields were quite similar to those found for FPPS inhibition by bisphosphonates. The activities of the bisphosphonates in gammadelta T cell activation were highly correlated with their activities in FPPS inhibition: R = 0.88, p = 0.002, versus a human recombinant FPPS (N = 9 compounds); R = 0.82, p < 0.0001, for an expressed Leishmania major FPPS (N = 45 compounds). The bisphosphonate gammadelta T cell activation pharmacophore differs considerably, however, from that reported previously for gammadelta T cell activation by phosphoantigens (Gossman, W.; Oldfield, E. J. Med. Chem. 2002, 45, 4868-4874), suggesting different primary targets for the two classes of compounds. The ability to quite accurately predict the activity of bisphosphonates as gammadelta T cell activators by using 3D QSAR techniques can be expected to help facilitate the design of additional bisphosphonates for potential use in immunotherapy. PMID:14711309

Sanders, John M; Ghosh, Subhash; Chan, Julian M W; Meints, Gary; Wang, Hong; Raker, Amy M; Song, Yongcheng; Colantino, Alison; Burzynska, Agnieszka; Kafarski, Pawel; Morita, Craig T; Oldfield, Eric

2004-01-15

52

Unique spirocyclopiperazinium salt. Part 2: synthesis and structure–activity relationship of dispirocyclopiperazinium salts as analgesics  

Microsoft Academic Search

Three series of spirocyclopiperazinium derivatives 5a–d, 6a–f and 17a–d were synthesized and evaluated for their in vivo analgesic activities. Compounds 5a, 17a and 17b exhibited excellent analgesic activity. Two important structure–activity relationships were observed from this study: (1) the quaternary ammonium functionality is a critical pharmacophore for analgesic activity; (2) it is important to adjust the lipophilic property of compounds

Xin Wang; Feng-Li Gao; Hong-Bin Piao; Tie-Ming Cheng; Run-Tao Li

2003-01-01

53

Synthesis, antioxidant evaluation, and quantitative structure–activity relationship studies of chalcones  

Microsoft Academic Search

Synthesis, antioxidant activity, and quantitative structure–activity relationship (QSAR) of 25 of chalcone derivatives is\\u000a reported here. They were synthesized by Claisen–Schmidt reaction and were characterized by FTIR, NMR, and mass spectroscopy.\\u000a Antioxidant activity is evaluated through four different methods namely, superoxide radical-scavenging, hydrogen peroxide\\u000a scavenging, reducing power, and DPPH radical-scavenging assays. Generally, compounds with –SCH3 and –OCH3 in the para

P. M. Sivakumar; P. K. Prabhakar; M. Doble

2011-01-01

54

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

PubMed Central

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 ?M to 7.04 ?M. 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. PMID:22272096

Frimayanti, Neni; Yam, Mun Li; Lee, Hong Boon; Othman, Rozana; Zain, Sharifuddin M.; Rahman, Noorsaadah Abd.

2011-01-01

55

DEVELOPMENT OF QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIPS FOR PREDICTING BIODEGRADATION KINETICS  

EPA Science Inventory

Results have been presented on the development of a structure-activity relationship for biodegradation using a group contribution approach. sing this approach, reported results of the kinetic rate constant agree within 20% with the predicted values. dditional compound studies are...

56

A Robust StructureActivity Relationship (SAR) Model for Esters that Cause Skin Irritation in Humans  

Microsoft Academic Search

A structure-activity relationship (SAR) model has been devel- oped to discriminate skin irritant from nonirritant esters. The model is based on the physicochemical properties of 42 esters that were tested in humans for skin irritation. Nineteen physicochem- ical parameters that represent transport, electronic, and steric properties were calculated for each chemical. Best subsets regres- sion analysis indicated candidate models for

Jeffrey S. Smith; Orest T. Macina; Nancy B. Sussman; Michael I. Luster; Meryl H. Karol

2000-01-01

57

Relationship between the antifreeze activities and the chemical structures of polyols  

NASA Astrophysics Data System (ADS)

In this paper, we study the antifreeze activities of aqueous solutions of carbohydrates by Scanning Calorimetry (DSC) technique. The observed antifreeze activity of carbohydrates is correlated to the chemical structures of the carbohydrates. Based on the DSC results, we develop a simple molecular model aimed at explaining the antifreeze activity of carbohydrates. Our molecular model demonstrates that carbohydrates with unique chemical structures that possessing a certain spatial O-O distance of 4.2-4.5 Å between the hydroxyl groups are essential for antifreeze activity. Additionally the structure-antifreeze activity relationship of the carbohydrates may be easily explained within the limits of the concept of their complementarity to the surface of the hexagonal ice. Overall our results provide new physical insights on the role of the complementary pattern of carbohydrates to ice surfaces and their antifreeze activity.

Baruch, Eti; Belostotskii, Anatoly M.; Mastai, Yitzhak

2008-02-01

58

Quantitative structure?activity relationships and compact analysis of a series of food mutagens  

Microsoft Academic Search

Quantitative structure?activity relationships between chemical structure and Ames mutagenicity for a group of 24 food mutagens, including 17 cooked?food heterocyclic amines, have been determined. For the TA98 strain of Salmonella typhimurium (frameshift mutagens) the best correlation of mutagenicity is with molecular diameter (R = 0.91), while for the TA 100 strain (base?pair mutations) the best correlation is with ?E, the

D. F. V. Lewis; C. Ioannides; R. Walker; D. V. Parke

1995-01-01

59

Structure–activity relationship and biological property of cortistatins, anti-angiogenic spongean steroidal alkaloids  

Microsoft Academic Search

Previously, bioassay-guided separation led us to isolate eleven novel steroidal alkaloids named cortistatins from the marine sponge Corticium simplex. These cortistatins were classified into three types based on the chemical structure of the side chain part, that is, isoquinoline, N-methyl piperidine or 3-methylpyridine units. From the structure–activity relationship study, the isoquinoline unit in the side chain was found to be

Shunji Aoki; Yasuo Watanabe; Daiki Tanabe; Masayoshi Arai; Hideaki Suna; Katsushiro Miyamoto; Hiroshi Tsujibo; Kazutake Tsujikawa; Hiroshi Yamamoto; Motomasa Kobayashi

2007-01-01

60

Quantitative structure-activity relationships of antimicrobial fatty acids and derivatives against Staphylococcus aureus *  

PubMed Central

Fatty acids and derivatives (FADs) are resources for natural antimicrobials. In order to screen for additional potent antimicrobial agents, the antimicrobial activities of FADs against Staphylococcus aureus were examined using a microplate assay. Monoglycerides of fatty acids were the most potent class of fatty acids, among which monotridecanoin possessed the most potent antimicrobial activity. The conventional quantitative structure-activity relationship (QSAR) and comparative molecular field analysis (CoMFA) were performed to establish two statistically reliable models (conventional QSAR: R 2=0.942, Q 2 LOO=0.910; CoMFA: R 2=0.979, Q 2=0.588, respectively). Improved forecasting can be achieved by the combination of these two models that provide a good insight into the structure-activity relationships of the FADs and that may be useful to design new FADs as antimicrobial agents. PMID:22302421

Zhang, Hui; Zhang, Lu; Peng, Li-juan; Dong, Xiao-wu; Wu, Di; Wu, Vivian Chi-Hua; Feng, Feng-qin

2012-01-01

61

Structure-activity relationship of cinnamic acylsulfonamide analogues on the human EP3 prostanoid receptor.  

PubMed

Potent and selective antagonists of the human EP3 receptor have been identified. The structure-activity relationship of the chemical series was conducted and we found several analogues displaying sub-nanomolar K(i) values at the EP3 receptor and micromolar activities at the EP1, EP2 and EP4 receptors. The effect of added human serum albumin (HSA) on the binding affinity at the EP3 receptor was also investigated. PMID:11504634

Juteau, H; Gareau, Y; Labelle, M; Sturino, C F; Sawyer, N; Tremblay, N; Lamontagne, S; Carrière, M C; Denis, D; Metters, K M

2001-08-01

62

4-Aminoquinolines Active against Chloroquine-Resistant Plasmodium falciparum: Basis of Antiparasite Activity and Quantitative Structure-Activity Relationship Analyses?  

PubMed Central

Chloroquine (CQ) is a safe and economical 4-aminoquinoline (AQ) antimalarial. However, its value has been severely compromised by the increasing prevalence of CQ resistance. This study examined 108 AQs, including 68 newly synthesized compounds. Of these 108 AQs, 32 (30%) were active only against CQ-susceptible Plasmodium falciparum strains and 59 (55%) were active against both CQ-susceptible and CQ-resistant P. falciparum strains (50% inhibitory concentrations [IC50s], ?25 nM). All AQs active against both CQ-susceptible and CQ-resistant P. falciparum strains shared four structural features: (i) an AQ ring without alkyl substitution, (ii) a halogen at position 7 (Cl, Br, or I but not F), (iii) a protonatable nitrogen at position 1, and (iv) a second protonatable nitrogen at the end of the side chain distal from the point of attachment to the AQ ring via the nitrogen at position 4. For activity against CQ-resistant parasites, side chain lengths of ?3 or ?10 carbons were necessary but not sufficient; they were identified as essential factors by visual comparison of 2-dimensional (2-D) structures in relation to the antiparasite activities of the AQs and were confirmed by computer-based 3-D comparisons and differential contour plots of activity against P. falciparum. The advantage of the method reported here (refinement of quantitative structure-activity relationship [QSAR] descriptors by random assignment of compounds to multiple training and test sets) is that it retains QSAR descriptors according to their abilities to predict the activities of unknown test compounds rather than according to how well they fit the activities of the compounds in the training sets. PMID:21383099

Hocart, Simon J.; Liu, Huayin; Deng, Haiyan; De, Dibyendu; Krogstad, Frances M.; Krogstad, Donald J.

2011-01-01

63

Structure-activity relationship of halophenols as a new class of protein tyrosine kinase inhibitors.  

PubMed

A series of new benzophenone and diphenylmethane halophenol derivatives were prepared. Their structures were established based on (1)H NMR, (13)C NMR and HRMS data. All prepared compounds were screened for their in vitro protein tyrosine kinase (PTK) inhibitory activities. The effects of modification of the linker, functional groups and substituted positions at the phenyl ring on PTK inhibitory activity were investigated. Twelve halophenols showed significant PTK inhibitory activity. Among them, compounds 6c, 6d, 7d, 9d, 10d, 11d and 13d exhibited stronger activities than that of genistein, the positive reference compound. The results gave a relatively full and definite description of the structure-activity relationship and provided a foundation for further design and structure optimization of the halophenols. PMID:22016647

Feng, Xiu E; Zhao, Wan Yi; Ban, Shu Rong; Zhao, Cheng Xiao; Li, Qing Shan; Lin, Wen Han

2011-01-01

64

Structure-Activity Relationship of Halophenols as a New Class of Protein Tyrosine Kinase Inhibitors  

PubMed Central

A series of new benzophenone and diphenylmethane halophenol derivatives were prepared. Their structures were established based on 1H NMR, 13C NMR and HRMS data. All prepared compounds were screened for their in vitro protein tyrosine kinase (PTK) inhibitory activities. The effects of modification of the linker, functional groups and substituted positions at the phenyl ring on PTK inhibitory activity were investigated. Twelve halophenols showed significant PTK inhibitory activity. Among them, compounds 6c, 6d, 7d, 9d, 10d, 11d and 13d exhibited stronger activities than that of genistein, the positive reference compound. The results gave a relatively full and definite description of the structure–activity relationship and provided a foundation for further design and structure optimization of the halophenols. PMID:22016647

Feng, Xiu E.; Zhao, Wan Yi; Ban, Shu Rong; Zhao, Cheng Xiao; Li, Qing Shan; Lin, Wen Han

2011-01-01

65

Quantitative structure-activity relationship studies on sulfonamide-based MMP inhibitors.  

PubMed

Matrix metalloproteinases (MMPs) regulate a wide range of biological functions, but their overactivation leads to a wide array of disease processes such as rheumatoid arthritis, ostereoarthritis, tumor metastatis, multiple sclerosis, congestive heart failure, and a host of others. Therefore, the study of MMP inhibitors has evoked a great interest among scientists. As a result, different groups of compounds have been synthesized and studied for MMP inhibitions. Among them, a large number of structurally novel sulfonamide derivatives have been reported to be potential MMP inhibitors, but only a few have reached to the final stage of clinical trial. Many authors have made quantitative structure-activity relationship (QSAR) studies on them to provide the guidelines to design more potent MMP inhibitors. This article presents a comprehensive review on all such QSARs reported with critical assessment in order to provide a deeper insight into the structure-activity relationship of sulfonamides which can be used to synthesize highly potential drugs of pharmaceutical importance. PMID:22642193

Patil, Vaishali M; Gupta, Satya P

2012-01-01

66

Quantitative structure–activity relationship (QSAR) methodology in forensic toxicology: Modeling postmortem redistribution of structurally diverse drugs using multivariate statistics  

Microsoft Academic Search

Postmortem redistribution (PMR) constitutes a multifaceted process, which renders the analytical results of drug concentrations inaccurate to be interpreted by forensic toxicologists. The aim of the present study was to evaluate whether quantitative structure–activity relationship (QSAR) methodology could serve as an effective tool to estimate the ability of drugs to redistribute across tissue barriers during postmortem period on the basis

Costas Giaginis; Anna Tsantili-Kakoulidou; Stamatios Theocharis

2009-01-01

67

How not to develop a quantitative structure–activity or structure–property relationship (QSAR\\/QSPR)  

Microsoft Academic Search

Although thousands of quantitative structure–activity and structure–property relationships (QSARs\\/QSPRs) have been published, as well as numerous papers on the correct procedures for QSAR\\/QSPR analysis, many analyses are still carried out incorrectly, or in a less than satisfactory manner. We have identified 21 types of error that continue to be perpetrated in the QSAR\\/QSPR literature, and each of these is discussed,

J. C. Dearden; M. T. D. Cronin; K. L. E. Kaiser

2009-01-01

68

Applications of quantitative structure-activity relationships to drug design of piperazine derivatives  

Microsoft Academic Search

Applications of quantitative structure-activity relationship (QSAR) procedures to our own practical drug research are reviewed. A benzylpiperazine cerebral vasodilator (KB-2796) and a piperazine-acetate antiulcer agent (KB-5492) were successfully optimized by use of QSAR information. In these cases, appropriate strategies of the synthetic research were devised and QSAR analyses were performed repeatedly in each step during the research. In the last

Hiroshi Ohtaka

1995-01-01

69

Synthetic modification of a novel microbial ionophore: exploration of anticoccidial structure-activity relationships.  

PubMed

While fermentation-derived polyether ionophores such as salinomycin are the dominant class of anticoccidial feed additives, there is little information concerning the structural features which confer optimal potency/efficacy in this important series. The recently discovered microbial polyether 1a, featuring potent, broad-spectrum anticoccidial activity, was employed as a template to explore structure-activity relationships. A number of single-step synthetic modifications targeted structural changes in both the lipophilic carbon backbone and the ion-binding cavity of 1a. Although previous semisynthetic transformations among the polyether ionophores almost always resulted in a substantial loss of anticoccidial activity, we obtained several analogues, altered on the periphery of the ionophore-ion complex, which retain good potency and efficacy. Monoglycone 7 (semduramicin sodium) has the most impressive anticoccidial profile of this series, and is undergoing further biological testing under field conditions. PMID:1588562

Glazer, E A; Koss, D A; Olson, J A; Ricketts, A P; Schaaf, T K; Wiscount, R J

1992-05-15

70

Structure-Activity Relationships for Side Chain Oxysterol Agonists of the Hedgehog Signaling Pathway  

PubMed Central

Oxysterols (OHCs) are byproducts of cholesterol oxidation that are known to activate the Hedeghog (Hh) signaling pathway. While OHCs that incorporate hydroxyl groups throughout the scaffold are known, those that act as agonists of Hh signaling primarily contain a single hydroxyl on the alkyl side chain. We sought to further explore how side chain hydroxylation patterns affect oxysterol-mediated Hh activation, by performing a structure–activity relationship study on a series of synthetic OHCs. The most active analogue, 23(R)-OHC (35), demonstrated potent activation of Hh signaling in two Hh-dependent cell lines (EC50 values 0.54–0.65 ?M). In addition, OHC 35 was approximately 3-fold selective for the Hh pathway as compared to the liver X receptor, a nuclear receptor that is also activated by endogenous OHCs. Finally, 35 induced osteogenic differentiation and osteoblast formation in cultured cells, indicating functional agonism of the Hh pathway. PMID:24900386

2012-01-01

71

Bioisosterism of Urea-Based GCPII Inhibitors: Synthesis and Structure-Activity Relationships Studies  

PubMed Central

We report a strategy based on bioisosterism to improve the physicochemical properties of existing hydrophilic, urea-based GCPII inhibitors. Comprehensive structure-activity relationship studies of the P1’ site of ZJ-43- and DCIBzL-based compounds identified several glutamate-free inhibitors with Ki values below 20 nM. Among them, compound 32d (Ki = 11 nM) exhibited selective uptake in GCPII-expressing tumors by SPECT-CT imaging in mice. A novel conformational change of amino acids in the S1’ pharmacophore pocket was observed in the X-ray crystal structure of GCPII complexed with 32d. PMID:19897367

Wang, Haofan; Byun, Youngjoo; Barinka, Cyril; Pullambhatla, Mrudula; Bhang, Hyoeun C.; Fox, James J.; Lubkowski, Jacek; Mease, Ronnie C.; Pomper, Martin G.

2009-01-01

72

Structure-activity relationship of the pro- and anticoagulant effects of Fucus vesiculosus fucoidan.  

PubMed

Fucoidan is a highly complex sulfated polysaccharide commonly extracted from brown seaweed. In addition to their many biological activities, fucoidans have recently been demonstrated to inhibit or increase coagulation at different concentration ranges. Their structural features, i.e. molecular weight (Mw), Mw distribution, degree of sulfation, monosaccharide composition, and different linkages, are known to affect these activities. Therefore, structure-activity relationship (SAR) analysis of fucoidan is crucial for its potential use as a procoagulant. In this study, Fucus vesiculosus (F.v.) fucoidan was fractionated by charge and size as well as over- and desulfated to different degrees to yield preparations with various structural properties. The fractions' pro- and anticoagulant activities were assessed by calibrated automated thrombography (CAT) and activated partial thromboplastin time(aPTT) assays. Binding to and inhibition of the anticoagulant protein tissue factor pathway inhibitor (TFPI) and the ability to activate coagulation via the contact pathway were also investigated. This paper discusses the impact of charge density, size, and sugar composition on fucoidan's pro- and anticoagulant activities. Fucoidan requires a minimal charge density of 0.5 sulfates per sugar unit and a size of 70 sugar units to demonstrate desired procoagulant activities for improvement of haemostasis in factor VIII/factor IX-deficient plasma. PMID:24285223

Zhang, Z; Till, S; Jiang, C; Knappe, S; Reutterer, S; Scheiflinger, F; Szabo, C M; Dockal, M

2014-03-01

73

Structure stability/activity relationships of sulfone stabilized N,N-dichloroamines.  

PubMed

Structure stability/activity relationships (SXR) of a new class of N,N-dichloroamine compounds were explored to improve antimicrobial activity against Escherichia coli, Staphylococcus aureus, and Candida albicans while maintaining aqueous solution stability. This study identified a new class of solution-stable and topical antimicrobial agents. These agents are sulfone-stabilized and possess either a quaternary ammonium or sulfonate appendages as a water solubilizing group. Several unique challenges were confronted in the synthesis of these novel compounds which are highlighted in the discussion. PMID:21570284

Low, Eddy; Kim, Bum; Francavilla, Charles; Shiau, Timothy P; Turtle, Eric D; O'Mahony, Donogh J R; Alvarez, Nichole; Houchin, Ashley; Xu, Ping; Zuck, Meghan; Celeri, Chris; Anderson, Mark B; Najafi, Ramin Ron; Jain, Rakesh K

2011-06-15

74

Use of selected toxicology information resources in assessing relationships between chemical structure and biological activity  

SciTech Connect

This paper addresses the subject of the use of the selected toxicology information resources in assessing relationships between chemical structure and specific end points. To assist the researcher in how to access the primary literature of genetic toxicology, teratogenesis, and carcinogenesis, three specific specialized information centers are discussed - Environmental Mutagen Information Center, Environmental Teratology Information Center, and Environmental Carcinogenesis Information Center. Also included are descriptions of information resources that contain evaluated (peer-reviewed) biological research results. The US Environmental Protection Agency Genetic Toxicology Program, the International Agency for Research on Cancer Monographs, and the Toxicology Data Bank are the best sources currently available to obtain peer-reviewed results for compounds tested for genotoxicity, carcinogenicity, and other toxicological end points. The value of published information lies in its use. It has become evident that most information cannot be accepted at face value for interpretation and analysis when subjected to stringent quality evaluation criteria. This deficit can be corrected by rigid editorship and the cognizance of authors. Increased interest in alternative methods to in vivo animal testing will be exemplified by use of short-term bioassays and in structure-activity relationship studies. With respect to this latter area, it must be remembered that mechanically (computer generated) derived data cannot substitute, at least at this stage, for data obtained from actual animal testing. The future of structure-activity relationship studies will rest only in their use as a predictive tool.

Wassom, J.S.

1985-09-01

75

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

PubMed

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 ?-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 ?-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 ?-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 ?-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 ?-glucosidase inhibitor. PMID:24070782

Fatmawati, Sri; Kondo, Ryuichiro; Shimizu, Kuniyoshi

2013-11-01

76

Mechanisms of toxic action and structure-activity relationships for organochlorine and synthetic pyrethroid insecticides.  

PubMed Central

The mechanisms and sites of action of organochlorine (DDT-types and chlorinated alicyclics) and synthetic pyrethroid insecticides are presented with discussion of symptoms, physiological effects, and selectivity. The structural requirements for toxicity are assessed, and structure-activity relationships are considered for each subclass. Lipophilicity is important for all the groups because it facilitates delivery of these neurotoxicants to the site of action in the nerve. Steric factors including molecular volume, shape, and isomeric configuration greatly influence toxicity. Electronic parameters also have been demonstrated to affect biological activity in some of the groups of insecticides, e.g., Hammett's sigma and Taft's sigma * as indicators of electronegativity. New synthetic pyrethroids continue to be developed, with varied structures and different physicochemical and biological properties. PMID:2176589

Coats, J R

1990-01-01

77

Synthesis, Structure-Activity Relationship, & Mode-of-Action Studies of Antimalarial Reversed Chloroquine Compounds  

PubMed Central

We have previously shown that a 'reversed chloroquine (RCQ)' molecule, composed of a chloroquine-like moiety and a resistance reversal-like moiety, can overcome chloroquine resistance in P. falciparum (Burgess, S. J.; Selzer, A.; Kelly, J. X.; Smilkstein, M. J.; Riscoe, M. K.; Peyton, D. H. J. Med. Chem. 2006, 49, 5623; Andrews, S.; Burgess, S. J.; Skaalrud, D.; Kelly, J. X.; Peyton, D. H. J. Med. Chem. 2010, 53, 916). Here, we present an investigation into the structure-activity relationship of the RCQ structures, resulting in an orally active molecule with good in vitro and in vivo antimalarial activity. We also present evidence of the mode of action, indicating that the RCQ molecules inhibit hemozoin formation in the parasite’s digestive vacuole in a manner similar to that of chloroquine. PMID:20684562

Burgess, Steven J.; Kelly, Jane X.; Shomloo, Shawheen; Wittlin, Sergio; Brun, Reto; Liebmann, Katherine; Peyton, David H.

2010-01-01

78

Studies of structure–activity relationship on plant polyphenol-induced suppression of human liver cancer cells  

Microsoft Academic Search

Purpose  To study anticancer activities of 68 plant polyphenols with different backbone structures and various substitutions and to\\u000a analyze the structure–activity relationships.\\u000a \\u000a \\u000a \\u000a Methods  Antiproliferative activity of 68 plant polyphenols on human liver cancer cells were screened by the 3-[4,5-dimethylthiazol-2yl]-2,5-diphenyltetrazolium\\u000a bromide method. Structure–activity relationships were analyzed by comparison of their activities with selected structures.\\u000a Cell cycle progression was assayed by flow cytometry analysis

Jacky Loa; Pierce Chow; Kai Zhang

2009-01-01

79

Structure-Activity Relationship of Fenamates as Slo2.1 Channel Activators  

PubMed Central

Niflumic acid, 2-{[3-(trifluoromethyl)phenyl]amino}pyridine-3-carboxylic acid (NFA), a nonsteroidal anti-inflammatory drug that blocks cyclooxygenase (COX), was shown previously to activate [Na+]i-regulated Slo2.1 channels. In this study, we report that other fenamates, including flufenamic acid, mefenamic acid, tolfenamic acid, meclofenamic acid, and a phenyl acetic acid derivative, diclofenac, also are low-potency (EC50 = 80 ?M to 2.1 mM), partial agonists of human Slo2.1 channels heterologously expressed in Xenopus oocytes. Substituent analysis determined that N-phenylanthranilic acid was the minimal pharmacophore for fenamate activation of Slo2.1 channels. The effects of fenamates were biphasic, with an initial rapid activation phase followed by a slow phase of current inhibition. Ibuprofen, a structurally dissimilar COX inhibitor, did not activate Slo2.1. Preincubation of oocytes with ibuprofen did not significantly alter the effects of NFA, suggesting that neither channel activation nor inhibition is associated with COX activity. A point mutation (A278R) in the pore-lining S6 segment of Slo2.1 increased the sensitivity to activation and reduced the inhibition induced by NFA. Together, our results suggest that fenamates bind to two sites on Slo2.1 channels: an extracellular accessible site to activate and a cytoplasmic accessible site in the pore to inhibit currents. PMID:22851714

Garg, Priyanka

2012-01-01

80

THEORETICAL AND COMPUTATIONAL APPROACH TO CHEMICAL EVALUATION BASED ON STRUCTURE-ACTIVITY RELATIONSHIPS  

EPA Science Inventory

During the past ten years we have been developing relationships to predict physical, chemical, environmental, and toxicological properties of chemicals directly from structure. he fundamental framework of our approach is to propose a theoretical basis for such relationships, comp...

81

Prediction of compounds in different local structure-activity relationship environments using emerging chemical patterns.  

PubMed

Active compounds can participate in different local structure-activity relationship (SAR) environments and introduce different degrees of local SAR discontinuity, depending on their structural and potency relationships in data sets. Such SAR features have thus far mostly been analyzed using descriptive approaches, in particular, on the basis of activity landscape modeling. However, compounds in different local SAR environments have not yet been predicted. Herein, we adapt the emerging chemical patterns (ECP) method, a machine learning approach for compound classification, to systematically predict compounds with different local SAR characteristics. ECP analysis is shown to accurately assign many compounds to different local SAR environments across a variety of activity classes covering the entire range of observed local SARs. Control calculations using random forests and multiclass support vector machines were carried out and a variety of statistical performance measures were applied. In all instances, ECP calculations yielded comparable or better performance than controls. The approach presented herein can be applied to predict compounds that complement local SARs or prioritize compounds with different SAR characteristics. PMID:24803014

Namasivayam, Vigneshwaran; Gupta-Ostermann, Disha; Balfer, Jenny; Heikamp, Kathrin; Bajorath, Jürgen

2014-05-27

82

Structure-activity relationships for withanolides as inducers of the cellular heat-shock response.  

PubMed

To understand the relationship between the structure and the remarkably diverse bioactivities reported for withanolides, we obtained withaferin A (WA; 1) and 36 analogues (2-37) and compared their cytotoxicity to cytoprotective heat-shock-inducing activity (HSA). By analyzing structure-activity relationships for the series, we found that the ring A enone is essential for both bioactivities. Acetylation of 27-OH of 4-epi-WA (28) to 33 enhanced both activities, whereas introduction of ?-OH to WA at C-12 (29) and C-15 (30) decreased both activities. Introduction of ?-OAc to 4,27-diacetyl-WA (16) at C-15 (37) decreased HSA without affecting cytotoxicity, but at C-12 (36), it had minimal effect. Importantly, acetylation of 27-OH, yielding 15 from 1, 16 from 14, and 35 from 34, enhanced HSA without increasing cytotoxicity. Our findings demonstrate that the withanolide scaffold can be modified to enhance HSA selectively, thereby assisting development of natural product-inspired drugs to combat protein aggregation-associated diseases by stimulating cellular defense mechanisms. PMID:24625088

Wijeratne, E M Kithsiri; Xu, Ya-Ming; Scherz-Shouval, Ruth; Marron, Marilyn T; Rocha, Danilo D; Liu, Manping X; Costa-Lotufo, Leticia V; Santagata, Sandro; Lindquist, Susan; Whitesell, Luke; Gunatilaka, A A Leslie

2014-04-10

83

Inhibition of flavonoids on acetylcholine esterase: binding and structure-activity relationship.  

PubMed

The inhibitory effects of flavonoids on acetylcholinesterase (AChE) have attracted great interest among researchers. However, few reports have focused on the structure-activity relationship for AChE inhibition of flavonoids. This work mainly concerns the structural aspects of inhibitory activities and binding affinities of flavonoids as AChE inhibitors. The results show that hydroxyl groups in the A ring of flavonoids are favorable for inhibiting AChE, and the hydroxylation increases the affinities for AChE. However, methoxylation may decrease or increase the activities depending on the class of flavonoids. The glycosylation decreases the AChE inhibitory activities of flavonoids and lowers the affinities for AChE by 1 to 5 times depending on the conjunction site and the type of sugar moiety. The hydrogenation of the C2-C3 double bond of apigenin decreases both the affinity for AChE and AChE inhibition. The molecular property-affinity relationship reveals that the hydrogen bond force plays an important role in binding flavonoids to AChE. The AChE inhibitions generally increase with the increasing affinities of flavonoids within the class, especially for flavones and flavonols. PMID:25143139

Xie, Yixi; Yang, Weijie; Chen, Xiaoqing; Xiao, Jianbo

2014-10-24

84

STUDIES OF RELATIONSHIPS BETWEEN MOLECULAR STRUCTURE AND BIOLOGICAL ACTIVITY BY PATTERN RECOGNITION METHODS  

EPA Science Inventory

The attempt to rationalize the connections between the molecular structures of organic compounds and their biological activities comprises the field of structure-activity relations (SAR) studies. Correlations between structure and activity are important for the understanding and ...

85

Tyrosinase inhibitors from Rhododendron collettianum and their structure-activity relationship (SAR) studies.  

PubMed

A new coumarinolignoid 8'-epi-cleomiscosin A (1) together with the new glycoside 8-O-beta-D-glucopyranosyl-6-hydroxy-2-methyl-4H-1-benzopyrane-4-one (2) have been isolated from the aerial parts of Rhododendron collettianum and their structures determined on the basis of spectroscopic evidences. Tyrosinase inhibition study of these compounds and their structure-activity relationship (SAR) were also investigated. The compounds exhibited potent to mild inhibition activity against the enzyme. Especially, the compound 1 showed strong inhibition (IC50=1.33 microM) against the enzyme tyrosinase, as compared to the standard tyrosinase inhibitors kojic acid (IC50=16.67 microM) and L-mimosine (IC50=3.68 microM), indicating its potential used for the treatment of hyperpigmentation associated with the high production of melanocytes. PMID:15577244

Ahmad, Viqar Uddin; Ullah, Farman; Hussain, Javid; Farooq, Umar; Zubair, Muhammad; Khan, Mahmud Tareq Hassan; Choudhary, Muhammad Iqbal

2004-12-01

86

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

PubMed

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. PMID:17077558

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

2006-11-01

87

Oxazolones: New tyrosinase inhibitors; synthesis and their structure–activity relationships  

Microsoft Academic Search

The tyrosinase inhibitory potential of seventeen synthesized oxazolone derivatives has been evaluated and their structure–activity relationships developed in the present work. All the synthesized derivatives, 3–19, demonstrated excellent in vitro tyrosinase inhibitory properties having IC50 values in the range of 1.23±0.37–17.73±2.69?M, whereas standard inhibitors l-mimosine and kojic acid have IC50 values 3.68±0.02 and 16.67±0.52?M,, respectively. Compounds 4–8 having IC50 values

Khalid Mohammed Khan; Uzma Rasool Mughal; Mahmud Tareq Hassan Khan; Zia-Ullah; Shahnaz Perveen; Muhammad Iqbal Choudhary

2006-01-01

88

Design, synthesis and structure-activity relationships of novel taxane-based multidrug resistance reversal agents.  

PubMed

A series of novel taxane-based multidrug resistance (MDR) reversal agents (TRAs) has been designed and synthesized. Structure-activity relationship (SAR) study clearly indicates that modification of the C-7 position with hydrophobic arenecarbonylcinnamoyl groups brings about high potency against drug efflux mediated by P-glycoprotein (P-gp). Six TRAs exhibit ability to modulate a wide range of ATP-binding cassette (ABC) transporters, such as P-gp, multidrug resistance-associated protein 1 (MRP1), and breast cancer resistance protein (BCRP), which may serve as novel broad-spectrum modulators of ABC transporters. PMID:15771464

Ojima, Iwao; Borella, Christopher P; Wu, Xinyuan; Bounaud, Pierre-Yves; Oderda, Cecilia Fumero; Sturm, Matthew; Miller, Michael L; Chakravarty, Subrata; Chen, Jin; Huang, Qing; Pera, Paula; Brooks, Tracy A; Baer, Maria R; Bernacki, Ralph J

2005-03-24

89

Structure-Activity Relationship of Highly Potent Galactonoamidine Inhibitors toward ?-Galactosidase (Aspergillus oryzae).  

PubMed

A small library of 22 N-substituted galactonoamidines was synthesized, and their structure-activity relationship for inhibition of the hydrolytic activity of ?-galactosidase (Aspergillus oryzae) was evaluated. A fast screening assay in 96-well plate format was used to follow the enzymatic hydrolysis of 2-chloro-4-nitrophenyl-?-d-galactopyranoside using UV-vis spectroscopy. The aglycon moiety of all compounds was found to have a profound effect on their inhibitory ability. In general, galactonoamidines derived from cyclic aliphatic and linear amines show higher inhibition activity than those derived from benzylamines. Hydrophobic interactions of the methyl group rather than ?-? stacking interactions of the aromatic ring in p-methylbenzyl-d-galactonoamidine were identified to cause its transition-state-like character and the remarkably high inhibitory ability (Ki = 8 nM). A flexible 3-carbon methylene spacer between the exo N atom of the sugar moiety and a phenyl group furthermore increased the observed apparent inhibition drastically. PMID:25295392

Fan, Qiu-Hua; Claunch, Kailey A; Striegler, Susanne

2014-11-13

90

Isoxazole analogues bind the system xc- transporter: structure-activity relationship and pharmacophore model.  

PubMed

Analogues of amino methylisoxazole propionic acid (AMPA), were prepared from a common intermediate 12, including lipophilic analogues using lateral metalation and electrophilic quenching, and were evaluated at System xc-. Both the 5-naphthylethyl-(16) and 5-naphthylmethoxymethyl-(17) analogues adopt an E-conformation in the solid state, yet while the former has robust binding at System xc-, the latter is virtually devoid of activity. The most potent analogues were amino acid naphthyl-ACPA 7g, and hydrazone carboxylic acid, 11e Y=Y'=3,5-(CF(3))(2), which both inhibited glutamate uptake by the System xc- transporter with comparable potency to the endogenous substrate cystine, whereas in contrast the closed isoxazolo[3,4-d] pyridazinones 13 have significantly lower activity. A preliminary pharmacophore model has been constructed to provide insight into the analogue structure-activity relationships. PMID:19932968

Patel, Sarjubhai A; Rajale, Trideep; O'Brien, Erin; Burkhart, David J; Nelson, Jared K; Twamley, Brendan; Blumenfeld, Alex; Szabon-Watola, Monika I; Gerdes, John M; Bridges, Richard J; Natale, Nicholas R

2010-01-01

91

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

PubMed Central

Background 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. Results 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. Conclusions 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. PMID:24171724

2013-01-01

92

Structure-activity relationships of HIV-1 integrase inhibitors--enzyme-ligand interactions.  

PubMed

HIV-1 integrase is an essential enzyme for retroviral replication. It is involved in the integration of HIV DNA into host chromosomal DNA and appears to have no functional equivalent in human cells. Therefore it is an attractive and rational target for selective anti-AIDS therapy. A great number of HIV-1 integrase inhibitors have been described in the last decade and numerous reviews have been published. The biochemical mechanism of HIV-1 DNA integration, the enzyme structure and the possible targets for drug intervention have been thoroughly analyzed. Structure-based drug design including both ligand-based (pharmacophore) and target-based (docking) methods has also been discussed. The recent report of the crystal structure of HIV-1 integrase core domain with an inhibitor has given a new boost leading in the last two years to the emergence of diketoacids (DKAs). To date, with the dicaffeoyltartaric acids they are the only two classes of molecules that meet the criteria necessary to be considered lead molecules in the search for clinically useful inhibitors of HIV-1 integrase. After a survey of the function and the structure of this enzyme and the different available assays for the identification of new IN inhibitors, structure-activity relationships of HIV-1 integrase inhibitors that are expected to interact with the active site (or in its vicinity) will be discussed with emphasis on their different proposed mechanisms of action. PMID:12871105

Maurin, C; Bailly, F; Cotelle, P

2003-09-01

93

ESTIMATION OF MICROBIAL REDUCTIVE TRANSFORMATION RATES FOR CHLORINATED BENZENES AND PHENOLS USING A QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIP APPROACH  

EPA Science Inventory

A set of literature data was used to derive several quantitative structure-activity relationships (QSARs) to predict the rate constants for the microbial reductive dehalogenation of chlorinated aromatics. Dechlorination rate constants for 25 chloroaromatics were corrected for th...

94

Structure-activity relationship studies on cholecystokinin: Analogues with partial agonist activity  

SciTech Connect

In the present study, hepta- and octapeptide analogues of the C-terminal part of cholecystokinin, modified on the C-terminal phenylalanine residue, were synthesized. CCK analogues were prepared in which the peptide bond between aspartic acid and phenylalanine had or had not been modified and were lacking the C-terminal primary amide function. These CCK derivatives were able to cause full stimulation of amylase release from rat pancreatic acini but without a decrease in amylase release at supramaximal concentrations. There was a close relationship between the abilities of these derivatives to stimulate amylase release and their abilities to inhibit binding of {sup 125}I-BH-CCK-9 to CCK receptors on rat and guinea pig pancreatic acini. These CCK analogues were also able to recognize the guinea pig brain CCK receptors, some of them being particularly potent. The findings indicate that the aromatic ring of phenylalanine is important for the binding to brain and pancreatic CCK receptors, whereas the C-terminal primary amide function is not essential for the binding to pancreatic CCK receptors but is crucial for biological activity of rat pancreatic acini.

Galas, M.C.; Lignon, M.F.; Rodriguez, M.; Mendre, C.; Fulcrand, P.; Laur, J.; Martinez, J. (Centre de Pharmacologie-Endocrinologie, Montpellier (France))

1988-02-01

95

Structure-activity relationships of organofluorine inhibitors of ?-amyloid self-assembly.  

PubMed

A broad group of structurally diverse small organofluorine compounds were synthesized and evaluated as inhibitors of ?-amyloid (A?) self-assembly. The main goal was to generate a diverse library of compounds with the same functional group and to observe general structural features that characterize inhibitors of A? oligomer and fibril formation, ultimately identifying structures for further focused inhibitor design. The common structural motifs in these compounds are CF(3) -C-OH and CF(3) -C-NH groups that were proposed to be binding units in our previous studies. A broad range of potential small-molecule inhibitors were synthesized by combining various carbocyclic and heteroaromatic rings with an array of substituents, generating a total of 106 molecules. The compounds were tested by standard methods such as thioflavin-T fluorescence spectroscopy for monitoring fibril formation, biotinyl A?(1-42) single-site streptavidin-based assays for observing oligomer formation, and atomic force microscopy for morphological studies. These assays revealed a number of structures that show significant inhibition against either A? fibril or oligomer formation. A detailed analysis of the structure-activity relationship of anti-fibril and -oligomer properties is provided. These data present further experimental evidence for the distinct nature of fibril versus oligomer formation and indicate that the interaction of the A? peptide with chiral small molecules is not stereospecific in nature. PMID:22351619

Török, Béla; Sood, Abha; Bag, Seema; Kulkarni, Aditya; Borkin, Dmitry; Lawler, Elizabeth; Dasgupta, Sujaya; Landge, Shainaz; Abid, Mohammed; Zhou, Weihong; Foster, Michelle; LeVine, Harry; Török, Marianna

2012-05-01

96

Structure-Activity Relationships and Molecular Modeling of Sphingosine Kinase Inhibitors  

PubMed Central

The design, synthesis, and evaluation of the potency of new isoform-selective inhibitors of sphingosine kinases 1 and 2 (SK1 and SK2), the enzyme that catalyzes the phosphorylation of d-erythro-sphingosine to produce the key signaling lipid, sphingosine 1-phosphate, are described. Recently, we reported that 1-(4-octylphenethyl)piperidin-4-ol (RB-005) is a selective inhibitor of SK1. Here we report the synthesis of 43 new analogues of RB-005, in which the lipophilic tail, polar headgroup, and linker region were modified to extend the structure–activity relationship profile for this lead compound, which we explain using modeling studies with the recently published crystal structure of SK1. We provide a basis for the key residues targeted by our profiled series and provide further evidence for the ability to discriminate between the two isoforms using pharmacological intervention. PMID:24164513

2013-01-01

97

Structure-activity relationships of fatty acid amide ligands in activating and desensitizing G protein-coupled receptor 119.  

PubMed

The purpose of the current study was to apply a high throughput assay to investigate the structure-activity relationships of fatty acid amides for activating and desensitizing G protein-coupled receptor 119, a promising therapeutic target for both type 2 diabetes and obesity. A cell-based, homogenous time resolved fluorescence (HTRF) method for measuring G protein-coupled receptor 119-mediated increase of cyclic adenosine monophosphate (cAMP) levels was validated and applied in this study. Using novel fatty acid amides and detailed potency and efficacy analyses, we have demonstrated that degree of saturation in acyl chain and charged head groups of fatty acid amides have profound effects on the ability of these compounds to activate G protein-coupled receptor 119. In addition, we have demonstrated for the first time that pretreatments with G protein-coupled receptor 119 agonists desensitize the receptor and the degrees of desensitization caused by fatty acid amides correlate well with their structure-activity relationships in activating the receptor. PMID:24184668

Kumar, Pritesh; Kumar, Akhilesh; Song, Zhao-Hui

2014-01-15

98

Quantitative structure-activity relationships of imidazolium oximes as nerve agent antidotes  

SciTech Connect

Organophosphorus-containing pesticides and chemical warfare agents are potent inhibitors of synaptic acetylcholinesterase, a key regulator of cholinergic neurotransmission. These nerve agents have for many years constituted a serious threat to military personnel. These threats stimulated considerable efforts to develop effective medical countermeasures. Several potential drugs have been found recently which are capable of protecting animals from lethal levels of nerve agents. A recent U. S. Army Medical Research and Development Command drug development project synthesized a large number of imidazolium oximes. These compounds were found to possess strong antidotal activity against one of the most lethal nerve agents, soman. The Army's approach, like most conventional drug discovery approaches, depended primarily on the trial and error method. This research was carried out to determine if these potential nerve agent antidotes could have been discovered through the use of Quantitative Structure Activity-Relationships (QSAR) technique.

Musallam, H.A.; Foye, W.O.; Hansch, C.; Harris, R.N.; Engle, R.R.

1993-05-13

99

Quantitative structure-activity relationship models of chemical transformations from matched pairs analyses.  

PubMed

The concepts of activity cliffs and matched molecular pairs (MMP) are recent paradigms for analysis of data sets to identify structural changes that may be used to modify the potency of lead molecules in drug discovery projects. Analysis of MMPs was recently demonstrated as a feasible technique for quantitative structure-activity relationship (QSAR) modeling of prospective compounds. Although within a small data set, the lack of matched pairs, and the lack of knowledge about specific chemical transformations limit prospective applications. Here we present an alternative technique that determines pairwise descriptors for each matched pair and then uses a QSAR model to estimate the activity change associated with a chemical transformation. The descriptors effectively group similar transformations and incorporate information about the transformation and its local environment. Use of a transformation QSAR model allows one to estimate the activity change for novel transformations and therefore returns predictions for a larger fraction of test set compounds. Application of the proposed methodology to four public data sets results in increased model performance over a benchmark random forest and direct application of chemical transformations using QSAR-by-matched molecular pairs analysis (QSAR-by-MMPA). PMID:24605924

Beck, Jeremy M; Springer, Clayton

2014-04-28

100

Investigations on Inhibitors of Hedgehog Signal Pathway: A Quantitative Structure-Activity Relationship Study  

PubMed Central

The hedgehog signal pathway is an essential agent in developmental patterning, wherein the local concentration of the Hedgehog morphogens directs cellular differentiation and expansion. Furthermore, the Hedgehog pathway has been implicated in tumor/stromal interaction and cancer stem cell. Nowadays searching novel inhibitors for Hedgehog Signal Pathway is drawing much more attention by biological, chemical and pharmological scientists. In our study, a solid computational model is proposed which incorporates various statistical analysis methods to perform a Quantitative Structure-Activity Relationship (QSAR) study on the inhibitors of Hedgehog signaling. The whole QSAR data contain 93 cyclopamine derivatives as well as their activities against four different cell lines (NCI-H446, BxPC-3, SW1990 and NCI-H157). Our extensive testing indicated that the binary classification model is a better choice for building the QSAR model of inhibitors of Hedgehog signaling compared with other statistical methods and the corresponding in silico analysis provides three possible ways to improve the activity of inhibitors by demethylation, methylation and hydroxylation at specific positions of the compound scaffold respectively. From these, demethylation is the best choice for inhibitor structure modifications. Our investigation also revealed that NCI-H466 served as the best cell line for testing the activities of inhibitors of Hedgehog signal pathway among others. PMID:21686166

Zhu, Ruixin; Liu, Qi; Tang, Jian; Li, Huiliang; Cao, Zhiwei

2011-01-01

101

Structure-activity relationships of retinoids in hamster tracheal organ culture.  

PubMed

Structure-activity relationships are summarized for 87 retinoids, using reversal of keratinization in the hamster tracheal organ culture system to measure biological activity. Classes of compounds evaluated include all-trans-retinoic acid and its esters, ring-modified analogs of all-trans-retinoic acid and its esters, side-chain-modified analogs of all-trans-retinoic acid and its esters, analogs in which both ring and side chain have been modified, all-trans-retinol and derivatives, all-trans-retinyl amine derivatives, all-trans-retinal derivatives, all-trans-retinoic acid amides, 13-cis-retinoic acid and derivatives, and 5,6-epoxyretinoids. the activity of many synthetic amide derivatives of all-trans- or 13-cis-retinoic acid approaches that of the parent compounds. No metabolite of all-trans- or 13-cis-retinoic acid has yet been identified which has greater activity than the parent compounds in this assay. New synthetic derivatives with a gem-dimethyl group at position 4 in the cyclohexenyl ring and two aromatic rings in the side chain have activity equal to or greater than that of all-trans- or 13-cis-retinoic acid, with some activity detectable in the 10(-11) M range. PMID:6159964

Newton, D L; Henderson, W R; Sporn, M B

1980-10-01

102

Syntheses of antifungal aureobasidin A analogs with alkyl chains for structure-activity relationship.  

PubMed

The syntheses of aureobasidin A (AbA) derivatives with alkyl chains and their in vitro structure-biological activity relationships are discussed. The analogs replaced at positions 6, 7, or 8 of AbA with either L-glutamic acid, delta-hydroxy-L-norvaline, or delta-hydroxy-N-methyl-L-norvaline are prepared. The gamma-carboxyl or delta-hydroxyl group of these new amino acids was coupled with acids, alcohols, or amines with alkyl chains. While the analogs having L-glutamic acid residue at positions 6 or 8 showed weak activity, esterification of the gamma-carboxyl group with benzyl or shorter alkyl (C4 or C6) alcohols, significantly enhanced the activities. Introduction of longer alkyl (C14) chain to the same amino acids residues at positions 6, 7, or 8 resulted in total loss of antifungal activity. Among the lipophilic analogs in [L-Glu6] derivatives, the C6 alcohol ester showed the strongest antifungal activity against Candida spp. so far tested. None of the derivatives showed activity against Cryptococcus neoformans. PMID:9589073

Kurome, T; Inoue, T; Takesako, K; Kato, I

1998-03-01

103

Toxicity and quantitative structure-activity relationships of nitriles based on Pseudokirchneriella subcapitata.  

PubMed

This study presents the toxicity data of various nitriles to Pseudokirchneriella subcapitata using a closed algal toxicity testing technique with no headspace. Two different response endpoints, i.e., dissolved oxygen (DO) production and algal growth rate, were used to evaluate the toxicity of nitriles. In general, the DO endpoint revealed higher inhibitory effects than that from algal growth rate. Furthermore, halogen-substituted nitriles were found to be extremely toxic to P. subcapitata. With increasing numbers of the halogen atoms, stronger toxicity was observed. The bromine substitutent also seems to be more toxic than chlorine substitutent. Quantitative structure-activity relationships (QSARs) were established based on the chemicals' Elumo values and hydrophobicity (logK(ow)). Such relationships may thus be useful in predicting the toxicity of other compounds of the same mode of toxic action. Furthermore, for various aquatic organisms, the relative sensitivity relationship is: Pimephales promelas > or = P. subcapitata> Tetrahymena Pyriformis>Daphnia magna>luminescent bacteria (Microtox). The alga, P. subcapitata, was found to be quite sensitive to nitriles compared to other organisms. PMID:16875732

Huang, Chun-Pin; Wang, Yun-Ju; Chen, Chung-Yuan

2007-07-01

104

Peptide inhibitors of botulinum neurotoxin serotype A: design, inhibition, cocrystal structures, structure-activity relationship and pharmacophore modeling  

SciTech Connect

Clostridium botulinum neurotoxins are classified as Category A bioterrorism agents by the Centers for Disease Control and Prevention (CDC). The seven serotypes (A-G) of the botulinum neurotoxin, the causative agent of the disease botulism, block neurotransmitter release by specifically cleaving one of the three SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) proteins and induce flaccid paralysis. Using a structure-based drug-design approach, a number of peptide inhibitors were designed and their inhibitory activity against botulinum serotype A (BoNT/A) protease was determined. The most potent peptide, RRGF, inhibited BoNT/A protease with an IC{sub 50} of 0.9 {micro}M and a K{sub i} of 358 nM. High-resolution crystal structures of various peptide inhibitors in complex with the BoNT/A protease domain were also determined. Based on the inhibitory activities and the atomic interactions deduced from the cocrystal structures, the structure-activity relationship was analyzed and a pharmacophore model was developed. Unlike the currently available models, this pharmacophore model is based on a number of enzyme-inhibitor peptide cocrystal structures and improved the existing models significantly, incorporating new features.

Kumar G.; Swaminathan S.; Kumaran, D.; Ahmed, S. A.

2012-05-01

105

Structure-activity relationships for xenobiotic transport substrates and inhibitory ligands of P-glycoprotein.  

PubMed Central

The multixenobiotic resistance phenotype is characterized by the reduced accumulation of xenobiotics by cells or organisms due to increased efflux of the compounds by P-glycoprotein (P-gp) or related transporters. An extensive xenobiotic database, consisting primarily of pesticides, was utilized in this study to identify molecular characteristics that render a xenobiotic susceptible to transport by or inhibition of P-gp. Transport substrates were differentiated by several molecular size/shape parameters, lipophilicity, and hydrogen bonding potential. Electrostatic features differentiated inhibitory ligands from compounds not catagorized as transport substrates and that did no interact with P-gp. A two-tiered system was developed using the derived structure-activity relationships to identify P-gp transport substrates and inhibitory ligands. Prediction accuracy of the approach was 82%. We then validated the system using six additional pesticides of which tow were predicted to be P-gp inhibitors and four were predicted to be noninteractors, based upon the structure-activity analyses. Experimental determinations using cells transfected with the human MDR1 gene demonstrated that five of the six pesticides were properly catagorized by the structure-activity analyses (83% accuracy). Finally, structure-activity analyses revealed that among P-gp inhibitors, relative inhibitory potency can be predicted based upon the surface area or volume of the compound. These results demonstrate that P-gp transport substrates and inhibitory ligands can be distinguished using molecular characteristics. Molecular characteristics of transport substrates suggest that P-gp may function in the elimination of hydroxylated metabolites of xenobiotics. Images Figure 1. A Figure 1. B Figure 1. C Figure 1. D Figure 1. E Figure 1. F Figure 1. G Figure 1. H Figure 2. Figure 2. Figure 2. Figure 2. Figure 2. Figure 2. Figure 3. A Figure 3. B PMID:9347896

Bain, L J; McLachlan, J B; LeBlanc, G A

1997-01-01

106

Introducing Spectral Structure Activity Relationship (S-SAR) Analysis. Application to Ecotoxicology  

PubMed Central

A novel quantitative structure-activity (property) relationship model, namely Spectral-SAR, is presented in an exclusive algebraic way replacing the old-fashioned multi-regression one. The actual S-SAR method interprets structural descriptors as vectors in a generic data space that is further mapped into a full orthogonal space by means of the Gram-Schmidt algorithm. Then, by coordinated transformation between the data and orthogonal spaces, the S-SAR equation is given under simple determinant form for any chemical-biological interactions under study. While proving to give the same analytical equation and correlation results with standard multivariate statistics, the actual S-SAR frame allows the introduction of the spectral norm as a valid substitute for the correlation factor, while also having the advantage to design the various related SAR models through the introduced “minimal spectral path” rule. An application is given performing a complete S-SAR analysis upon the Tetrahymena pyriformis ciliate species employing its reported eco-toxicity activities among relevant classes of xenobiotics. By representing the spectral norm of the endpoint models against the concerned structural coordinates, the obtained S-SAR endpoints hierarchy scheme opens the perspective to further design the ecotoxicological test batteries with organisms from different species.

Putz, Mihai V.; Lacr?m?, Ana-Maria

2007-01-01

107

Targeted Mutations of Bacillus anthracis Dihydrofolate Reductase Condense Complex Structure-Activity Relationships  

SciTech Connect

Several antifolates, including trimethoprim (TMP) and a series of propargyl-linked analogues, bind dihydrofolate reductase from Bacillus anthracis (BaDHFR) with lower affinity than is typical in other bacterial species. To guide lead optimization for BaDHFR, we explored a new approach to determine structure-activity relationships whereby the enzyme is altered and the analogues remain constant, essentially reversing the standard experimental design. Active site mutants of the enzyme, Ba(F96I)DHFR and Ba(Y102F)DHFR, were created and evaluated with enzyme inhibition assays and crystal structures. The affinities of the antifolates increase up to 60-fold with the Y102F mutant, suggesting that interactions with Tyr 102 are critical for affinity. Crystal structures of the enzymes bound to TMP and propargyl-linked inhibitors reveal the basis of TMP resistance and illuminate the influence of Tyr 102 on the lipophilic linker between the pyrimidine and aryl rings. Two new inhibitors test and validate these conclusions and show the value of the technique for providing new directions during lead optimization.

J Beierlein; N Karri; A Anderson

2011-12-31

108

Structure-hepatoprotective activity relationship study of sesquiterpene lactones: A QSAR analysis  

NASA Astrophysics Data System (ADS)

This study has been carried out using quantitative structure-activity relationship analysis (QSAR) for 22 sesquiterpene lactones to correlate and predict their hepatoprotective activity. Sesquiterpenoids, the largest class of terpenoids, are a widespread group of substances occurring in various plant organisms. QSAR analysis was carried out using methods such as genetic algorithm for variables selection among generated and calculated descriptors and multiple linear regression analysis. Quantum-chemical calculations have been performed by density functional theory at B3LYP/6-311G(d, p) level for evaluation of electronic properties using reference geometries optimized by semi-empirical AM1 approach. Three models describing hepatoprotective activity values for series of sesquiterpene lactones are proposed. The obtained models are useful for description of sesquiterpene lactones hepatoprotective activity and can be used to estimate the hepatoprotective activity of new substituted sesquiterpene lactones. The models obtained in our study show not only statistical significance, but also good predictive ability. The estimated predictive ability (rtest2) of these models lies within 0.942-0.969.

Paukku, Yuliya; Rasulev, Bakhtiyor; Syrov, Vladimir; Khushbaktova, Zainab; Leszczynski, Jerzy

109

Synthesis, biological evaluation and structure-activity relationships of new quinoxaline derivatives as anti-Plasmodium falciparum agents.  

PubMed

We report the synthesis and antimalarial activities of eighteen quinoxaline and quinoxaline 1,4-di-N-oxide derivatives, eight of which are completely novel. Compounds 1a and 2a were the most active against Plasmodium falciparum strains. Structure-activity relationships demonstrated the importance of an enone moiety linked to the quinoxaline ring. PMID:24552985

Gil, Ana; Pabón, Adriana; Galiano, Silvia; Burguete, Asunción; Pérez-Silanes, Silvia; Deharo, Eric; Monge, Antonio; Aldana, Ignacio

2014-01-01

110

Selective COX-2 Inhibitors: A Review of Their Structure-Activity Relationships  

PubMed Central

Non-steroidal anti-inflammatory drugs (NSAIDs) are the competitive inhibitors of cyclooxygenase (COX), the enzyme which mediates the bioconversion of arachidonic acid to inflammatory prostaglandins (PGs). Their use is associated with the side effects such as gastrointestinal and renal toxicity. The therapeutic anti-inflammatory action of NSAIDs is produced by the inhibition of COX-2, while the undesired side effects arise from inhibition of COX-1 activity. Thus, it was though that more selective COX-2 inhibitors would have reduced side effects. Based upon a number of selective COX-2 inhibitors (rofecoxib, celecoxib, valdecoxibetc.) were developed as safer NSAIDs with improved gastric safety profile. However, the recent market removal of some COXIBs such as rofecoxib due to its adverse cardiovascular side effects clearly encourages the researchers to explore and evaluate alternative templates with COX-2 inhibitory activity. Recognition of new avenues for selective COX-2 inhibitors in cancer chemotherapy and neurological diseases such as Parkinson and Alzheimer’s diseases still continues to attract investigations on the development of COX-2 inhibitors. This review highlights the various structural classes of selective COX-2 inhibitors with special emphasis on their structure-activity relationships. PMID:24250402

Zarghi, Afshin; Arfaei, Sara

2011-01-01

111

Structure–activity relationship of memapsin 2: implications on physiological functions and Alzheimer's disease  

PubMed Central

Memapsin 2 (BACE1, ?-secretase), a membrane aspartic protease, functions in the cleavage of the type I transmembrane protein, ?-amyloid precursor protein (APP), leading to the production of amyloid ? (A?) in the brain. Since A? is closely associated with the pathogenesis of Alzheimer's disease, understanding the biological function, particularly the catalytic activities of memapsin 2, would assist in a better understanding of the disease and the development of its inhibitors. The transmembrane and cytosolic domains of memapsin 2 function in cellular transport and localization, which are important regulatory mechanisms for its activity. The catalytic ectodomain contains a long substrate cleft that is responsible for substrate recognition, specificity, and peptide bond hydrolysis. The substrate cleft accommodates 11 residues of the substrate in separate binding subsites. Besides APP, a number of membrane proteins have been reported to be substrates of memapsin 2. The elucidation for the specificity of these subsites and the amino acid sequences surrounding the memapsin 2 cleavage site in these proteins has led to the establishment of a predictive model that can quantitatively estimate the efficiency of cleavage for any potential substrates. Such tools may be employed for future studies of memapsin 2 about its biological function. Herein, we review the current knowledge on the structure–function relationship of memapsin 2 and its relationship in the biological function. PMID:23676825

Li, Xiaoman; Hong, Lin; Coughlan, Kathleen; Wang, Liang; Cao, Liu; Tang, Jordan

2013-01-01

112

Structure-activity relationships for chloro- and nitrophenol toxicity in the pollen tube growth test  

SciTech Connect

Acute toxicity of 10 chlorophenols and 10 nitrophenols with identical substitution patterns is analyzed with the pollen tube growth (PTG) test. Concentration values of 50% growth inhibition (IC50) between 0.1 and 300 mg/L indicate that the absolute sensitivity of this alternative biotest is comparable to conventional aquatic test systems. Analysis of quantitative structure-activity relationships using lipophilicity (log K{sub ow}), acidity (pK{sub a}), and quantum chemical parameters to model intrinsic acidity, solvation interactions, and nucleophilicity reveals substantial differences between the intraseries trends of log IC50. With chlorophenols, a narcotic-type relationship is derived, which, however, shows marked differences in slope and intercept when compared to reference regression equations for polar narcosis. Regression analysis of nitrophenol toxicity suggests interpretation in terms of two modes of action: oxidative uncoupling activity is associated with a pK{sub a} window from 3.8 to 8.5, and more acidic congeners with diortho-substitution show a transition from uncoupling to a narcotic mode of action with decreasing pK{sub a} and log K{sub ow}. Model calculations for phenol nucleophilicity suggest that differences in the phenol readiness for glucuronic acid conjugation as a major phase-II detoxication pathway have no direct influence on acute PTG toxicity of the compounds.

Schueuermann, G. [UFZ Centre for Environmental Research, Leipzig (Germany). Dept. of Chemical Ecotoxicology; Somashekar, R.K. [Bangalore Univ. (India). Dept. of Botany; Kristen, U. [Univ. Hamburg (Germany). Inst. fuer Allgemeine Botanik

1996-10-01

113

Structure-activity relationship of a glycolipid, sulfoquinovosyl diacylglycerol, with the DNA binding activity of p53.  

PubMed

The in vitro relationship between the human p53 DNA binding domain (p53 DBD) and glycolipids was investigated. We isolated the glycolipid fraction from spinach (Spinacia oleracea L.) and found that the fraction inhibited the double-stranded DNA (dsDNA) binding activity of p53 DBD. Since the fraction contained mainly three glycolipids, monogalactosyl diacylglycerol (MGDG), digalactosyl diacylglycerol (DGDG) and sulfoquinovosyl diacylglycerol (SQDG), and each glycolipid was purified using silica gel column chromatography. Purified SQDG inhibited the activity, however, purified MGDG and DGDG had no influence. In this study, we demonstrated the structure-function relationship between chemically synthetic SQDG and p53 DBD. The major action is probably dependent on the fatty acid effect, although SQDG was a much stronger inhibitor than the fatty acid alone present in SQDG. The inhibitory activity of SQDG was weakened by the R248A mutant of p53 DBD, suggesting that R248 in the dsDNA binding site of p53 must be important for the inhibitory activity of SQDG. SQDG binding to p53 DBD could be reversed with a non-ionic detergent, Nonidet P-40. This is the first study of a glycolipid, SQDG, acting as a dsDNA binding inhibitor of p53, and it could be considered that a SQDG-containing thylakoid membrane in plant chloroplasts might regulate the activity of p53 for cell division, cell cycle checkpoint and tumor suppression. PMID:17143546

Iijima, Hiroshi; Kasai, Nobuyuki; Chiku, Hiroyuki; Takeuchi, Toshifumi; Kuramochi, Kouji; Hanashima, Shinya; Kobayashi, Susumu; Sugawara, Fumio; Sakaguchi, Kengo; Yoshida, Hiromi; Mizushina, Yoshiyuki

2007-01-01

114

In vitro anti-cancer activity and structure–activity relationships of natural products isolated from fruits of Panax ginseng  

Microsoft Academic Search

Purpose  \\u000a Panax ginseng and its extracts have long been used for medical purposes; there is increasing interest in developing ginseng products as\\u000a cancer preventive or therapeutic agents. The present study was designed to determine biological structure–activity relationships\\u000a (SAR) for saponins present in Panax ginseng fruits.\\u000a \\u000a \\u000a \\u000a Methods  Eleven saponins were extracted from P. ginseng fruits and purified by use of D101 resin

Wei Wang; Yuqing Zhao; Elizabeth R. Rayburn; Donald L. Hill; Hui Wang; Ruiwen Zhang

2007-01-01

115

Amyloid-? probes: Review of structure–activity and brain-kinetics relationships  

PubMed Central

Summary The number of people suffering from Alzheimer’s disease (AD) is expected to increase dramatically in the coming years, placing a huge burden on society. Current treatments for AD leave much to be desired, and numerous research efforts around the globe are focused on developing improved therapeutics. In addition, current diagnostic tools for AD rely largely on subjective cognitive assessment rather than on identification of pathophysiological changes associated with disease onset and progression. These facts have led to numerous efforts to develop chemical probes to detect pathophysiological hallmarks of AD, such as amyloid-? plaques, for diagnosis and monitoring of therapeutic efficacy. This review provides a survey of chemical probes developed to date for AD with emphasis on synthetic methodologies and structure–activity relationships with regards to affinity for target and brain kinetics. Several probes discussed herein show particularly promising results and will be of immense value moving forward in the fight against AD. PMID:23766818

Eckroat, Todd J; Mayhoub, Abdelrahman S

2013-01-01

116

Neuroprotective peptide-macrocycle conjugates reveal complex structure-activity relationships in their interactions with amyloid ?.  

PubMed

Interactions between amyloid ? (A?) and metal ions are thought to mediate the neuropathogenic effects of A? in Alzheimer's disease. The construction of small molecules capable of synergistically chelating metal ions and recognizing A? would allow new insights into the biology of this disease and provide a possible therapeutic approach. We report herein the synthesis and biological evaluation of tetraazamacrocycle-(G)KLVFF hybrids and their metal complexes. The results obtained from ThT and bis-ANS extrinsic fluorescence assays, tyrosine intrinsic fluorescence assay and proteolytic assay imply complex, multifaceted structure-activity relationships in the interaction of these conjugates with A?. Many of the compounds tested rescued cells from A?-induced cytotoxicity. The attendant simplicity and ready diversification of the synthesis of these conjugates makes them attractive for further investigation. PMID:25132118

Yu, Mingfeng; Ryan, Timothy M; Ellis, Samantha; Bush, Ashley I; Triccas, James A; Rutledge, Peter J; Todd, Matthew H

2014-10-01

117

Design, Synthesis, and Structure-Activity Relationships of Highly Potent 5-HT3 Receptor Ligands  

PubMed Central

The 5-HT3 receptor, a pentameric ligand-gated ion channel (pLGIC), is an important therapeutic target. During a recent fragment screen, 6-chloro-N-methyl-2-(4-methyl-1,4-diazepan-1-yl)quinazolin-4-amine (1) was identified as a 5-HT3R hit fragment. Here we describe the synthesis and structure–activity relationships (SAR) of a series of (iso)quinoline and quinazoline compounds that were synthesized and screened for 5-HT3R affinity using a [3H]granisetron displacement assay. These studies resulted in the discovery of several high affinity ligands of which compound 22 showed the highest affinity (pKi > 10) for the 5-HT3 receptor. The observed SAR is in agreement with established pharmacophore models for 5-HT3 ligands and is used for ligand–receptor binding mode prediction using homology modeling and in silico docking approaches. PMID:23006041

2012-01-01

118

Structure-activity relationship study of novel anticancer aspirin-based compounds  

PubMed Central

We performed a structure-activity relationship (SAR) study of a novel aspirin (ASA) derivative, which shows strong anticancer activity in vitro and in vivo. A series of ASA-based benzyl esters (ABEs) were synthesized and their inhibitory activity against human colon (HT-29 and SW480) and pancreatic (BxPC-3 and MIA PaCa-2) cancer cell lines was evaluated. The ABEs that we studied largely comprise organic benzyl esters bearing an ASA or acyloxy group (X) at the meta or para position of the benzyl ring and one of four different leaving groups. The nature of the salicyloyl/acyloxy function, the leaving group, and the additional substituents affecting the electron density of the benzyl ring, all were influential determinants of the inhibitory activity on cancer cell growth for each ABE. Positional isomerism also played a significant role in this effect. The mechanism of action of these compounds appears consistent with the notion that they generate either a quinone methide or an m-oxybenzyl zwitterion (or an m-hydroxybenzyl cation), which then reacts with a nucleophile, mediating their biological effect. Our SAR study provides an insight into the biological properties of this novel class of compounds and underscores their potential as anticancer agents. PMID:21805049

JOSEPH, STANCY; NIE, TING; HUANG, LIQUN; ZHOU, HUI; ATMAKUR, KRISHNAIAH; GUPTA, RAMESH C.; JOHNSON, FRANCIS; RIGAS, BASIL

2013-01-01

119

Syntheses and structure-activity relationships in cytotoxicities of 13-substituted quaternary coptisine derivatives.  

PubMed

Twenty five 13-substituted quaternary coptisine derivatives were synthesized to test their cytotoxicities against several cancer cell-lines and on intestinal epithelial cell-6 (IEC-6) in vitro to evaluate structure-activity relationship (SAR). Introduction of the alkyl groups into the C-13 position of quaternary coptisine (1) led to significant increase of the cytotoxic activity, while the substitution of arylmethyl groups and others at the same position showed no effect on improving cytotoxicities against the same cancer cell-lines. The cytotoxicities of quaternary 13-alkylcoptisines was significantly reinforced as the length of the aliphatic chain increased, with quaternary 13-n-undecylcoptisine (4l) showing 7, 23, 12, and 9 times, respectively, more active than quaternary coptisine (1) against HCT, A549, Bel7402, and C33A, and being 4, 11, 2, and 3 times, respectively, more active than the positive control, fluorouracil (5-FU), against the same cell-lines, by IC50 values. In comparison to quaternary 13-n-undecylcoptisine (4l) and the above references, quaternary 13-n-dodecylcoptisine (4m) almost showed the same cytotoxicities. In contrast with the n-alkyl chains, the arylmethyl substituents at C-13 displayed low cytotoxicity, except for naphthyl rings or phenyl rings with CF3 or methyl substituents. However, their low cytotoxicity could make them useful as drug candidates for other diseases (bowel, etc). PMID:25203783

Zhang, Zhi-Hui; Deng, An-Jun; Wu, Lian-Qiu; Fang, Lian-Hua; Yu, Jin-Qian; Li, Zhi-Hong; Yuan, Tian-Yi; Wang, Wen-Jie; Du, Guan-Hua; Qin, Hai-Lin

2014-10-30

120

Antioxidant properties of phenolic Schiff bases: structure-activity relationship and mechanism of action.  

PubMed

Phenolic Schiff bases are known for their diverse biological activities and ability to scavenge free radicals. To elucidate (1) the structure-antioxidant activity relationship of a series of thirty synthetic derivatives of 2-methoxybezohydrazide phenolic Schiff bases and (2) to determine the major mechanism involved in free radical scavenging, we used density functional theory calculations (B3P86/6-31+(d,p)) within polarizable continuum model. The results showed the importance of the bond dissociation enthalpies (BDEs) related to the first and second (BDEd) hydrogen atom transfer (intrinsic parameters) for rationalizing the antioxidant activity. In addition to the number of OH groups, the presence of a bromine substituent plays an interesting role in modulating the antioxidant activity. Theoretical thermodynamic and kinetic studies demonstrated that the free radical scavenging by these Schiff bases mainly proceeds through proton-coupled electron transfer rather than sequential proton loss electron transfer, the latter mechanism being only feasible at relatively high pH. PMID:24243063

Anouar, El Hassane; Raweh, Salwa; Bayach, Imene; Taha, Muhammad; Baharudin, Mohd Syukri; Di Meo, Florent; Hasan, Mizaton Hazizul; Adam, Aishah; Ismail, Nor Hadiani; Weber, Jean-Frédéric F; Trouillas, Patrick

2013-11-01

121

Structure-activity relationships for perfluoroalkane-induced in vitro interference with rat liver mitochondrial respiration?  

PubMed Central

Perfluorinated alkyl acids (PFAAs) represent a broad class of commercial products designed primarily for the coatings industry. However, detection of residues globally in a variety of species led to the discontinuation of production in the U.S. Although PFAAs cause activation of the PPAR? and CAR nuclear receptors, interference with mitochondrial bioenergetics has been implicated as an alternative mechanism of cytotoxicity. Although the mechanisms by which the eight carbon chain PFAAs interfere with mitochondrial bioenergetics are fairly well described, the activities of the more highly substituted or shorter chain PFAAs are far less well characterized. The current investigation was designed to explore structure–activity relationships by which PFAAs interfere with mitochondrial respiration in vitro. Freshly isolated rat liver mitochondria were incubated with one of 16 different PFAAs, including perfluorinated carboxylic, acetic, and sulfonic acids, sulfonamides and sulfamido acetates, and alcohols. The effect on mitochondrial respiration was measured at five concentrations and dose–response curves were generated to describe the effects on state 3 and 4 respiration and respiratory control. With the exception of PFOS, all PFAAs at sufficiently high concentrations (>20 ?M) stimulated state 4 and inhibited state 3 respiration. Stimulation of state 4 respiration was most pronounced for the carboxylic acids and the sulfonamides, which supports prior evidence that the perfluorinated carboxylic and acetic acids induce the mitochondrial permeability transition, whereas the sulfonamides are protonophoric uncouplers of oxidative phosphorylation. In both cases, potency increased with increasing carbon number, with a prominent inflection point between the six and eight carbon congeners. The results provide a foundation for classifying PFAAs according to specific modes of mitochondrial activity and, in combination with toxicokinetic considerations, establishing structure–activity-based boundaries for initial estimates of risk for noncancer endpoints for PFAAs for which minimal in vivo toxicity testing currently exists. PMID:23954199

Wallace, K.B.; Kissling, G.E.; Melnick, R.L.; Blystone, C.R.

2014-01-01

122

Structure-activity and structure-affinity relationships of 19-nor-progesterone derivatives in rat uterus.  

PubMed

19-nor-progesterone (19NP) is a potent progestagen which possesses a high affinity for the progesterone receptor (PgR). In contrast, 17 alpha-hydroxylated-progesterone (17OHP) shows no hormonal activity and does not compete with progesterone (P) for the PgR. The aim of the present work was to analyse in parallel the structure-affinity and the structure-activity relationships for new molecules obtained by modifications of 19NP and 17OHP. The attachment of a 17 alpha-hydroxyl group on 19NP led to a dramatic decrease in both affinity and activity for the end-product, 17 alpha-hydroxylated-19-nor-progesterone (17OH-19NP). The further addition of a methyl group combined with the formation of a double-bound at C6 on 17OH-19NP results in nomegestrol (NOM), the relative affinity of which remained low. Negligible activity was also associated with this affinity in comparison to the parent 19NP. Strikingly, the protection of the free 17 alpha-hydroxyl group of NOM by an acetate led to a potent progestin with high affinity for PgR. It is concluded that the sum of the modifications brought into the 17OHP-19NP molecule reestablishes both affinity and activity of the original 19NP molecule. The same conclusion holds if P is considered as the parent compound, as already stated in the literature. PMID:2090671

Botella, J; Duc, I; Delansorne, R; Paris, J; Lahlou, B

1990-12-01

123

Improved Quantitative Structure-Activity Relationship Models to Predict Antioxidant Activity of Flavonoids in Chemical, Enzymatic, and Cellular Systems  

PubMed Central

Quantitative structure-activity relationship (QSAR) models are useful in understanding how chemical structure relates to the biological activity of natural and synthetic chemicals and for design of newer and better therapeutics. In the present study, 46 flavonoids and related polyphenols were evaluated for direct/indirect antioxidant activity in three different assay systems of increasing complexity (chemical, enzymatic, and intact phagocytes). Based on these data, two different QSAR models were developed using i) physicochemical and structural (PC&S) descriptors to generate multiparameter partial least squares (PLS) regression equations derived from optimized molecular structures of the tested compounds and ii) a partial 3D comparison of the 46 compounds with local fingerprints obtained from fragments of the molecules by the frontal polygon (FP) method. We obtained much higher QSAR correlation coefficients (r) for flavonoid end-point antioxidant activity in all 3 assay systems using the FP method (0.966, 0.948, and 0.965 for datasets in evaluated in the biochemical, enzymatic, and whole cells assay systems, respectively). Furthermore, high leave-one-out cross-validation coefficients (q2) of 0.907, 0.821, and 0.897 for these datasets, respectively, indicated enhanced predictive ability and robustness of the model. Using the FP method, structural fragments (submolecules) responsible for the end-point antioxidant activity in the three assay systems were also identified. To our knowledge, this is the first QSAR model derived for description of flavonoid direct/indirect antioxidant effects in a cellular system, and this model could form the basis for further drug development of flavonoid-like antioxidant compounds with therapeutic potential. PMID:17166721

Khlebnikov, Andrei I.; Schepetkin, Igor A.; Domina, Nina G.; Kirpotina, Liliya N.; Quinn, Mark T.

2007-01-01

124

Synthesis and structure-activity relationship of thiobarbituric acid derivatives as potent inhibitors of urease.  

PubMed

A series of thiobarbituric acid derivatives 1-27 were synthesized and evaluated for their urease inhibitory potential. Exciting results were obtained from the screening of these compounds 1-27. Compounds 5, 7, 8, 11, 16, 17, 22, 23 and 24 showed excellent urease inhibition with IC50 values 18.1 ± 0.52, 16.0 ± 0.45, 16.0 ± 0.22, 14.3 ± 0.27, 6.7 ± 0.27, 10.6 ± 0.17, 19.2 ± 0.29, 18.2 ± 0.76 and 1.61 ± 0.18 ?M, respectively, much better than the standard urease inhibitor thiourea (IC??=21 ± 0.11 ?M). Compound 3, 4, 10, and 26 exhibited comparable activities to the standard with IC?? values 21.4 ± 1.04 and 21.5 ± 0.61 ?M, 22.8 ± 0.32, 25.2 ± 0.63, respectively. However the remaining compounds also showed prominent inhibitory potential The structure-activity relationship was established for these compounds. This study identified a novel class of urease inhibitors. The structures of all compounds were confirmed through spectroscopic techniques such as EI-MS and (1)H NMR. PMID:24986232

Khan, Khalid Mohammed; Rahim, Fazal; Khan, Ajmal; Shabeer, Muhammad; Hussain, Shafqat; Rehman, Wajid; Taha, Muhammad; Khan, Momin; Perveen, Shahnaz; Choudhary, M Iqbal

2014-08-01

125

Gold(i) thiolates containing amino acid moieties. Cytotoxicity and structure-activity relationship studies.  

PubMed

Several gold(i) complexes containing a thiolate ligand functionalised with several amino acid or peptide moieties of the type [Au(SPyCOR)(PPh2R')] (where R = OH, amino acid or dipeptide and R' = Ph or Py) were prepared. These thiolate gold complexes bearing biological molecules possess potential use as antitumor agents. Cytotoxicity assays in different tumour cell lines such as A549 (lung carcinoma), Jurkat (T-cell leukaemia) and MiaPaca2 (pancreatic carcinoma) revealed that the complexes exhibit good antiproliferative activity, with IC50 values in the low micromolar range. Several structural modifications such as in the type of phosphine, number of metal atoms and amino acid (type, stereochemistry and functionalisation) were carried out in order to establish the structure-activity relationship in this family of complexes, which has led to the design of new and more potent cytotoxic complexes. Observations of different cellular events after addition of the complexes indicated the possible mechanism of action or the biological targets of this type of new gold(i) drug. PMID:25302929

Gutiérrez, Alejandro; Gracia-Fleta, Lucia; Marzo, Isabel; Cativiela, Carlos; Laguna, Antonio; Gimeno, M Concepción

2014-10-28

126

Acute toxicity estimation by calculation--Tubifex assay and quantitative structure-activity relationships.  

PubMed

A quantitative structure-activity relationship (QSAR) model dependent on log P(n - octanol/water), or log P(OW), was developed with acute toxicity index EC50, the median effective concentration measured as inhibition of movement of the oligochaeta Tubifex tubifex with 3 min exposure, EC50(Tt) (mol/L): log EC50(Tt) = -0.809 (+/-0.035) log P(OW) - 0.495 (+/-0.060), n=82, r=0.931, r2=0.867, residual standard deviation of the estimate 0.315. A learning series for the QSAR model with the oligochaete contained alkanols, alkenols, and alkynols; saturated and unsaturated aldehydes; aniline and chlorinated anilines; phenol and chlorinated phenols; and esters. Three cross-validation procedures proved the robustness and stability of QSAR models with respect to the chemical structure of compounds tested within a series of compounds used in the learning series. Predictive ability was described by q2 .801 (cross-validated r2; predicted variation estimated with cross-validation) in LSO (leave-a structurally series-out) cross-validation. PMID:18522479

Tichý, Milon; Rucki, Marian; Hanzlíková, Iveta; Roth, Zdenek

2008-11-01

127

Molecular-orbital analysis of the electronic structure and determination of quantitative structure-activity and structure-toxicity relationships for water-soluble ionol derivatives  

SciTech Connect

In this paper the authors attempt to establish a quantitative relationship between experimental data on antitumor activity and the toxicity of ionol and its derivatives on the one hand, and on the other hand the electronic structure parameters of the compounds obtained as a result of the quantum chemical calculation.

Bushelev, S.N.

1985-08-01

128

2-Substituted-5-nitroheterocycles: in vitro anti-Helicobacter pylori activity and structure-activity relationship study.  

PubMed

Helicobacter pylori infection is the main cause of gastritis and gastroduodenal ulcer disease, and is associated with gastric cancer. In order to develop new potential anti-Helicobacter pylori candidates, we have investigated the antimicrobial activity of some 2-substituted-5-nitroheterocycles against H. pylori. The anti-Helicobacter pylori activity of selected compounds along with commercially available antibacterial metronidazole was evaluated by comparing the inhibition zone diameters determined using the paper disc diffusion bioassay. The compounds that exhibited strong anti-H. pylori activity at concentration of 8-32 microg/disc (average of inhibition zone >20 mm) were further tested against 20 clinical isolates of H. pylori at lower concentrations. In general, we have identified a series of 5-nitroheterocyles including nitrofurans, nitrothiophenes and nitroimidazoles bearing a carboxaldehyde thiosemicarbazone or 2-substituted-1,3,4-thiadiazole residues in the 2-position of the 5-nitroheteroaryl ring as potent anti- Helicobacter pylori agents. It was found that chloro-/ amino-/ mercapto-substituted 1,3,4-thiadiazole moiety attached to 5-nitroheteroaryl ring served as promising C-2 substituents for 2-substituted-5-nitroheterocycles. The Structure-activity relationship of this series indicates that both the structure of the nitroaryl scaffold and the C-2 attached residue have dramatic impact on anti-Helicobacter pylori activity. PMID:19673692

Foroumadi, Alireza; Sorkhi, Maedeh; Moshafi, Mohammad Hassan; Safavi, Maliheh; Rineh, Ardeshir; Siavoshi, Farideh; Shafiee, Abbas; Emami, Saeed

2009-11-01

129

Quantitative structure-activity relationship models for ready biodegradability of chemicals.  

PubMed

The European REACH regulation requires information on ready biodegradation, which is a screening test to assess the biodegradability of chemicals. At the same time REACH encourages the use of alternatives to animal testing which includes predictions from quantitative structure-activity relationship (QSAR) models. The aim of this study was to build QSAR models to predict ready biodegradation of chemicals by using different modeling methods and types of molecular descriptors. Particular attention was given to data screening and validation procedures in order to build predictive models. Experimental values of 1055 chemicals were collected from the webpage of the National Institute of Technology and Evaluation of Japan (NITE): 837 and 218 molecules were used for calibration and testing purposes, respectively. In addition, models were further evaluated using an external validation set consisting of 670 molecules. Classification models were produced in order to discriminate biodegradable and nonbiodegradable chemicals by means of different mathematical methods: k nearest neighbors, partial least squares discriminant analysis, and support vector machines, as well as their consensus models. The proposed models and the derived consensus analysis demonstrated good classification performances with respect to already published QSAR models on biodegradation. Relationships between the molecular descriptors selected in each QSAR model and biodegradability were evaluated. PMID:23469921

Mansouri, Kamel; Ringsted, Tine; Ballabio, Davide; Todeschini, Roberto; Consonni, Viviana

2013-04-22

130

Synthesis, antifungal activities and qualitative structure activity relationship of carabrone hydrazone derivatives as potential antifungal agents.  

PubMed

Aimed at developing novel fungicides for relieving the ever-increasing pressure of agricultural production caused by phytopathogenic fungi, 28 new hydrazone derivatives of carabrone, a natural bioactive sesquisterpene, in three types were designed, synthesized and their antifungal activities against Botrytis cinerea and Colletotrichum lagenarium were evaluated. The result revealed that all the derivatives synthesized exhibited considerable antifungal activities in vitro and in vivo, which led to the improved activities for carabrone and its analogues and further confirmed their potential as antifungal agents. PMID:24619221

Wang, Hao; Ren, Shuang-Xi; He, Ze-Yu; Wang, De-Long; Yan, Xiao-Nan; Feng, Jun-Tao; Zhang, Xing

2014-01-01

131

Synthesis, Antifungal Activities and Qualitative Structure Activity Relationship of Carabrone Hydrazone Derivatives as Potential Antifungal Agents  

PubMed Central

Aimed at developing novel fungicides for relieving the ever-increasing pressure of agricultural production caused by phytopathogenic fungi, 28 new hydrazone derivatives of carabrone, a natural bioactive sesquisterpene, in three types were designed, synthesized and their antifungal activities against Botrytis cinerea and Colletotrichum lagenarium were evaluated. The result revealed that all the derivatives synthesized exhibited considerable antifungal activities in vitro and in vivo, which led to the improved activities for carabrone and its analogues and further confirmed their potential as antifungal agents. PMID:24619221

Wang, Hao; Ren, Shuang-Xi; He, Ze-Yu; Wang, De-Long; Yan, Xiao-Nan; Feng, Jun-Tao; Zhang, Xing

2014-01-01

132

Structure-activity Relationship Analysis of N-Benzoylpyrazoles for Elastase Inhibitory Activity: A Simplified Approach Using Atom Pair Descriptors  

PubMed Central

Previously, we utilized high throughput screening of a chemical diversity library to identify potent inhibitors of human neutrophil elastase and found that many of these compounds had N-benzoylpyrazole core structures. We also found individual ring substituents had significant impact on elastase inhibitory activity and compound stability. In the present study, we utilized computational structure–activity relationship (SAR) analysis of a series of 53 N-benzoylpyrazole derivatives to further optimize these lead molecules. We present an improved approach to SAR methodology based on atom pair descriptors in combination with 2-dimentional (2D) molecular descriptors. This approach utilizes the rich representation of chemical structure and leads to SAR analysis that is both accurate and intuitively easy to understand. A sequence of ANOVA, linear discriminant, and binary classification tree analyses of the molecular descriptors led to the derivation of SAR rule-based algorithms. These rules revealed that the main factors influencing elastase inhibitory activity of N-benzoylpyrazole molecules were the presence of methyl groups in the pyrazole moiety and ortho-substituents in the benzoyl radical. Furthermore, our data showed that physicochemical characteristics (energy of frontier molecular orbitals, molar refraction, lipophilicity) were not necessary for achieving good SAR, as comparable quality of SAR classification was obtained with atom pairs and 2D descriptors only. This simplified SAR approach may be useful to qualitative SAR recognition problems in a variety of data sets. PMID:18234502

Khlebnikov, Andrei I.; Schepetkin, Igor A.; Quinn, Mark T.

2008-01-01

133

Antinociceptive activity and preliminary structure-activity relationship of chalcone-like compounds.  

PubMed

Chalcones belong to a class of alpha,beta,-unsaturated aromatic ketones which occur abundantly in nature, especially in plants. They are promising and interesting compounds due to their vast applications in pharmaceuticals, agriculture and industry. Several studies have shown that these compounds exert important biological activities in different experimental models. The present work deals with the antinociceptive activity, evaluated against the writhing test, of three series of chalcone-like compounds obtained by the Claisen-Schmidt condensation, using different aldehydes and substituted acetophenones. The results reveal that the compounds synthesized show a significant antinociceptive effect compared with nonsteroidal drugs such as aspirin, paracetamol and diclofenac. They also show that the electronic demand of the substituents is the dominant factor of the biological activity. PMID:19227830

Corrêa, Rogério; Fenner, Bruna Proiss; Buzzi, Fátima de Campos; Cechinel Filho, Valdir; Nunes, Ricardo José

2008-01-01

134

Structural design, synthesis and structure-activity relationships of thiazolidinones with enhanced anti-Trypanosoma cruzi activity.  

PubMed

Pharmacological treatment of Chagas disease is based on benznidazole, which displays poor efficacy when administered during the chronic phase of infection. Therefore, the development of new therapeutic options is needed. This study reports on the structural design and synthesis of a new class of anti-Trypanosoma cruzi thiazolidinones (4?a-p). (2-[2-Phenoxy-1-(4-bromophenyl)ethylidene)hydrazono]-5-ethylthiazolidin-4-one (4?h) and (2-[2-phenoxy-1-(4-phenylphenyl)ethylidene)hydrazono]-5-ethylthiazolidin-4-one (4?l) were the most potent compounds, resulting in reduced epimastigote proliferation and were toxic for trypomastigotes at concentrations below 10??M, while they did not display host cell toxicity up to 200??M. Thiazolidinone 4?h was able to reduce the in vitro parasite burden and the blood parasitemia in mice with similar potency to benznidazole. More importantly, T.?cruzi infection reduction was achieved without exhibiting mouse toxicity. Regarding the molecular mechanism of action, these thiazolidinones did not inhibit cruzain activity, which is the major trypanosomal protease. However, investigating the cellular mechanism of action, thiazolidinones altered Golgi complex and endoplasmic reticulum (ER) morphology, produced atypical cytosolic vacuoles, as well as induced necrotic parasite death. This structural design employed for the new anti-T.?cruzi thiazolidinones (4?a-p) led to the identification of compounds with enhanced potency and selectivity compared to first-generation thiazolidinones. These compounds did not inhibit cruzain activity, but exhibited strong antiparasitic activity by acting as parasiticidal agents and inducing a necrotic parasite cell death. PMID:24203393

Moreira, Diogo Rodrigo Magalhães; Leite, Ana Cristina Lima; Cardoso, Marcos Verissimo Oliveira; Srivastava, Rajendra Mohan; Hernandes, Marcelo Zaldini; Rabello, Marcelo Montenegro; da Cruz, Luana Faria; Ferreira, Rafaela Salgado; de Simone, Carlos Alberto; Meira, Cássio Santana; Guimaraes, Elisalva Teixeira; da Silva, Aline Caroline; dos Santos, Thiago André Ramos; Pereira, Valéria Rêgo Alves; Soares, Milena Botelho Pereira

2014-01-01

135

Quantitative structure-activity relationship for toxicity of ionic liquids to Daphnia magna: aromaticity vs. lipophilicity.  

PubMed

Water solubility of ionic liquids (ILs) allows their dispersion into aquatic systems and raises concerns on their pollutant potential. Again, lipophilicity can contribute to the toxicity of ILs due to increased ability of the compounds to cross lipoidal bio-membranes. In the present work, we have performed statistical model development for toxicity of a set of ionic liquids to Daphnia magna, a widely accepted model organism for toxicity testing, using computed lipophilicity, atom-type fragment, quantum topological molecular similarity (QTMS) and extended topochemical atom (ETA) descriptors. The models have been developed and validated in accordance with the Organization for Economic Co-operation and Development (OECD) guidelines for quantitative structure-activity relationships (QSARs). The best partial least squares (PLS) model outperforms the previously reported multiple linear regression (MLR) model in statistical quality and predictive ability (R(2)=0.955, Q(2)=0.917, Rpred(2)=0.848). In this work, the ETA descriptors show importance of branching and aromaticity while the QTMS descriptor ellipticity efficiently shows which compounds are influential in the data set, with reference to the model. While obvious importance of lipophilicity is evident from the models, the best model clearly shows the importance of aromaticity suggesting that more lipophilic ILs with less toxicity may be designed by avoiding aromaticity, nitrogen atoms and increasing branching in the cationic structure. The developed quantitative models are in consonance with the recent hypothesis of importance of aromaticity for toxicity of ILs. PMID:25048897

Roy, Kunal; Das, Rudra Narayan; Popelier, Paul L A

2014-10-01

136

Tyrosinase inhibitory effect of benzoic acid derivatives and their structure-activity relationships.  

PubMed

A series of benzoic acid derivatives 1-10 have been synthesised by two different methods. Compounds 1-6 were synthesised by a facile procedure for esterification using N,N'-dicyclohexylcarbodiimide (DCC) as a coupling agent, methylene chloride as a solvent system and dimethylaminopyridine (DMAP). While 7-10 were synthesised by converting benzoic acid into benzoyl chloride by treating with thionyl chloride in the presence of benzene and performing a further reaction with amine in dried benzene. The structures of all the synthesised derivatives of benzoic acid (1-10) were assigned on the basis of extensive NMR studies. All of them showed inhibitory potential against tyrosinase. Among them, compound 7 was found to be the most potent (1.09 ?M) when compared with the standard tyrosinase inhibitors of kojic acid (16.67 ?M) and L-mimosine (3.68 ?M). Finally in this paper, we have discussed the structure-activity relationships of the synthesised molecules. PMID:20476840

Khan, Sher Bahadar; Hassan Khan, Mahmud Tareq; Jang, Eui Sung; Akhtar, Kalsoom; Seo, Jongchul; Han, Haksoo

2010-12-01

137

Structure–Activity Relationships for Antioxidant Activities of a Series of Flavonoids in a Liposomal System  

Microsoft Academic Search

Structurally diverse plant phenolics were examined for their abilities to inhibit lipid peroxidation induced either by Fe(II) and Fe(III) metal ions or by azo-derived peroxyl radicals in a liposomal membrane system. The antioxidant abilities of flavonoids were compared with those of coumarin and tert-butylhydroquinone (TBHQ). The antioxidant efficacies of these compounds were evaluated on the basis of their abilities to

Arti Arora; Muraleedharan G. Nair; Gale M. Strasburg

1998-01-01

138

Structure-activity relationship studies of argiotoxins: selective and potent inhibitors of ionotropic glutamate receptors.  

PubMed

Argiotoxin-636 (ArgTX-636), a natural product from the spider Argiope lobata, is a potent but nonselective open-channel blocker of ionotropic glutamate (iGlu) receptors. Here, three series of analogues were designed to exploit selectivity among iGlu receptors, taking advantage of a recently developed solid-phase synthetic methodology for the synthesis of ArgTX-636 and analogues. Initially, the importance of secondary amino groups in the polyamine chain was studied by the synthesis of systematically modified ArgTX-636 analogues, which were evaluated for pharmacological activity at NMDA and AMPA receptors. This led to the identification of two compounds with preference for NMDA and AMPA receptors, respectively. These were further elaborated by systematically changing the aromatic headgroup and linker amino acid leading to compounds with increased potency and selectivity for NMDA and AMPA receptors, respectively. Thus, the first structure-activity relationship study of ArgTX-636 has been carried out and has provided lead compounds for probing the ion channel region of iGlu receptors. PMID:23320429

Poulsen, Mette H; Lucas, Simon; Bach, Tinna B; Barslund, Anne F; Wenzler, Claudius; Jensen, Christel B; Kristensen, Anders S; Strømgaard, Kristian

2013-02-14

139

Syntheses and Structure-Activity Relationships of Novel 3'-Difluoromethyl and 3'-Trifluoromethyl-Taxoids.  

PubMed

A series of novel 3'-difluoromethyl-taxoids and 3'-trifluoromethyl-taxoids with modifications at the C2 and C10 positions were synthesized and evaluated for their in vitro cytotoxicities against human breast carcinoma (MCF7-S, MCF7-R, LCC6-WT, LCC6-MDR), non-small cell lung carcinoma (H460) and colon adenocarcinoma (HT-29) cell lines. These second-generation fluoro-taxoids exhibited several times to more than 20 times better potency than paclitaxel against drug-sensitive cancer cell lines, MCF7-S, LCC6-WT, H460, and HT-29. These fluoro-taxoids also possess two orders of magnitude higher potency than paclitaxel against drug-resistant cancer cell lines, MCF7-R and LCC6-MDR. Structure-activity relationship study shows the importance of the C10 modification for increasing the activity against multidrug-resistant cancer cell lines. Effects of the C2-benzoate modifications on the potency in the 3-difluoromethyl-taxoid series are very clear (i.e., F < MeO < Cl < N(3)), while those in the 3-trifluoromethyl-taxoid series are less obvious. Also, different trends in the sensitivity to the C2-substitution are observed between drug-sensitive cell lines and drug-resistant cancer cell lines that overexpress efflux pumps. PMID:19448839

Kuznetsova, Larissa V; Pepe, Antonella; Ungureanu, Ioana M; Pera, Paula; Bernacki, Ralph J; Ojima, Iwao

2008-01-01

140

Inhibition of cancer-associated mutant isocitrate dehydrogenases: synthesis, structure-activity relationship, and selective antitumor activity.  

PubMed

Mutations of isocitrate dehydrogenase 1 (IDH1) are frequently found in certain cancers such as glioma. Different from the wild-type (WT) IDH1, the mutant enzymes catalyze the reduction of ?-ketoglutaric acid to d-2-hydroxyglutaric acid (D2HG), leading to cancer initiation. Several 1-hydroxypyridin-2-one compounds were identified to be inhibitors of IDH1(R132H). A total of 61 derivatives were synthesized, and their structure-activity relationships were investigated. Potent IDH1(R132H) inhibitors were identified with Ki values as low as 140 nM, while they possess weak or no activity against WT IDH1. Activities of selected compounds against IDH1(R132C) were found to be correlated with their inhibitory activities against IDH1(R132H), as well as cellular production of D2HG, with R(2) of 0.83 and 0.73, respectively. Several inhibitors were found to be permeable through the blood-brain barrier in a cell-based model assay and exhibit potent and selective activity (EC50 = 0.26-1.8 ?M) against glioma cells with the IDH1 R132H mutation. PMID:25271760

Liu, Zhen; Yao, Yuan; Kogiso, Mari; Zheng, Baisong; Deng, Lisheng; Qiu, Jihui J; Dong, Shuo; Lv, Hua; Gallo, James M; Li, Xiao-Nan; Song, Yongcheng

2014-10-23

141

Chalcones as promising pesticidal agents against diamondback moth ( Plutella xylostella ): microwave-assisted synthesis and structure–activity relationship  

Microsoft Academic Search

A series of chalcones (A–CH=CH–CO–B) were synthesized under microwave irradiation, and for the first time their pesticidal activity against diamondback moth\\u000a (Plutella xylostella) was evaluated to identify the promising lead structures. The structure–activity relationship (SAR) analysis revealed that\\u000a electron-withdrawing substituents on ring A of chalcone provided good pesticidal agents, whereas, ring B can bear either electron-withdrawing or electron-releasing substituents. Moreover,

Rakesh Kumar; Prabha Sharma; Amit Shard; Dhananjay Kumar Tewary; Gireesh Nadda; Arun Kumar Sinha

142

Mechanism-based quantitative structure–activity relationships for the inhibition of substituted phenols on germination rate of Cucumis sativus  

Microsoft Academic Search

Comparative inhibition activity (GC50) of 42 structurally diverse substituted phenols on seed germination rate of Cucumis sativus was investigated. Quantitative structure–activity relationships (QSARs) were developed by using hydrophobicity (1-octanol\\/water partition coefficient, logKow) and electrophilicity (the energy of the lowest unoccupied molecule orbital, Elumo) for the toxicity of phenols according to their modes of toxic action. Most phenols elicited their response

Xiaodong Wang; Jianzhen Yu; Yu Wang; Liansheng Wang

2002-01-01

143

A relational learning approach to Structure-Activity Relationships in drug design toxicity studies.  

PubMed

It has been recognized that the development of new therapeutic drugs is a complex and expensive process. A large number of factors affect the activity in vivo of putative candidate molecules and the propensity for causing adverse and toxic effects is recognized as one of the major hurdles behind the current "target-rich, lead-poor" scenario. Structure-Activity Relationship (SAR) studies, using relational Machine Learning (ML) algorithms, have already been shown to be very useful in the complex process of rational drug design. Despite the ML successes, human expertise is still of the utmost importance in the drug development process. An iterative process and tight integration between the models developed by ML algorithms and the know-how of medicinal chemistry experts would be a very useful symbiotic approach. In this paper we describe a software tool that achieves that goal--iLogCHEM. The tool allows the use of Relational Learners in the task of identifying molecules or molecular fragments with potential to produce toxic effects, and thus help in stream-lining drug design in silico. It also allows the expert to guide the search for useful molecules without the need to know the details of the algorithms used. The models produced by the algorithms may be visualized using a graphical interface, that is of common use amongst researchers in structural biology and medicinal chemistry. The graphical interface enables the expert to provide feedback to the learning system. The developed tool has also facilities to handle the similarity bias typical of large chemical databases. For that purpose the user can filter out similar compounds when assembling a data set. Additionally, we propose ways of providing background knowledge for Relational Learners using the results of Graph Mining algorithms. PMID:21926445

Camacho, Rui; Pereira, Max; Costa, Vítor Santos; Fonseca, Nuno A; Adriano, Carlos; Simões, Carlos J V; Brito, Rui M M

2011-01-01

144

Structure-activity relationship studies of carboxamido-biaryl ethers as opioid receptor antagonists (OpRAs). Part 1.  

PubMed

A structurally unique and new class of opioid receptor antagonists (OpRAs) that bear no structural resemblance with morphine or endogenous opioid peptides has been discovered. A series of carboxamido-biaryl ethers were identified as potent receptor antagonists against mu, kappa and delta opioid receptors. The structure-activity relationship indicated para-substituted aryloxyaryl primary carboxamide bearing an amine tether on the distal phenyl ring was optimal for potent in vitro functional antagonism against three opioid receptor subtypes. PMID:17720493

Takeuchi, Kumiko; Holloway, William G; McKinzie, Jamie H; Suter, Todd M; Statnick, Michael A; Surface, Peggy L; Emmerson, Paul J; Thomas, Elizabeth M; Siegel, Miles G; Matt, James E; Wolfe, Chad N; Mitch, Charles H

2007-10-01

145

Antioxidant and anti-inflammatory related activities of selected synthetic chalcones: structure-activity relationship studies using computational tools.  

PubMed

Synthetic derivatives of 1-(2-hydroxy-3-(2-hydroxy-cyclohexyl)-4,6-dimethoxy-phenyl)-methanone were evaluated in-vitro for their activities related to antioxidant and anti-inflammatory. The antioxidant potential was determined by calculating reducing potential, OH and DPPH (2,2-diphenyl-1-picryl hydrazine) radical scavenging activities. The in-vitro anti-inflammatory related activities of synthetic chalcones (SCs) were demonstrated by performing inhibition assays of trypsin, beta-glucuronidase and diene conjugates. The results of the various parameters studied shows that the selected derivatives were found to be effective reducing agents and were reactive towards stabilizing the OH and DPPH radicals. The compounds have showed moderate to poor or no inhibition profile towards trypsin and beta-glucuronidase, but were found to be effective inhibitor of dien conjugates (hydroperoxides). An attempt has been made to define structure activity relationship using BioMed CAChe 6.1.10: a computer-aided molecular modeling tool which applies equations from classical and quantum mechanics. The experimental and in silico results of the present investigation shows that the basic nucleus 1-(2-hydroxy-3-(2-hydroxy-cyclohexyl)-4,6-dimethoxy-phenyl)-methanone can be considered as a potential candidate for the design and development of lead antioxidant and anti-inflammatory agents. PMID:18591798

Gacche, Rajesh; Khsirsagar, Mansi; Kamble, Srikant; Bandgar, Babasaheb; Dhole, Nagesh; Shisode, Kavita; Chaudhari, Ajay

2008-07-01

146

Quantitative structure-activity relationship models of clinical pharmacokinetics: clearance and volume of distribution.  

PubMed

Reliable prediction of two fundamental human pharmacokinetic (PK) parameters, systemic clearance (CL) and apparent volume of distribution (Vd), determine the size and frequency of drug dosing and are at the heart of drug discovery and development. Traditionally, estimated CL and Vd are derived from preclinical in vitro and in vivo absorption, distribution, metabolism, and excretion (ADME) measurements. In this paper, we report quantitative structure-activity relationship (QSAR) models for prediction of systemic CL and steady-state Vd (Vdss) from intravenous (iv) dosing in humans. These QSAR models avoid uncertainty associated with preclinical-to-clinical extrapolation and require two-dimensional structure drawing as the sole input. The clean, uniform training sets for these models were derived from the compilation published by Obach et al. (Drug Metab. Disp. 2008, 36, 1385-1405). Models for CL and Vdss were developed using both a support vector regression (SVR) method and a multiple linear regression (MLR) method. The SVR models employ a minimum of 2048-bit fingerprints developed in-house as structure quantifiers. The MLR models, on the other hand, are based on information-rich electro-topological states of two-atom fragments as descriptors and afford reverse QSAR (RQSAR) analysis to help model-guided, in silico modulation of structures for desired CL and Vdss. The capability of the models to predict iv CL and Vdss with acceptable accuracy was established by randomly splitting data into training and test sets. On average, for both CL and Vdss, 75% of test compounds were predicted within 2.5-fold of the value observed and 90% of test compounds were within 5.0-fold of the value observed. The performance of the final models developed from 525 compounds for CL and 569 compounds for Vdss was evaluated on an external set of 56 compounds. The predictions were either better or comparable to those predicted by other in silico models reported in the literature. To demonstrate the practical application of the RQSAR approach, the structure of vildagliptin, a high-CL and a high-Vdss compound, is modified based on the atomic contributions to its predicted CL and Vdss to propose compounds with lower CL and lower Vdss. PMID:23451981

Gombar, Vijay K; Hall, Stephen D

2013-04-22

147

Quantitative structure-activity relationships for weak acid respiratory uncouplers to Vibrio fisheri  

SciTech Connect

Acute toxicity values of 16 organic compounds thought to elicit their response via the weak acid respiratory uncoupling mechanism of toxic action were secured from the literature. Regression analysis of toxicities revealed that a measured 5-min V. fisheri potency value can be used as a surrogate for the 30-min value. Regression analysis of toxicity versus hydrophobicity, measured as the 1-octanol/water partition coefficient (log K{sub ow}), was used to formulate a quantitative structure-activity relationship (QSAR). The equation log pT{sub 30}{sup {minus}1} = 0.489(log K{sub ow}) + 0.126 was found to be a highly predictive model. This V. fisheri QSAR is statistically similar to QSARs generated from weak acid uncoupler potency data for Pimephales promelas survivability and Tetrahymena pyriformis population growth impairment. This work, therefore, suggests that the weak acid respiratory uncoupling mechanism of toxic action is present in V. fisheri, and as such is not restricted to mitochondria-containing organisms.

Schultz, T.W. [Univ. of Tennessee, Knoxville, TN (United States). Coll. of Veterinary Medicine; Cronin, M.T.D. [Liverpool John Moores Univ. (United Kingdom). School of Pharmacy and Chemistry

1997-02-01

148

Prooxidant toxicity of polyphenolic antioxidants to HL-60 cells: description of quantitative structure-activity relationships.  

PubMed

Polyphenolic antioxidants exhibited a dose-dependent toxicity against human promyelocytic leukemia cells (HL-60). Their action was accompanied by malondialdehyde formation, and was partly prevented by desferrioxamine and the antioxidant N,N'-diphenyl-p-phenylene diamine. This points to a prooxidant character of their cytotoxicity. A quantitative structure-activity relationship (QSAR) has been obtained to describe the cytotoxicity of 13 polyphenolic antioxidants belonging to three different groups (flavonoids, derivatives of gallic and caffeic acid): log cL50 (microM) = (2.7829+/-0.2339)+(1.2734+/-0.4715) Ep/2 (V)-(0.3438+/-0.0582) log P (r2 = 0.8129), where cL50 represents the concentration for 50% cell survival, Ep/2 represents the voltammetric midpoint potential, and P represents the octanol/water partition coefficient. Analogous QSARs were obtained using enthalpies of single-electron oxidation of these compounds, obtained by quantum-mechanical calculations. These findings clearly point to two important characteristics determining polyphenol cytotoxicity, namely their ease of oxidation and their lipophilicity. PMID:10622732

Sergediene, E; Jönsson, K; Szymusiak, H; Tyrakowska, B; Rietjens, I M; Cenas, N

1999-12-01

149

Structure-Activity Relationships of ?-Keto Oxazole Inhibitors of Fatty Acid Amide Hydrolase  

PubMed Central

A systematic study of the structure–activity relationships (SAR) of 2b (OL-135), a potent inhibitor of fatty acid amide hydrolase (FAAH), is detailed targeting the C2 acyl side chain. A series of aryl replacements or substituents for the terminal phenyl group provided effective inhibitors (e.g., 5c, aryl = 1-napthyl, Ki = 2.6 nM) with 5hh (aryl = 3-Cl-Ph, Ki = 900 pM) being 5-fold more potent than 2b. Conformationally-restricted C2 side chains were examined and many provided exceptionally potent inhibitors of which 11j (ethylbiphenyl side chain) was established to be a 750 pM inhibitor. A systematic series of heteroatoms (O, NMe, S), electron-withdrawing groups (SO, SO2), and amides positioned within and hydroxyl substitutions on the linking side chain were investigated which typically led to a loss in potency. The most tolerant positions provided effective inhibitors (12p, 6-position S, Ki = 3 nM or 13d, 2-position OH, Ki = 8 nM) comparable in potency to 2b. Proteomic-wide screening of selected inhibitors from the systematic series of >100 candidates prepared revealed that they are selective for FAAH over all other mammalian serine proteases. PMID:17559203

Hardouin, Christophe; Kelso, Michael J.; Romero, F. Anthony; Rayl, Thomas J.; Leung, Donmienne; Hwang, Inkyu; Cravatt, Benjamin F.; Boger, Dale L.

2008-01-01

150

Utilization of quantitative structure-activity relationships (QSARs) in risk assessment: Alkylphenols  

SciTech Connect

Alkylphenols are a class of environmentally pervasive compounds, found both in natural (e.g., crude oils) and in anthropogenic (e.g., wood tar, coal gasification waste) materials. Despite the frequent environmental occurrence of these chemicals, there is a limited toxicity database on alkylphenols. The authors have therefore developed a 'toxicity equivalence approach' for alkylphenols which is based on their ability to inhibit, in a specific manner, the enzyme cyclooxygenase. Enzyme-inhibiting ability for individual alkylphenols can be estimated based on the quantitative structure-activity relationship developed by Dewhirst (1980) and is a function of the free hydroxyl group, electron-donating ring substituents, and hydrophobic aromatic ring substituents. The authors evaluated the toxicological significance of cyclooxygenase inhibition by comparison of the inhibitory capacity of alkylphenols with the inhibitory capacity of acetylsalicylic acid, or aspirin, a compound whose low-level effects are due to cyclooxygenase inhibition. Since nearly complete absorption for alkylphenols and aspirin is predicted, based on estimates of hydrophobicity and fraction of charged molecules at gastrointestinal pHs, risks from alkylphenols can be expressed directly in terms of 'milligram aspirin equivalence,' without correction for absorption differences. They recommend this method for assessing risks of mixtures of alkylphenols, especially for those compounds with no chronic toxicity data.38 references.

Beck, B.D.; Toole, A.P.; Callahan, B.G.; Siddhanti, S.K. (Gradient Corporation, Cambridge, MA (United States))

1991-12-01

151

Aquatic toxicity of acrylates and methacrylates: quantitative structure-activity relationships based on Kow and LC50  

SciTech Connect

Recent EPA scrutiny of acrylate and methacrylate monomers has resulted in restrictive consent orders and Significant New Use Rules under the Toxic Substances Control Act, based on structure-activity relationships using mouse skin painting studies. The concern is centered on human health issues regarding worker and consumer exposure. Environmental issues, such as aquatic toxicity, are still of concern. Understanding the relationships and environmental risks to aquatic organisms may improve the understanding of the potential risks to human health. This study evaluates the quantitative structure-activity relationships from measured log Kow's and log LC50's for Pimephales promelas (fathead minnow) and Carassius auratus (goldfish). Scientific support of the current regulations is also addressed. Two monomer classes were designated: acrylates and methacrylates. Spearman rank correlation and linear regression were run. Based on this study, an ecotoxicological difference exists between acrylates and methacrylates. Regulatory activities and scientific study should reflect this difference.

Reinert, K.H.

1987-12-01

152

[Perspective of predictive toxicity assessment of in vivo repeated dose toxicity using structural activity relationship].  

PubMed

Tens of thousands of existing chemicals have been widely used for manufacture, agriculture, household and other purposes in worldwide. Only approximately 10% of chemicals have been assessed for human health hazard. The health hazard assessment of residual large number of chemicals for which little or no information of their toxicity is available is urgently needed for public health. However, the conduct of traditional toxicity tests which involves using animals for all of these chemicals would be economically impractical and ethically unacceptable. (Quantitative) Structure-Activity Relationships [(Q)SARs] are expected as method to have the potential to estimate hazards of chemicals from their structure, while reducing time, cost and animal testing currently needed. Therefore, our studies have been focused on evaluation of available (Q)SAR systems for estimating in vivo repeated toxicity on the liver. The results from our preliminary analysis showed the distribution for LogP of the chemicals which have potential to induce liver toxicity was bell-shape and indicating the possibility to estimate liver toxicity of chemicals from their physicochemical property. We have developed (Q)SAR models to in vivo liver toxicity using three commercially available systems (DEREK, ADMEWorks and MultiCASE) as well as combinatorial use of publically available chemoinformatic tools (CDK, MOSS and WEKA). Distinct data-sets of the 28-day repeated dose toxicity test of new and existing chemicals evaluated in Japan were used for model development and performance test. The results that concordances of commercial systems and public tools were almost same which below 70% may suggest currently attainable knowledge of in silico estimation of complex biological process, though it possible to obtain complementary and enhanced performance by combining predictions from different programs. In future, the combinatorial application of in silico and in vitro tests might provide more accurate information which support regulatory decisions. At the same time, an appropriate strategy to use (Q)SAR for of the efficiency and accuracy in chemical management is necessary. PMID:21381395

Ono, Atsushi

2010-01-01

153

Structure-activity relationship studies toward the discovery of selective apelin receptor agonists.  

PubMed

Apelin is the endogenous ligand for the previously orphaned G protein-coupled receptor APJ. Apelin and its receptor are widely distributed in the brain, heart, and vasculature, and are emerging as an important regulator of body fluid homeostasis and cardiovascular functions. To further progress in the pharmacology and the physiological role of the apelin receptor, the development of small, bioavailable agonists and antagonists of the apelin receptor, is crucial. In this context, E339-3D6 (1) was described as the first nonpeptidic apelin receptor agonist. We show here that 1 is actually a mixture of polymethylated species, and we describe an alternative and versatile solid-phase approach that allows access to highly pure 27, the major component of 1. This approach was also applied to prepare a series of derivatives in order to identify the crucial structural determinants required for the ligand to maintain its affinity for the apelin receptor as well as its capacity to promote apelin receptor signaling and internalization. The study of the structure-activity relationships led to the identification of ligands 19, 21, and 38, which display an increased affinity compared to that of 27. The latter and 19 behave as full agonists with regard to cAMP production and apelin receptor internalization, whereas 21 is a biased agonist toward cAMP production. Interestingly, the three ligands display a much higher stability in mouse plasma (T1/2 > 10 h) than the endogenous apelin-17 peptide 2 (T1/2 < 4 min). PMID:24625069

Margathe, Jean-François; Iturrioz, Xavier; Alvear-Perez, Rodrigo; Marsol, Claire; Riché, Stéphanie; Chabane, Hadjila; Tounsi, Nassera; Kuhry, Maxime; Heissler, Denis; Hibert, Marcel; Llorens-Cortes, Catherine; Bonnet, Dominique

2014-04-10

154

Quantitative Structure Activity Relationship for Inhibition of Human Organic Cation/Carnitine Transporter (OCTN2)  

PubMed Central

Organic cation/carnitine transporter (OCTN2; SLC22A5) is an important transporter for L-carnitine homeostasis, but can be inhibited by drugs, which may cause L-carnitine deficiency and possibly other OCTN2-mediated drug-drug interactions. One objective was to develop a quantitative structure–activity relationship (QSAR) of OCTN2 inhibitors, in order to predict and identify other potential OCTN2 inhibitors and infer potential clinical interactions. A second objective was to assess two high renal clearance drugs that interact with OCTN2 in vitro (cetirizine and cephaloridine) for possible OCTN2-mediated drug-drug interactions. Using previously generated in vitro data of 22 drugs, a 3D quantitative pharmacophore model and a Bayesian machine learning model were developed. The four pharmacophore features include two hydrophobic groups, one hydrogen-bond acceptor, and one positive ionizable center. The Bayesian machine learning model was developed using simple interpretable descriptors and function class fingerprints of maximum diameter 6 (FCFP_6). An external test set of 27 molecules, including 15 newly identified OCTN2 inhibitors, and a literature test set of 22 molecules were used to validate both models. The computational models afforded good capability to identify structurally diverse OCTN2 inhibitors, providing a valuable tool to predict new inhibitors efficiently. Inhibition results confirmed our previously observed association between rhabdomyolysis and Cmax/Ki ratio. The two high renal clearance drugs cetirizine and cephaloridine were found not to be OCTN2 substrates and their diminished elimination by other drugs is concluded not to be mediated by OCTN2. PMID:20831193

Diao, Lei; Ekins, Sean; Polli, James E.

2010-01-01

155

Novel lopinavir analogues incorporating heterocyclic replacements of six-member cyclic urea--synthesis and structure-activity relationships.  

PubMed

The HIV protease inhibitor ABT-378 (lopinavir) has a six-member cyclic urea in the P-2 position. A series of analogues in which the six-member cyclic urea is replaced by various heterocycles was synthesized and the structure-activity relationships explored. PMID:15109669

Sham, Hing L; Betebenner, David A; Rosenbrook, William; Herrin, Thomas; Saldivar, Ayda; Vasavanonda, Sudthida; Plattner, Jacob J; Norbeck, Daniel W

2004-05-17

156

Synthesis and structure-activity relationships of a novel series of HIV-1 protease inhibitors encompassing ABT-378 (Lopinavir).  

PubMed

The HIV protease inhibitor ABT-378 (Lopinavir) has a 2,6-dimethylphenoxyacetyl group in the P-2' position. Analogues in which this group is replaced with various substituted phenyl or heteroaryl groups were synthesized and the structure-activity relationships explored. PMID:11934584

Sham, Hing L; Betebenner, David A; Chen, Xiaoqi; Saldivar, Ayda; Vasavanonda, Sudthida; Kempf, Dale J; Plattner, Jacob J; Norbeck, Daniel W

2002-04-22

157

Novel lopinavir analogues incorporating non-Aromatic P-1 side chains--synthesis and structure--activity relationships.  

PubMed

The HIV protease inhibitor Lopinavir has a pseudosymmetric core unit incorporating benzyl groups at both P-1, P-1' positions. A series of analogues incorporating non-aromatic side chains at the P-1 position were synthesized and the structure-activity relationships explored. PMID:12372511

Sham, Hing L; Zhao, Chen; Li, Leping; Betebenner, David A; Saldivar, Ayda; Vasavanonda, Sudthida; Kempf, Dale J; Plattner, Jacob J; Norbeck, Daniel W

2002-11-01

158

The new chemicals process at the Environmental Protection Agency (EPA): structure-activity relationships for hazard identification and risk assessment  

Microsoft Academic Search

Section 5 of the Toxic Substances Control Act (TSCA) does not require any toxicity testing as a prerequisite for submission of a Premanufacturing Notice (PMN) for a new chemical. In order to compensate for the lack of actual test data, a process involving structure-activity relationships (SAR) for assessing hazard potential was constructed. The hazard assessment is then coupled with an

P. M. Wagner; J. V. Nabholz; R. J. Kent

1995-01-01

159

The relationship between molecular structure and biological activity of alkali metal salts of vanillic acid: Spectroscopic, theoretical and microbiological studies  

NASA Astrophysics Data System (ADS)

In this paper we investigate the relationship between molecular structure of alkali metal vanillate molecules and their antimicrobial activity. To this end FT-IR, FT-Raman, UV absorption and 1H, 13C NMR spectra for lithium, sodium, potassium, rubidium and caesium vanillates in solid state were registered, assigned and analyzed. Microbial activity of studied compounds was tested against Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, Proteus vulgaris, Bacillus subtilis and Candida albicans. In order to evaluate the dependence between chemical structure and biological activity of alkali metal vanillates the statistical analysis was performed for selected wavenumbers from FT-IR spectra and parameters describing microbial activity of vanillates. The geometrical structures of the compounds studied were optimized and the structural characteristics were determined by density functional theory (DFT) using at B3LYP method with 6-311++G** as basis set. The obtained statistical equations show the existence of correlation between molecular structure of vanillates and their biological properties.

?wis?ocka, Renata; Piekut, Jolanta; Lewandowski, W?odzimierz

160

Discovery of 4-Substituted Methoxybenzoyl-Aryl-Thiazole as Novel Anticancer Agents: Synthesis, Biological Evaluation and Structure-Activity Relationships  

PubMed Central

A series of 4-substituted methoxylbenzoyl-aryl-thiazoles (SMART) have been discovered and synthesized as a result of structural modifications of the lead compound 2-arylthiazolidine-4-carboxylic acid amides (ATCAA). The antiproliferative activity of the SMART agents against melanoma and prostate cancer cells was improved from ?M to low nM range compared with ATCAA series. The structure-activity relationship was discussed from modifications of “A”, “B” “C” rings and the linker. Preliminary mechanism of action studies indicated that these compounds exert their anticancer activity through inhibition of tubulin polymerization. PMID:19243174

Lu, Yan; Li, Chien-Ming; Wang, Zhao; Ross, Charles R.; Chen, Jianjun; Dalton, James; Li, Wei; Miller, Duane.D.

2009-01-01

161

Nonenolides and cytochalasins with phytotoxic activity against Cirsium arvense and Sonchus arvensis: a structure-activity relationships study.  

PubMed

A structure-activity relationships study was conducted assaying 15 natural analogues and derivatives belonging to two groups of organic compounds, nonenolides and cytochalasins, for their toxicity against the composite perennial weeds Cirsium arvense and Sonchus arvensis occurring through the temperate region of world. The toxic nonenolides (stagonolide, putaminoxin, pinolidoxin) and cytochalasins (deoxaphomin, cytochalasins A, B, F, T, Z2 and Z3) were isolated from phytopathogenic Stagonospora, Phoma and Ascochyta spp. The pinolidoxin (7,8-O,O'-diacetyl- and 7,8-O,O'-isopropylidene-pinolidoxin) and cytochalasins B (21,22-dihydro-, 7-O-acetyl- and 7,20-O,O'-diacetyl-cytochalasin B) derivatives were obtained by chemical modifications of the corresponding toxins. Among the 15 compounds tested, stagonolide and deoxaphomin proved to be the most phytotoxic to C. arvense and S. arvensis leaves, respectively. The tested phytotoxic nonenolides were stronger inhibitors of photosynthesis in C. arvense leaves than cytochalasines A and B. Stagonolide had less effect on membrane permeability in C. arvense leaves than cytochalasin B. Significant changes of light absorption by C. arvense leaves in visible and infrared spectra were caused by stagonolide. The functional groups and the conformational freedom of the ring, appear to be important structural features for the nonenolides toxicity, whereas and the presence of the hydroxy group at C-7, the functional group at C-20 and the conformational freedom of the macrocyclic ring are important for the cytochalasins toxicity. PMID:18155260

Berestetskiy, Alexander; Dmitriev, Andrey; Mitina, Galina; Lisker, Iosif; Andolfi, Anna; Evidente, Antonio

2008-02-01

162

Quantitative structure-activity relationships (QSARs) for the transformation of organic micropollutants during oxidative water treatment.  

PubMed

Various oxidants such as chlorine, chlorine dioxide, ferrate(VI), ozone, and hydroxyl radicals can be applied for eliminating organic micropollutant by oxidative transformation during water treatment in systems such as drinking water, wastewater, and water reuse. Over the last decades, many second-order rate constants (k) have been determined for the reaction of these oxidants with model compounds and micropollutants. Good correlations (quantitative structure-activity relationships or QSARs) are often found between the k-values for an oxidation reaction of closely related compounds (i.e. having a common organic functional group) and substituent descriptor variables such as Hammett or Taft sigma constants. In this study, we developed QSARs for the oxidation of organic and some inorganic compounds and organic micropollutants transformation during oxidative water treatment. A number of 18 QSARs were developed based on overall 412 k-values for the reaction of chlorine, chlorine dioxide, ferrate, and ozone with organic compounds containing electron-rich moieties such as phenols, anilines, olefins, and amines. On average, 303 out of 412 (74%) k-values were predicted by these QSARs within a factor of 1/3-3 compared to the measured values. For HO(·) reactions, some principles and estimation methods of k-values (e.g. the Group Contribution Method) are discussed. The developed QSARs and the Group Contribution Method could be used to predict the k-values for various emerging organic micropollutants. As a demonstration, 39 out of 45 (87%) predicted k-values were found within a factor 1/3-3 compared to the measured values for the selected emerging micropollutants. Finally, it is discussed how the uncertainty in the predicted k-values using the QSARs affects the accuracy of prediction for micropollutant elimination during oxidative water treatment. PMID:22939392

Lee, Yunho; von Gunten, Urs

2012-12-01

163

Drug-induced lysosomal storage of sulfated glycosaminoglycans. Studies on the underlying structure-activity relationships.  

PubMed

Some immunomodulatory drugs have previously been shown to induce lysosomal storage of sulfated glycosaminoglycans (sGAG) in intact organisms and cultured cells. These compounds consist of a planary aromatic ring system and two symmetric side chains each carrying a protonizable nitrogen. The purpose of this study was to test a larger collection of such compounds for their potencies to induce lysosomal storage of sGAG in cultured fibroblasts of rat cornea. The cells were exposed (72 h) to various compounds differing with respect to the aromatic ring system or the side chains. Lysosomal sGAG-storage was demonstrated by selective cytochemical staining with cuprolinic blue. The threshold concentration, i.e., the concentration necessary to induce cuprolinic blue-positive cytoplasmic inclusions in at least 1% of the cells, was determined for each compound. The threshold concentrations were distributed over a range of 0.3-30 microM. It should be emphasized that the threshold concentration of a given compound is not a constant, but depends on the volume of cell culture medium per surface area of cell monolayer, since the lysosomal accumulation lowers the initial drug concentration in the medium. If the ratio of medium volume:cell monolayer surface is increased as compared with standard cell culture conditions, the threshold concentration will be lowered. The compounds were ranked according to their threshold concentrations as determined under standard conditions. The following conclusions can be drawn from the ranking: the type of the central aromatic ring system and the distance between the ring system and the protonizable nitrogen atoms of the side chains influence the potency to induce lysosomal sGAG-storage. Regarding the ring system, the potency decreases as follows: acridine approximately anthrachinone > fenfluorenone approximately fenfluorene > xanthenone; xanthene > dibenzofuran approximately dibenzothiophene. In intact organisms, these structure-activity relationships may be superimposed by drug metabolism and pharmacokinetic factors. PMID:8303713

Handrock, K; Lüllmann-Rauch, R; Vogt, R D

1993-12-31

164

Quantitative structure-activity relationships (QSARs) using the novel marine algal toxicity data of phenols.  

PubMed

The present study reports for the first time in its entirety the toxicity of 30 phenolic compounds to marine alga Dunaliella tertiolecta. Toxicity of polar narcotics and respiratory uncouplers was strongly correlated to hydrophobicity as described by the logarithm of the octanol/water partition coefficient (Log P). Compounds expected to act by more reactive mechanisms, particularly hydroquinones, were shown to have toxicity in excess of that predicted by Log P. A quality quantitative structure-activity relationship (QSAR) was obtained with Log P and a 2D autocorrelation descriptor weighted by atomic polarizability (MATS3p) only after the removal of hydroquinones from the data set. In an attempt to model the whole data set including hydroquinones, 3D descriptors were included in the modeling process and three quality QSARs were developed using multiple linear regression (MLR). One of the most significant results of the present study was the superior performance of the consensus MLR model, obtained by averaging the predictions from each individual linear model, which provided excellent prediction accuracy for the test set (Q(test)²=0.94). The four-parameter Counter Propagation Artificial Neural Network (CP ANN) model, which was constructed using four out of six descriptors that appeared in the linear models, also provided an excellent external predictivity (Q(test)²=0.93). The proposed algal QSARs were further tested in their predictivity using an external set comprising toxicity data of 44 chemicals on freshwater alga Pseudokirchneriella subcapitata. The two-parameter global model employing a 3D descriptor (Mor24m) and a charge-related descriptor (C(ortho)) not only had high external predictivity (Q(ext)²=0.74), but it also had excellent external data set coverage (%97). PMID:23085159

Ertürk, M Do?a; Saçan, Melek Türker; Novic, Marjana; Minovski, Nikola

2012-09-01

165

The synthesis and structure-activity relationship of 4-benzimidazolyl-piperidinylcarbonyl-piperidine analogs as histamine H3 antagonists.  

PubMed

A structure-activity relationship study of the lead piperazinylcarbonylpiperidine compound 3 resulted in the identification of 4-benzimidazolyl-piperidinylcarbonyl-piperidine 6h as a histamine-3 (H(3)) receptor antagonist. Additional optimization of 6h led to the identification of compounds 11i-k with K(i) activity. PMID:20685118

Ting, Pauline C; Lee, Joe F; Albanese, Margaret M; Wu, Jie; Aslanian, Robert; Favreau, Leonard; Nardo, Cymbelene; Korfmacher, Walter A; West, Robert E; Williams, Shirley M; Anthes, John C; Rivelli, Maria A; Corboz, Michel R; Hey, John A

2010-09-01

166

Quantitative structure activities relationships of some 2-mercaptoimidazoles as CCR2 inhibitors using genetic algorithm-artificial neural networks.  

PubMed

Quantitative relationships between structures of twenty six of 2-mercaptoimidazoles as C-C chemokine receptor type 2 (CCR2) inhibitors were assessed. Modeling of the biological activities of compounds of interest as a function of molecular structures was established by means of genetic algorithm multivariate linear regression (GA-MLR) and genetic algorithm (GA-ANN). The results showed that, the pIC50 values calculated by GA-ANN are in good agreement with the experimental data, and the performance of the artificial neural networks regression model is superior to the multivariate linear regression-based (MLR) model. With respect to the obtained results, it can be deduced that there is a non-linear relationship between the pIC50 s and the calculated structural descriptors of the 2-mercaptoimidazoles. The obtained models were able to describe about 78% and 93% of the variance in the experimental activity of molecules in training set, respectively. The study provided a novel and effective approach for predicting biological activities of 2-mercaptoimidazole derivatives as CCR2 inhibitors and disclosed that combined genetic algorithm and GA-ANN can be used as a powerful chemometric tools for quantitative structure activity relationship (QSAR) studies. PMID:24019819

Saghaie, L; Shahlaei, M; Fassihi, A

2013-04-01

167

Structure-activity relationship study of the plant-derived decapeptide OSIP108 inhibiting Candida albicans biofilm formation.  

PubMed

We performed a structure-activity relationship study of the antibiofilm plant-derived decapeptide OSIP108. Introduction of positively charged amino acids R, H, and K resulted in an up-to-5-fold-increased antibiofilm activity against Candida albicans compared to native OSIP108, whereas replacement of R9 resulted in complete abolishment of its antibiofilm activity. By combining the most promising amino acid substitutions, we found that the double-substituted OSIP108 analogue Q6R/G7K had an 8-fold-increased antibiofilm activity. PMID:24913176

Delattin, Nicolas; De Brucker, Katrijn; Craik, David J; Cheneval, Olivier; De Coninck, Barbara; Cammue, Bruno P A; Thevissen, Karin

2014-08-01

168

The structure-activity relationships of mono-THF ACGs on mitochondrial complex I with a molecular modelling study.  

PubMed

Annonaceous acetogenins (ACGs) are one of the most powerful groups of mitochondrial complex I inhibitors. In this study, 24 ACGs with different chemical structures have been tested against mitochondrial complex I isolated in our laboratory. Molecular modelling study of the six mono-tetrahydrofuran (THF) ACGs in these 24 compounds has been performed to investigate the relationship between their inhibitory activity and chemical structures. IC50 of every ACGs against mitochondrial complex I was determined with a micro plate reader. The results show that every ACG can inhibit mitochondrial complex I and the six mono-THF ACGs' activities are in agreement with their molecular modelling results. It is suggested that proper length and flexibility of the alkyl spacer moiety, which links the THF and the ?,?-unsaturated Q-lactone ring moieties, are essential for the potent activity. Both the number of hydroxyl groups and stereochemical structures of mono-THF ACGs impact the activity. PMID:25183444

Miao, Yun-Jie; Xu, Xiao-Fang; Xu, Fei; Chen, Yong; Chen, Jian-Wei; Li, Xiang

2014-11-01

169

Oximes: Inhibitors of Human Recombinant Acetylcholinesterase. A Structure-Activity Relationship (SAR) Study  

PubMed Central

Acetylcholinesterase (AChE) reactivators were developed for the treatment of organophosphate intoxication. Standard care involves the use of anticonvulsants (e.g., diazepam), parasympatolytics (e.g., atropine) and oximes that restore AChE activity. However, oximes also bind to the active site of AChE, simultaneously acting as reversible inhibitors. The goal of the present study is to determine how oxime structure influences the inhibition of human recombinant AChE (hrAChE). Therefore, 24 structurally different oximes were tested and the results compared to the previous eel AChE (EeAChE) experiments. Structural factors that were tested included the number of pyridinium rings, the length and structural features of the linker, and the number and position of the oxime group on the pyridinium ring. PMID:23959117

Sepsova, Vendula; Karasova, Jana Zdarova; Korabecny, Jan; Dolezal, Rafael; Zemek, Filip; Bennion, Brian J.; Kuca, Kamil

2013-01-01

170

Structure-activity relationship of marinostatin, a serine protease inhibitor isolated from a marine organism.  

PubMed

A 12-residue MST isolated from a marine organism is a potent serine protease inhibitor that has a double cyclic structure composed of two ester linkages formed between the beta-hydroxyl and beta-carboxyl groups, Thr(3)-Asp(9) and Ser(8)-Asp(11). MST was synthesized by a regioselective esterification procedure employing two sets of orthogonally removable side-chain protecting groups for the Asp and Ser/Thr residues. In the MST molecule, there were no significant changes observed in yield by changing the order of esterification. SAR study of MST revealed that the minimum required structure for expressing the inhibitory activity is the sequence (1-9) in a monocyclic structure where Pro(7) located in the ring plays a crucial role in keeping the structural rigidity. By applying the structural motif of MST, we rationally designed protease inhibitory specificities that differ from those of the natural product. PMID:20552565

Taichi, Misako; Yamazaki, Tohimasa; Kawahara, Kazuki; Motooka, Daisuke; Nakamura, Shota; Harada, Shusaku; Teshima, Tadashi; Ohkubo, Tadayasu; Kobayashi, Yuji; Nishiuchi, Yuji

2010-07-01

171

Synthesis and structure-activity relationships of novel amino/nitro substituted 3-arylcoumarins as antibacterial agents.  

PubMed

A new series of amino/nitro-substituted 3-arylcoumarins were synthesized and their antibacterial activity against clinical isolates of Staphylococcus aureus (Gram-positive) and Escherichia coli (Gram-negative) was evaluated. Some of these molecules exhibited antibacterial activity against S. aureus comparable to the standards used (oxolinic acid and ampicillin). The preliminary structure-activity relationship (SAR) study showed that the antibacterial activity against S. aureus depends on the position of the 3-arylcoumarin substitution pattern. With the aim of finding the structural features for the antibacterial activity and selectivity, in the present manuscript different positions of nitro, methyl, methoxy, amino and bromo substituents on the 3-arylcoumarin scaffold were reported. PMID:23348993

Matos, Maria J; Vazquez-Rodriguez, Saleta; Santana, Lourdes; Uriarte, Eugenio; Fuentes-Edfuf, Cristina; Santos, Ysabel; Muñoz-Crego, Angeles

2013-01-01

172

Quantitative structure activity relationships of some pyridine derivatives as corrosion inhibitors of steel in acidic medium.  

PubMed

Quantum chemical calculations using the density functional theory (B3LYP/6-31G DFT) and semi-empirical AM1 methods were performed on ten pyridine derivatives used as corrosion inhibitors for mild steel in acidic medium to determine the relationship between molecular structure and their inhibition efficiencies. Quantum chemical parameters such as total negative charge (TNC) on the molecule, energy of highest occupied molecular orbital (E (HOMO)), energy of lowest unoccupied molecular orbital (E (LUMO)) and dipole moment (?) as well as linear solvation energy terms, molecular volume (Vi) and dipolar-polarization (?) were correlated to corrosion inhibition efficiency of ten pyridine derivatives. A possible correlation between corrosion inhibition efficiencies and structural properties was searched to reduce the number of compounds to be selected for testing from a library of compounds. It was found that theoretical data support the experimental results. The results were used to predict the corrosion inhibition of 24 related pyridine derivatives. PMID:21695505

El Ashry, El Sayed H; El Nemr, Ahmed; Ragab, Safaa

2012-03-01

173

Relationship between peptide structure and antimicrobial activity as studied by de novo designed peptides.  

PubMed

As fundamental components in innate immunity, antimicrobial peptides (AMPs) hold great potentials in the treatment of persistent infections involving slow-growing or dormant bacteria in which, selective inhibition of prokaryotic bacteria in the context of eukaryotic cells is not only an essential requirement, but also a critical challenge in the development of antimicrobial peptides. To identify the sequence and structural properties critical for antimicrobial activity, a series of peptides varying in sequence, length, hydrophobicity/charge ratio, and secondary structure, were designed and synthesized. Their antimicrobial activities were then tested using Escherichia coli and HEK293 cells, together with several index activities against model membrane, including liposome leakage, fusion, and aggregation. While no evident correlation between the antimicrobial activity and the property of the peptides was observed, common activities against model membrane were nevertheless identified for the active antimicrobial peptides: mediating efficient membrane leakage, negligible membrane fusion and liposome aggregation. Therefore, in addition to identifying one highly active antimicrobial peptide, our study further sheds light on the design principle for these molecules. PMID:25157672

Sun, Jianbo; Xia, Yuqiong; Li, Dong; Du, Quan; Liang, Dehai

2014-12-01

174

Quantitative structure–activity relationship modeling of polycyclic aromatic hydrocarbon mutagenicity by classification methods based on holistic theoretical molecular descriptors  

Microsoft Academic Search

Various polycyclic aromatic hydrocarbons (PAHs), ubiquitous environmental pollutants, are recognized mutagens and carcinogens. A homogeneous set of mutagenicity data (TA98 and TA100,+S9) for 32 benzocyclopentaphenanthrenes\\/chrysenes was modeled by the quantitative structure–activity relationship classification methods k-nearest neighbor and classification and regression tree, using theoretical holistic molecular descriptors. Genetic algorithm provided the selection of the best subset of variables for modeling mutagenicity.

Paola Gramatica; Ester Papa; Assunta Marrocchi; Lucio Minuti; Aldo Taticchi

2007-01-01

175

Structure-activity relationship (SAR) studies of quinoxalines as novel HCV NS5B RNA-dependent RNA polymerase inhibitors.  

PubMed

From chemical compound library screening using an HCV NS5B RNA-dependent RNA polymerase enzymatic assay, we identified a substituted quinoxaline hit with an IC(50) of 5.5 microM. A series of substituted quinoxaline amide derivatives were synthesized based on the hit's pharmacophore, and a good structure-activity relationship was observed. Computer modeling analysis was employed to help comprehend the SAR. PMID:17258458

Rong, Frank; Chow, Suetying; Yan, Shunqi; Larson, Gary; Hong, Zhi; Wu, Jim

2007-03-15

176

Identification and structure-activity relationships of substituted pyridones as inhibitors of Pim-1 kinase.  

PubMed

A novel series of highly potent substituted pyridone Pim-1 kinase inhibitors is described. Structural requirements for in vitro activity are outlined as well as a complex crystal structure with the most potent Pim-1 inhibitor reported (IC(50)=50 nM). A hydrogen bond matrix involving the Pim-1 inhibitor, two water molecules, and the catalytic core, together with a potential weak hydrogen bond between an aromatic hydrogen on the R(1) phenyl ring and a main-chain carbonyl of Pim-1, accounts for the overall potency of this inhibitor. PMID:17251021

Cheney, I Wayne; Yan, Shunqi; Appleby, Todd; Walker, Heli; Vo, Todd; Yao, Nanhua; Hamatake, Robert; Hong, Zhi; Wu, Jim Z

2007-03-15

177

Structure-Activity Relationship Study around Guanabenz Identifies Two Derivatives Retaining Antiprion Activity but Having Lost ?2-Adrenergic Receptor Agonistic Activity.  

PubMed

Guanabenz (GA) is an orally active ?2-adrenergic agonist that has been used for many years for the treatment of hypertension. We recently described that GA is also active against both yeast and mammalian prions in an ?2-adrenergic receptor-independent manner. These data suggest that this side-activity of GA could be explored for the treatment of prion-based diseases and other amyloid-based disorders. In this perspective, the potent antihypertensive activity of GA happens to be an annoying side-effect that could limit its use. In order to get rid of GA agonist activity at ?2-adrenergic receptors, we performed a structure-activity relationship study around GA based on changes of the chlorine positions on the benzene moiety and then on the modifications of the guanidine group. Hence, we identified the two derivatives 6 and 7 that still possess a potent antiprion activity but were totally devoid of any agonist activity at ?2-adrenergic receptors. Similarly to GA, 6 and 7 were also able to inhibit the protein folding activity of the ribosome (PFAR) which has been suggested to be involved in prion appearance/maintenance. Therefore, these two GA derivatives are worth being considered as drug candidates. PMID:25244284

Nguyen, Phu Hai; Hammoud, Hassan; Halliez, Sophie; Pang, Yanhong; Evrard, Justine; Schmitt, Martine; Oumata, Nassima; Bourguignon, Jean-Jacques; Sanyal, Suparna; Beringue, Vincent; Blondel, Marc; Bihel, Frédéric; Voisset, Cécile

2014-10-15

178

Evaluation and Structure-Activity Relationship Analysis of a New Series of Arylnaphthalene lignans as Potential Anti-Tumor Agents  

PubMed Central

Arylnaphthalene lignan lactones have attracted considerable interest because of their anti-tumor and anti-hyperlipidimic activities. However, to our knowledge, few studies have explored the effects of these compounds on human leukemia cell lines. In this study, five arylnaphthalene lignans including 6?-hydroxy justicidin A (HJA), 6?-hydroxy justicidin B (HJB), justicidin B (JB), chinensinaphthol methyl ether (CME) and Taiwanin E methyl ether (TEME) were isolated from Justicia procumbens and their effects on the proliferation and apoptosis of the human leukemia K562 cell line were investigated then used to assess structure-activity relationships. To achieve these aims, cytotoxicity was assayed using the MTT assay, while intracellular SOD activity was detected using the SOD Activity Assay kit. Apoptosis was measured by both the using a cycle TEST PLUS DNA reagent kit as well as the FITC Annexin V apoptosis detection kit in combination with flow cytometry. Activation of caspase-mediated apoptosis was evaluated using a FITC active Caspase-3 apoptosis kit and flow cytometry. The results indicated that HJB, HJA and JB significantly inhibited the growth of K562 cells by decreasing both proliferation and SOD activity and inducing apoptosis. The sequence of anti-proliferative activity induced by the five tested arylnaphthalenes by decreasing strength was HJB > HJA > JB > CME > TEME. HJB, HJA and JB also decreased SOD activity and induced apoptosis in a dose-dependent manner. Activation of caspase-3 further indicated that HJB, HJA and JB induced caspase-dependent intrinsic and/or extrinsic apoptosis pathways. Together, these assays suggest that arylnaphthalene lignans derived from Justicia procumbens induce apoptosis to varying degrees, through a caspase-dependent pathway in human leukemia K562 cells. Furthermore, analysis of structure-activity relationships suggest that hydroxyl substitution at C-1 and C-6? significantly increased the antiproliferative activity of arylnaphthalene lignans while a methoxyl at C-1 significantly decreased the effect. PMID:24675875

Luo, Jiaoyang; Hu, Yichen; Kong, Weijun; Yang, Meihua

2014-01-01

179

Evaluation and structure-activity relationship analysis of a new series of arylnaphthalene lignans as potential anti-tumor agents.  

PubMed

Arylnaphthalene lignan lactones have attracted considerable interest because of their anti-tumor and anti-hyperlipidimic activities. However, to our knowledge, few studies have explored the effects of these compounds on human leukemia cell lines. In this study, five arylnaphthalene lignans including 6'-hydroxy justicidin A (HJA), 6'-hydroxy justicidin B (HJB), justicidin B (JB), chinensinaphthol methyl ether (CME) and Taiwanin E methyl ether (TEME) were isolated from Justicia procumbens and their effects on the proliferation and apoptosis of the human leukemia K562 cell line were investigated then used to assess structure-activity relationships. To achieve these aims, cytotoxicity was assayed using the MTT assay, while intracellular SOD activity was detected using the SOD Activity Assay kit. Apoptosis was measured by both the using a cycle TEST PLUS DNA reagent kit as well as the FITC Annexin V apoptosis detection kit in combination with flow cytometry. Activation of caspase-mediated apoptosis was evaluated using a FITC active Caspase-3 apoptosis kit and flow cytometry. The results indicated that HJB, HJA and JB significantly inhibited the growth of K562 cells by decreasing both proliferation and SOD activity and inducing apoptosis. The sequence of anti-proliferative activity induced by the five tested arylnaphthalenes by decreasing strength was HJB > HJA > JB > CME > TEME. HJB, HJA and JB also decreased SOD activity and induced apoptosis in a dose-dependent manner. Activation of caspase-3 further indicated that HJB, HJA and JB induced caspase-dependent intrinsic and/or extrinsic apoptosis pathways. Together, these assays suggest that arylnaphthalene lignans derived from Justicia procumbens induce apoptosis to varying degrees, through a caspase-dependent pathway in human leukemia K562 cells. Furthermore, analysis of structure-activity relationships suggest that hydroxyl substitution at C-1 and C-6' significantly increased the antiproliferative activity of arylnaphthalene lignans while a methoxyl at C-1 significantly decreased the effect. PMID:24675875

Luo, Jiaoyang; Hu, Yichen; Kong, Weijun; Yang, Meihua

2014-01-01

180

Relationship between microbial activity and microbial community structure in six full-scale anaerobic digesters.  

PubMed

High activity levels and balanced anaerobic microbial communities are necessary to attain proper anaerobic digestion performance. Therefore, this work was focused on the kinetic performance and the microbial community structure of six full-scale anaerobic digesters and one lab-scale co-digester. Hydrolytic (0.6-3.5 g COD g(-1) VSS d(-1)) and methanogenic (0.01-0.84 g COD g(-1) VSS d(-1)) activities depended on the type of biomass, whereas no significant differences were observed among the acidogenic activities (1.5-2.2 g COD g(-1) VSS d(-1)). In most cases, the higher the hydrolytic and the methanogenic activity, the higher the Bacteroidetes and Archaea percentages, respectively, in the biomasses. Hydrogenotrophic methanogenic activity was always higher than acetoclastic methanogenic activity, and the highest values were achieved in those biomasses with lower percentages of Methanosaeta. In sum, the combination of molecular tools with activity tests seems to be essential for a better characterization of anaerobic biomasses. PMID:22770715

Regueiro, Leticia; Veiga, Patricia; Figueroa, Mónica; Alonso-Gutierrez, Jorge; Stams, Alfons J M; Lema, Juan M; Carballa, Marta

2012-12-20

181

Computational identification of RNA functional determinants by three-dimensional quantitative structure–activity relationships  

PubMed Central

Anti-infection drugs target vital functions of infectious agents, including their ribosome and other essential non-coding RNAs. One of the reasons infectious agents become resistant to drugs is due to mutations that eliminate drug-binding affinity while maintaining vital elements. Identifying these elements is based on the determination of viable and lethal mutants and associated structures. However, determining the structure of enough mutants at high resolution is not always possible. Here, we introduce a new computational method, MC-3DQSAR, to determine the vital elements of target RNA structure from mutagenesis and available high-resolution data. We applied the method to further characterize the structural determinants of the bacterial 23S ribosomal RNA sarcin–ricin loop (SRL), as well as those of the lead-activated and hammerhead ribozymes. The method was accurate in confirming experimentally determined essential structural elements and predicting the viability of new SRL variants, which were either observed in bacteria or validated in bacterial growth assays. Our results indicate that MC-3DQSAR could be used systematically to evaluate the drug-target potentials of any RNA sites using current high-resolution structural data. PMID:25200082

Blanchet, Marc-Frédérick; St-Onge, Karine; Lisi, Véronique; Robitaille, Julie; Hamel, Sylvie; Major, François

2014-01-01

182

Computational identification of RNA functional determinants by three-dimensional quantitative structure-activity relationships.  

PubMed

Anti-infection drugs target vital functions of infectious agents, including their ribosome and other essential non-coding RNAs. One of the reasons infectious agents become resistant to drugs is due to mutations that eliminate drug-binding affinity while maintaining vital elements. Identifying these elements is based on the determination of viable and lethal mutants and associated structures. However, determining the structure of enough mutants at high resolution is not always possible. Here, we introduce a new computational method, MC-3DQSAR, to determine the vital elements of target RNA structure from mutagenesis and available high-resolution data. We applied the method to further characterize the structural determinants of the bacterial 23S ribosomal RNA sarcin-ricin loop (SRL), as well as those of the lead-activated and hammerhead ribozymes. The method was accurate in confirming experimentally determined essential structural elements and predicting the viability of new SRL variants, which were either observed in bacteria or validated in bacterial growth assays. Our results indicate that MC-3DQSAR could be used systematically to evaluate the drug-target potentials of any RNA sites using current high-resolution structural data. PMID:25200082

Blanchet, Marc-Frédérick; St-Onge, Karine; Lisi, Véronique; Robitaille, Julie; Hamel, Sylvie; Major, François

2015-01-01

183

Folate-vinca alkaloid conjugates for cancer therapy: a structure-activity relationship.  

PubMed

Vintafolide is a potent folate-targeted vinca alkaloid small molecule drug conjugate (SMDC) that has shown promising results in multiple clinical oncology studies. Structurally, vintafolide consists of 4 essential modules: (1) folic acid, (2) a hydrophilic peptide spacer, (3) a disulfide-containing, self-immolative linker, and (4) the cytotoxic drug, desacetylvinblastine hydrazide (DAVLBH). Here, we report a structure-activity study evaluating the biological impact of (i) substituting DAVLBH within the vintafolide molecule with other vinca alkaloid analogues such as vincristine, vindesine, vinflunine, or vinorelbine; (ii) substituting the naturally (S)-configured Asp-Arg-Asp-Asp-Cys peptide with alternative hydrophilic spacers of varied composition; and (iii) varying the composition of the linker module. A series of vinca alkaloid-containing SMDCs were synthesized and purified by HPLC and LCMS. The SMDCs were screened in vitro against folate receptor (FR)-positive cells, and anti-tumor activity was tested against well-established subcutaneous FR-positive tumor xenografts. The cytotoxic and anti-tumor activity was directly compared to that produced by vintafolide. Among all the folate vinca alkaloid SMDCs tested, DAVLBH-containing SMDCs were active, while those constructed with vincristine, vindesine, or vinorelbine analogues failed to produce meaningful biological activity. Within the DAVLBH series, having a bioreleasable, self-immolative linker system was found to be critical for activity since multiple analogues constructed with thioether-based linkers all failed to produce meaningful activity both in vitro and in vivo. Substitutions of some or all of the natural amino acids within vintafolide's hydrophilic spacer module did not significantly change the in vitro or in vivo potency of the SMDCs. Vintafolide remains one of the most potent folate-vinca alkaloid SMDCs produced to date, and continued clinical development is warranted. PMID:24564229

Leamon, Christopher P; Vlahov, Iontcho R; Reddy, Joseph A; Vetzel, Marilynn; Santhapuram, Hari Krishna R; You, Fei; Bloomfield, Alicia; Dorton, Ryan; Nelson, Melissa; Kleindl, Paul; Vaughn, Jeremy F; Westrick, Elaine

2014-03-19

184

A distinct atomic structure-catalytic activity relationship in 3-10 nm supported Au particles  

NASA Astrophysics Data System (ADS)

Bulk Au is very inert but Au nanoparticles less than 5 nm in size have been found to be catalytically active for several reactions, in particular for low-temperature oxidation of CO. Using high-energy X-ray diffraction coupled with atomic pair distribution function analysis and computer simulations we determine the structure of 3 nm and 10 nm Au particles supported on titania and silica as typical representatives of reducible and irreducible supports, respectively. We find that the synthesis protocol adopted in our work affects strongly and differently the structure of the Au nanoparticles on the different supports. This leads to clearly distinct dependences of the catalytic activity of the nanoparticles on their size. In the case of the silica support the catalytic activity of Au nanoparticles increases and in the case of the titania support it decreases with decreasing nanoparticle size. The experimental results are considered in terms of current theoretical predictions and found to be in good accord with them.Bulk Au is very inert but Au nanoparticles less than 5 nm in size have been found to be catalytically active for several reactions, in particular for low-temperature oxidation of CO. Using high-energy X-ray diffraction coupled with atomic pair distribution function analysis and computer simulations we determine the structure of 3 nm and 10 nm Au particles supported on titania and silica as typical representatives of reducible and irreducible supports, respectively. We find that the synthesis protocol adopted in our work affects strongly and differently the structure of the Au nanoparticles on the different supports. This leads to clearly distinct dependences of the catalytic activity of the nanoparticles on their size. In the case of the silica support the catalytic activity of Au nanoparticles increases and in the case of the titania support it decreases with decreasing nanoparticle size. The experimental results are considered in terms of current theoretical predictions and found to be in good accord with them. Electronic supplementary information (ESI) available: XRD patterns, and TEM and catalytic activity data. See DOI: 10.1039/c3nr05362h

Petkov, Valeri; Ren, Yang; Shan, Shiyao; Luo, Jin; Zhong, Chuan-Jian

2013-12-01

185

PLS modelling of structure-activity relationships of catechol O-methyltransferase inhibitors.  

PubMed

Quantitative structure-activity analysis was carried out for in vitro inhibition of rat brain soluble catechol O-methyltransferase by a series (N = 99) of 1,5-substituted-3,4-dihydroxybenzenes using computational chemistry and multivariate PLS modelling of data sets. The molecular structural descriptors (N = 19) associated with the electronics of the catecholic ring and sizes of substituents were derived theoretically. For the whole set of molecules two separate PLS models have to be used. A PLS model with two significant (crossvalidated) model dimensions describing 82.2% of the variance in inhibition activity data was capable of predicting all molecules except those having the largest R1 substituent or having a large R5 substituent compared to the NO2 group. The other PLS model with three significant (crossvalidated) model dimensions described 83.3% of the variance in inhibition activity data. This model could not handle compounds having a small R5 substituent, compared to the NO2 group, or the largest R1 substituent. The predictive capability of these PLS models was good. The models reveal that inhibition activity is nonlinearly related to the size of the R5 substituent. The analysis of the PLS models also shows that the binding affinity is greatly dependent on the electronic nature of both R1 and R5 substituents. The electron-withdrawing nature of the substituents enhances inhibition activity. In addition, the size of the R1 substituent and its lipophilicity are important in the binding of inhibitors. The size of the R1 substituent has an upper limit. On the other hand, ionized R1 substituents decrease inhibition activity. PMID:1517777

Lotta, T; Taskinen, J; Bäckström, R; Nissinen, E

1992-06-01

186

Structure-activity relationships of derivatives of fusapyrone, an antifungal metabolite of Fusarium semitectum.  

PubMed

Fusapyrone (1) and deoxyfusapyrone (2) are two 3-substituted-4-hydroxy-6-alkyl-2-pyrones isolated from Fusarium semitectum that have considerable antifungal activity against molds. Because of their low zootoxicity and selective action they are potentially utilizable along with biocontrol yeasts for control of postharvest crop diseases. Seven derivatives of 1 (3 and 5-10) and one derivative of 2 (4) were obtained by chemical modifications of the glycosyl residue, the 2-pyrone ring, the aliphatic chain, or a combination thereof, and a structure-activity correlation study was carried out with regard to their zootoxicity and antifungal activity. Derivatives 7-10, as well as 1, were slightly zootoxic in Artemia salina (brine shrimp) bioassays, whereas pentaacetylation of 1 into 3, 5, and 6 resulted in a strong increase in toxicity. Compound 4, the tetraacetyl derivative of 2, was as toxic as 2. Because the structural changes of 1 that resulted in an increase of biological activity in A. salina bioassay were those that affected mainly the water solubility of the molecule, it appears that toxicity is related to hydrophobicity. Compounds 1 and 2 showed strong antifungal activity toward Botrytis cinerea, Aspergillus parasiticus, and Penicilliun brevi-compactum (minimum inhibitory concentration at 24 h = 0.78-6.25 microg/mL). Among derivatives 3-10, only compounds 7, 9, and 10 retained some activity, limited to B. cinerea and at high concentration (25-50 microg/mL). None of the compounds 1-10 inhibited the growth of the biocontrol yeasts Pichia guilliermondii and Rhodotorula glutinis at the highest concentration tested (50 microg/mL). PMID:15137845

Altomare, Claudio; Pengue, Raffaele; Favilla, Mara; Evidente, Antonio; Visconti, Angelo

2004-05-19

187

Cationic membrane peptides: atomic-level insight of structure-activity relationships from solid-state NMR.  

PubMed

Many membrane-active peptides, such as cationic cell-penetrating peptides (CPPs) and antimicrobial peptides (AMPs), conduct their biological functions by interacting with the cell membrane. The interactions of charged residues with lipids and water facilitate membrane insertion, translocation or disruption of these highly hydrophobic species. In this review, we will summarize high-resolution structural and dynamic findings towards the understanding of the structure-activity relationship of lipid membrane-bound CPPs and AMPs, as examples of the current development of solid-state NMR (SSNMR) techniques for studying membrane peptides. We will present the most recent atomic-resolution structure of the guanidinium-phosphate complex, as constrained from experimentally measured site-specific distances. These SSNMR results will be valuable specifically for understanding the intracellular translocation pathway of CPPs and antimicrobial mechanism of AMPs, and more generally broaden our insight into how cationic macromolecules interact with and cross the lipid membrane. PMID:23108593

Su, Yongchao; Li, Shenhui; Hong, Mei

2013-03-01

188

Antimicrobial Photodynamic Therapy with Functionalized Fullerenes: Quantitative Structure-activity Relationships  

PubMed Central

Photosensitive dyes or photo sensitizers (PS) in combination with visible light and oxygen produce reactive oxygen species that kill cells in the process known as photodynamic therapy (PDT). Antimicrobial PDT employs PS that is selective for microbial cells and is a new treatment for infections. Most antimicrobial PS is based on tetrapyrrole or phenothiazinium structures that have been synthesized to carry quaternary cationic charges or basic amino groups. However we recently showed that cationic-substituted fullerene derivative were highly effective in killing a broad spectrum of microbial cells after illumination with white light. In the present report we compared a new group of synthetic fullerene derivatives that possessed either basic or quaternary amino groups as antimicrobial PS against Gram-positive (Staphylococcus aureus), Gram-negative bacteria (Escherichia coli) and fungi (Candida albicans). Quantitative structure-function relationships were derived with LogP and hydrophilic lipophilic balance parameters. Compounds with non-quaternary amino groups tended to form nanoaggregates in water and were only effective against S. aureus. The most important determinant of effectiveness was an increased number of quaternary cationic groups that were widely dispersed around the fullerene cage to minimize aggregation. S. aureus was most susceptible; E. coli was intermediate, while C. albicans was the most resistant species tested. The high effectiveness of antimicrobial PDT with quaternized fullerenes suggest they may have applications in treatment of superficial infections (for instance in wounds and burns) where light penetration into tissue is not problematic. PMID:21743839

Mizuno, Kazue; Zhiyentayev, Timur; Huang, Liyi; Khalil, Sarwat; Nasim, Faria; Tegos, George P; Gali, Hariprasad; Jahnke, Ashlee; Wharton, Tim; Hamblin, Michael R

2011-01-01

189

Calophyllum inophyllum and Calophyllum soulattri source of anti-proliferative xanthones and their structure-activity relationships.  

PubMed

Extensive chromatographic isolation and purification of the extracts of the stem bark of Calophyllum inophyllum and Calophyllum soulattri have resulted in 11 xanthones. C. inophyllum gave inophinnin (1), inophinone (2), pyranojacareubin (5), rheediaxanthone A (6), macluraxanthone (7) and 4-hydroxyxanthone (8), while C. soulattri afforded soulattrin (3), phylattrin (4), caloxanthone C (9), brasixanthone B (10) and trapezifolixanthone (11). The structures of these compounds were determined on the basis of spectroscopic analyses such as 1D and 2D NMR, GC-MS, IR and UV. Cytotoxicity screening (MTT assay) carried out in vitro on all the xanthones using five human cancer cell lines indicated good activities for some of these xanthones. The structure-activity relationship study revealed that the inhibitory activities exhibited by these xanthone derivatives to be closely related to the existence and nature of the pyrano and the prenyl substituent groups on their skeleton. PMID:25229947

Mah, Siau Hui; Ee, Gwendoline Cheng Lian; Teh, Soek Sin; Sukari, Mohd Aspollah

2015-01-01

190

Investigation of DNA-binding properties of an aminoglycoside-polyamine library using quantitative structure-activity relationship (QSAR) models.  

PubMed

We have recently developed a novel multivalent cationic library based on the derivatization of aminoglycosides by linear polyamines. In the current study, we describe the DNA-binding activity of this library. Screening results indicated that several candidates from the library showed high DNA-binding activities with some approaching those of cationic polymers. Quantitative Structure-Activity Relationship (QSAR) models of the screening data were employed to investigate the physicochemical effects governing polyamine-DNA binding. The utility of these models for the a priori prediction of polyamine-DNA-binding affinity was also demonstrated. Molecular descriptors selected in the QSAR modeling indicated that molecular size, basicity, methylene group spacing between amine centers, and hydrogen-bond donor groups of the polyamine ligands were important contributors to their DNA-binding efficacy. The research described in this paper has led to the development of new multivalent ligands with high DNA-binding activity and improved our understanding of structure-activity relationships involved in polyamine-DNA binding. These results have implications for the discovery of novel polyamine ligands for nonviral gene delivery, plasmid DNA purification, and anticancer therapeutics. PMID:16309293

Rege, Kaushal; Ladiwala, Asif; Hu, Shanghui; Breneman, Curt M; Dordick, Jonathan S; Cramer, Steven M

2005-01-01

191

Structure-activity relationships of piscidin 4, a piscine antimicrobial peptide.  

PubMed

Piscidin 4, an antimicrobial peptide recently isolated from mast cells of hybrid striped bass (Morone chrysops female × Morone saxatilis male), is unusual in that it is twice as long (44 amino acids) as the typical members of the piscidin family. We previously showed that native piscidin 4 had a modified amino acid at position 20, but synthetic piscidin 4 (having an unmodified Trp at position 20) had similar potent activity against a number of both human and fish bacterial pathogens. In this study, the structure and membrane topology of synthetic piscidin 4 were examined using liposomes as model bilayers. Circular dichroism analyses revealed that it had a disordered structure in aqueous solution and folded to form a relatively weak ?-helical structure in both membrane-mimetic trifluoroethanol solutions and liposome suspensions. Fluorescence data (piscidin 4 embedded in liposomes) and leakage experiments indicated that piscidin 4 interacted strongly with the hydrophobic part of the liposome. Binding of piscidin 4 to liposomes induced significant blue shifts of the emission spectra of the single Trp residue (Trp20). Quenching of Trp20 by water-soluble quencher (either acrylamide or I-) indicated that the fluorescence of Trp20 decreased more in the presence of liposomes than in buffer solution, thus revealing that Trp20 is less accessible to the quenchers in the presence of liposomes. The relative leakage abilities of piscidin 4 (1 ?M) with liposomes were in the following order: DPPC (100%)?EYPC (94%)>DPPC/DPPG (65%)>EYPC/EYPG (0%). This high activity against DPPC and EYPC liposomes was contrary to our data suggesting that piscidin 4 has a much weaker tendency to form an ?-helix than other piscidins, such as piscidin 1. However, the structural similarity of protozoan membranes to EYPC liposomes might explain our discovery of the potent activity of piscidin 4 against the important skin/gill parasite ich (Ichthyophthirius multifiliis), but its negligible hemolytic activity against vertebrate membranes (hybrid striped bass or human erythrocytes). It also suggests that other conformation(s) in addition to the ?-helix of this peptide may be responsible for its selective activity. This differential toxicity also suggests that piscidin 4 plays a significant role in the innate defense system of hybrid striped bass and may be capable of functioning extracellularly. PMID:21355570

Park, N G; Silphaduang, U; Moon, H S; Seo, J-K; Corrales, J; Noga, E J

2011-04-26

192

Structure–activity relationships in Kluyveromyces lactis ?-toxin, a eukaryal tRNA anticodon nuclease  

PubMed Central

tRNA anticodon damage inflicted by secreted ribotoxins such as Kluyveromyces lactis ?-toxin and bacterial colicins underlies a rudimentary innate immune system that distinguishes self from nonself species. The intracellular expression of ?-toxin (a 232-amino acid polypeptide) arrests the growth of Saccharomyces cerevisiae by incising a single RNA phosphodiester 3? of the modified wobble base of tRNAGlu. Fungal ?-toxin bears no primary structure similarity to any known nuclease and has no plausible homologs in the protein database. To gain insight to ?-toxin's mechanism, we tested the effects of alanine mutations at 62 basic, acidic, and polar amino acids on ribotoxin activity in vivo. We thereby identified 22 essential residues, including 10 lysines, seven arginines, three glutamates, one cysteine, and one histidine (His209, the only histidine present in ?-toxin). Structure–activity relations were gleaned from the effects of 44 conservative substitutions. Recombinant tag-free ?-toxin, a monomeric protein, incised an oligonucleotide corresponding to the anticodon stem–loop of tRNAGlu at a single phosphodiester 3? of the wobble uridine. The anticodon nuclease was metal independent. RNA cleavage was abolished by ribose 2?-H and 2?-F modifications of the wobble uridine. Mutating His209 to alanine, glutamine, or asparagine abolished nuclease activity. We propose that ?-toxin catalyzes an RNase A-like transesterification reaction that relies on His209 and a second nonhistidine side chain as general acid–base catalysts. PMID:19383764

Keppetipola, Niroshika; Jain, Ruchi; Meineke, Birthe; Diver, Melinda; Shuman, Stewart

2009-01-01

193

The relationship between molecular structure and biological activity of alkali metal salts of vanillic acid: spectroscopic, theoretical and microbiological studies.  

PubMed

In this paper we investigate the relationship between molecular structure of alkali metal vanillate molecules and their antimicrobial activity. To this end FT-IR, FT-Raman, UV absorption and (1)H, (13)C NMR spectra for lithium, sodium, potassium, rubidium and caesium vanillates in solid state were registered, assigned and analyzed. Microbial activity of studied compounds was tested against Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, Proteus vulgaris, Bacillus subtilis and Candida albicans. In order to evaluate the dependence between chemical structure and biological activity of alkali metal vanillates the statistical analysis was performed for selected wavenumbers from FT-IR spectra and parameters describing microbial activity of vanillates. The geometrical structures of the compounds studied were optimized and the structural characteristics were determined by density functional theory (DFT) using at B3LYP method with 6-311++G** as basis set. The obtained statistical equations show the existence of correlation between molecular structure of vanillates and their biological properties. PMID:22341494

?wis?ocka, Renata; Piekut, Jolanta; Lewandowski, W?odzimierz

2013-01-01

194

Structure-Activity Relationship in Nanostructured Copper-Ceria-Based Preferential CO Oxidation Catalysts  

SciTech Connect

Two series of nanostructured oxidized copper-cerium catalysts with varying copper loadings, and prepared, respectively, by impregnation of ceria and by coprecipitation of the two components within reverse microemulsions, have been characterized in detail at structural and electronic levels by X-ray diffraction (XRD), Raman spectroscopy, high-resolution electron microscopy (HREM), X-ray energy dispersive spectroscopy (XEDS), X-ray photoelectron spectroscopy (XPS) (including Ar{sup +}-sputtering), and X-ray absorption fine structure (XAFS). These results have been correlated with analysis of their catalytic properties for preferential oxidation of CO in a H{sub 2}-rich stream (CO-PROX), complemented by Operando-DRIFTS. A relevant difference between the two series of catalysts concerns the nature of the support for the surface-dispersed copper oxide entities, which is essentially ceria for the samples prepared by impregnation and a Ce-Cu mixed oxide for those prepared by microemulsion-coprecipitation. The existence of copper segregation in the form of copper oxide or copper-enriched Cu-Ce mixed oxides for the latter type of samples is uniquely revealed by nanoprobe XEDS and XPS Ar{sup +}-sputtering experiments. The CO oxidation activity under CO-PROX conditions is correlated to the degree of support-promoted reduction achieved by the dispersed copper oxide particles under reaction conditions. Nevertheless, catalysts which display higher CO oxidation activity are generally more efficient also for the undesired H{sub 2} oxidation reaction. The balance between both reactions results in differences in the CO-PROX activity between the two series of catalysts which are examined on the basis of the structural differences found.

Gamarra,D.; Munuera, G.; Hungria, A.; Fernandez-Garcia, M.; Conesa, J.; Midgley, P.; Wang, X.; Hanson, J.; Rodriguez, J.; Martinez-Arias, A.

2007-01-01

195

Quantitative structure-activity relationship (QSAR) studies for predicting activation of the ryanodine receptor type 1 channel complex (RyR1) by polychlorinated biphenyl (PCB) congeners  

Microsoft Academic Search

A quantitative structure-activity relationship (QSAR) was developed to predict the congener specific ryanodine receptor type RyR1 activity of all 209 polychlorinated biphenyl (PCB) congeners. A three-variable QSAR equation was obtained via stepwise forward linear regression on an unsupervised forward selection reduced data set from an initial database. Application of the QSAR towards predicting EC2x values for all 209 PCB congeners

Sierra Rayne; Kaya Forest

2010-01-01

196

Respiratory syncytial virus fusion inhibitors. Part 7: Structure–activity relationships associated with a series of isatin oximes that demonstrate antiviral activity in vivo  

Microsoft Academic Search

A series of bezimidazole-isatin oximes were prepared and profiled as inhibitors of respiratory syncytial virus (RSV) replication in cell culture. Structure–activity relationship studies were directed toward optimization of antiviral activity, cell permeability and metabolic stability in human liver micorosomes (HLM). Parallel combinatorial synthetic chemistry was employed to functionalize isatin oximes via O-alkylation which quickly identified a subset of small, lipophilic

Ny Sin; Brian L. Venables; Keith D. Combrink; H. Belgin Gulgeze; Kuo-Long Yu; Rita L. Civiello; Jan Thuring; X. Alan Wang; Zheng Yang; Lisa Zadjura; Anthony Marino; Kathleen F. Kadow; Christopher W. Cianci; Junius Clarke; Eugene V. Genovesi; Ivette Medina; Lucinda Lamb; Mark Krystal; Nicholas A. Meanwell

2009-01-01

197

Synthesis and structure-activity relationship of dihydrobenzofuran derivatives as novel human GPR119 agonists.  

PubMed

Through appropriate medicinal chemistry design tactics and computer-assisted conformational modeling, the initial lead A was evolved into a series of dihydrobenzofuran derivatives 3 as potent GPR119 agonists. This Letter describes the optimization of general structure 3, including the substituent(s) on dihydrobenzofuran, the R(1) attachment on right-hand piperidine nitrogen, and the left-hand piperidine/piperazine and its attachment R(2). The efforts led to the identification of compounds 13c and 24 as potent human GPR119 modulators with favorable metabolic stability, ion channel activity, and PXR profiles. PMID:24755425

Ye, Xiang-Yang; Morales, Christian L; Wang, Ying; Rossi, Karen A; Malmstrom, Sarah E; Abousleiman, Mojgan; Sereda, Larisa; Apedo, Atsu; Robl, Jeffrey A; Miller, Keith J; Krupinski, John; Wacker, Dean A

2014-06-01

198

Structure-Function Relationships in [FeFe]-Hydrogenase Active Site Maturation*  

PubMed Central

Since the discovery that, despite the active site complexity, only three gene products suffice to obtain active recombinant [FeFe]-hydrogenase, significant light has been shed on this process. Both the source of the CO and CN? ligands to iron and the assembly site of the catalytic subcluster are known, and an apo structure of HydF has been published recently. However, the nature of the substrate(s) for the synthesis of the bridging dithiolate ligand to the subcluster remains to be established. From both spectroscopy and model chemistry, it is predicted that an amine function in this ligand plays a central role in catalysis, acting as a base in the heterolytic cleavage of hydrogen. PMID:22389497

Nicolet, Yvain; Fontecilla-Camps, Juan C.

2012-01-01

199

Quantitative structure-activity relationship analysis of acute toxicity of diverse chemicals to Daphnia magna with whole molecule descriptors.  

PubMed

Quantitative structure-activity relationship analysis and estimation of toxicological effects at lower-mid trophic levels provide first aid means to understand the toxicity of chemicals. Daphnia magna serves as a good starting point for such toxicity studies and is also recognized for regulatory use in estimating the risk of chemicals. The ECOTOX database was queried and analysed for available data and a homogenous subset of 253 compounds for the endpoint LC50 48?h was established. A four-parameter quantitative structure-activity relationship was derived (coefficient of determination, r (2)?=?0.740) for half of the compounds and internally validated (leave-one-out cross-validated coefficient of determination, [Formula: see text]?=?0.714; leave-many-out coefficient of determination, [Formula: see text]?=?0.738). External validation was carried out with the remaining half of the compounds (coefficient of determination for external validation, [Formula: see text]?=?0.634). Two of the descriptors in the model (log P, average bonding information content) capture the structural characteristics describing penetration through bio-membranes. Another two descriptors (energy of highest occupied molecular orbital, weighted partial negative surface area) capture the electronic structural characteristics describing the interaction between the chemical and its hypothetic target in the cell. The applicability domain was subsequently analysed and discussed. PMID:21999753

Moosus, M; Maran, U

2011-10-01

200

Synthesis and structure-activity relationship of N-(cinnamyl) chitosan analogs as antimicrobial agents.  

PubMed

The current study focuses on the preparation of new N-(cinnamyl) chitosan derivatives as antimicrobial agents against nine types of crop-threatening pathogens. Chitosan was reacted with a set of aromatic cinnamaldehyde analogs by reductive amination involving formation of the corresponding imines, followed by reduction with sodium borohydride to produce N-(cinnamyl) chitosan derivatives. The structural characterization was confirmed by (1)H and (13)C NMR spectroscopy and the degrees of substitution ranged from 0.08 to 0.28. The antibacterial activity was evaluated in vitro by minimum inhibitory concentration (MIC) against Agrobacterium tumefaciens and Erwinia carotovora. A higher inhibition activity was obtained by N-(?-methylcinnamyl) chitosan with MIC 1275 and 1025 mg/L against A. tumefaciens and E. carotovora, respectively followed by N-(o-methoxycinnamyl) chitosan (MIC=1925 and 1550 mg/L, respectively). The antifungal assessment was evaluated in vitro by mycelial radial growth technique against Alternaria alternata, Botrytis cinerea, Botryodiplodia theobromae, Fusarium oxysporum, Fusarium solani, Pythium debaryanum and Phytophthora infestans. N-(o-methoxycinnamyl) chitosan showed the highest antifungal activity among the tested compounds against the airborne fungi A. alternata, B. cinerea, Bd. theobromae and Ph. infestans with EC?? of 672, 796, 980 and 636 mg/L, respectively. However, N-(p-N-dimethylaminocinnamyl) chitosan was the most active against the soil born fungi F. oxysporum, F. solani and P. debaryanum (EC50=411, 566 and 404 mg/L, respectively). On the other hand, the chitosan derivatives caused significant reduction in spore germination of A. alternata, B. cinerea, F. oxysporum and F. solani compared to chitosan and the reduction in spore germination was higher than that of the mycelia inhibition. The synthesis and characterization of new chitosan derivatives are ongoing in our laboratory aiming to obtain derivatives with higher antimicrobial activities and used as safe alternatives to harmful microbicides. PMID:23511055

Badawy, Mohamed E I; Rabea, Entsar I

2013-06-01

201

Structure-Activity Relationship of New Antituberculosis Agents Derived from Oxazoline and Oxazole Esters  

PubMed Central

During the syntheses and studies of natural iron chelators (mycobactins), we serendipitously discovered that a simple, small molecule, oxazoline-containing intermediate 3 displayed surprising anti-tuberculosis activity (MIC of 7.7 µM, average). Herein we report elaboration of SAR around this hit as well as the syntheses and evaluation of a hundred oxazoline- and oxazole-containing compounds derived from an efficient three step process: 1) formation of ?-hydroxy amides with serine or threonine; 2) cyclization to afford oxazolines; and 3) dehydration to give the corresponding oxazoles. A number of compounds prepared by this method were shown to possess impressive activity against M. tuberculosis, extremely low toxicity and therefore high therapeutic indexes, as well as activity against even the more recalcitrant non-replicating form of M. tuberculosis. The uniqueness of their structures and their simplicity should allow them to be further optimized to meet ADME (absorption, distribution, metabolism, excretion) requirements. The syntheses of eight of the most potent in vitro compounds were scaled up and the compounds were tested in an in vivo mouse infection model to evaluate their efficacy before engaging upon more elaborate compound design and optimization. PMID:20116900

Moraski, Garrett C.; Chang, Mayland; Villegas-Estrada, Adriel; Franzblau, Scott G.; Möllmann, Ute; Miller, Marvin J.

2010-01-01

202

Structure-activity relationships of mineral dusts as heterogeneous nuclei for ammonium sulfate crystallization from supersaturated aqueous solutions.  

PubMed

Mineral inclusions, present in aqueous atmospheric salt droplets, regulate crystallization when relative humidity decreases by providing a surface for heterogeneous nucleation and thus reducing the critical supersaturation. Although laboratory studies have quantified these processes to some extent, the diverse atmospheric mineralogy presents more chemical systems than practically feasible for direct study. Structure--activity relationships are necessary. To that end, in the present work the interactions of ammonium sulfate with corundum, hematite, mullite, rutile, anatase, and baddeleyite were studied by diffuse reflectance fourier transform infrared spectroscopy (DRIFTS) and by epitaxial modeling. The spectroscopic results show that shifts in sulfate peak positions due to chemisorption are not a correlative indicator of the efficacy of heterogeneous nucleation. In contrast, epitaxial modeling results of unreconstructed surfaces explain the sequence of critical supersaturations for constant particle size. If validated by further work, this computer modeling method would provide an important structure--activity tool for the estimation of heterogeneous nucleation properties of the atmospheric mineralogy. PMID:11329712

Martin, S T; Schlenker, J; Chelf, J H; Duckworth, O W

2001-04-15

203

Pharmacophore modeling and 3D quantitative structure-activity relationship analysis of febrifugine analogues as potent antimalarial agent  

PubMed Central

Febrifugine and its derivatives are effective against Plasmodium falciparum. Using PHASE algorithm, a five-point pharmacophore model with two hydrogen bond acceptor (A), one positively ionizable (P) and two aromatic rings (R), was developed to derive a predictive ligand-based statistically significant 3D-quantitative structure-activity relationship (QSAR) model (r2 = 0.972, SD = 0.3, F = 173.4, Q2 = 0.712, RMSE = 0.3, Person-R = 0.94, and r2pred = 0.8) to explicate the structural attributes crucial for antimalarial activity. The developed pharmacophore model and 3D QSAR model can be a substantial tool for virtual screening and related antimalarial drug discovery research. PMID:23662282

Sen, Debanjan; Chatterjee, Tapan Kumar

2013-01-01

204

Design, synthesis and structure-activity relationships of azole acids as novel, potent dual PPAR alpha/gamma agonists.  

PubMed

The design, synthesis and structure-activity relationships of a novel series of N-phenyl-substituted pyrrole, 1,2-pyrazole and 1,2,3-triazole acid analogs as PPAR ligands are outlined. The triazole acid analogs 3f and 4f were identified as potent dual PPARalpha/gamma agonists both in binding and functional assays in vitro. The 3-oxybenzyl triazole acetic acid analog 3f showed excellent glucose and triglyceride lowering in diabetic db/db mice. PMID:19201606

Zhang, Hao; Ryono, Denis E; Devasthale, Pratik; Wang, Wei; O'Malley, Kevin; Farrelly, Dennis; Gu, Liqun; Harrity, Thomas; Cap, Michael; Chu, Cuixia; Locke, Kenneth; Zhang, Litao; Lippy, Jonathan; Kunselman, Lori; Morgan, Nathan; Flynn, Neil; Moore, Lisa; Hosagrahara, Vinayak; Zhang, Lisa; Kadiyala, Pathanjali; Xu, Carrie; Doweyko, Arthur M; Bell, Aneka; Chang, Chiehying; Muckelbauer, Jodi; Zahler, Robert; Hariharan, Narayanan; Cheng, Peter T W

2009-03-01

205

Synthesis, Structure-Activity Relationship, and Pharmacological Profile of Analogs of The ASIC-3 Inhibitor A-317567  

PubMed Central

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. PMID:22778804

2009-01-01

206

Structure-activity relationships in the free-radical metabolism of xenobiotics  

SciTech Connect

Many xenobiotics, including naturally occurring compounds, drugs, and environmental agents, are metabolized both in vivo and in vitro to free-radical intermediates. The one-electron reduction of nitroaromatic compounds, quinones, and a wide variety of other chemicals is catalyzed enzymatically by a number of reductases and dehydrogenases. Structure-activity studies have shown that the cytotoxicities of nitroaromatic compounds and quinones are related to their one-electron reduction potentials (E/sub 7//sup 1/). Other factors such as oil:water partition coefficients may also be important. Xenobiotics may also be oxidized to free radicals by peroxidases and oxidases. Hammett's rules apply to the one-electron oxidation of simple meta- and para-substituted phenols and amines by horseradish peroxidase, compound I.

Chignell, C.F.

1985-09-01

207

Structure-activity relationships of pentamidine-affected ion channel trafficking and dofetilide mediated rescue  

PubMed Central

Background and Purpose Drug interference with normal hERG protein trafficking substantially reduces the channel density in the plasma membrane and thereby poses an arrhythmic threat. The chemical substructures important for hERG trafficking inhibition were investigated using pentamidine as a model drug. Furthermore, the relationship between acute ion channel block and correction of trafficking by dofetilide was studied. Experimental Approach hERG and KIR2.1 trafficking in HEK293 cells was evaluated by Western blot and immunofluorescence microscopy after treatment with pentamidine and six pentamidine analogues, and correction with dofetilide and four dofetilide analogues that displayed different abilities to inhibit IKr. Molecular dynamics simulations were used to address mode, number and type of interactions between hERG and dofetilide analogues. Key Results Structural modifications of pentamidine differentially affected plasma membrane levels of hERG and KIR2.1. Modification of the phenyl ring or substituents directly attached to it had the largest effect, affirming the importance of these chemical residues in ion channel binding. PA-4 had the mildest effects on both ion channels. Dofetilide corrected pentamidine-induced hERG, but not KIR2.1 trafficking defects. Dofetilide analogues that displayed high channel affinity, mediated by pi-pi stacks and hydrophobic interactions, also restored hERG protein levels, whereas analogues with low affinity were ineffective. Conclusions and Implications Drug-induced trafficking defects can be minimized if certain chemical features are avoided or ‘synthesized out’; this could influence the design and development of future drugs. Further analysis of such features in hERG trafficking correctors may facilitate the design of a non-blocking corrector for trafficking defective hERG proteins in both congenital and acquired LQTS. PMID:23586323

Varkevisser, R; Houtman, M J C; Linder, T; de Git, K C G; Beekman, H D M; Tidwell, R R; IJzerman, A P; Stary-Weinzinger, A; Vos, M A; van der Heyden, M A G

2013-01-01

208

Anti-Cancer Efficacy of Silybin Derivatives - A Structure-Activity Relationship  

PubMed Central

Silybin or silibinin, a flavonolignan isolated from Milk thistle seeds, is one of the popular dietary supplements and has been extensively studied for its antioxidant, hepatoprotective and anti-cancer properties. We have envisioned that potency of silybin could be further enhanced through suitable modification/s in its chemical structure. Accordingly, here, we synthesized and characterized a series of silybin derivatives namely 2,3-dehydrosilybin (DHS), 7-O-methylsilybin (7OM), 7-O-galloylsilybin (7OG), 7,23-disulphatesilybin (DSS), 7-O-palmitoylsilybin (7OP), and 23-O-palmitoylsilybin (23OP); and compared their anti-cancer efficacy using human bladder cancer HTB9, colon cancer HCT116 and prostate carcinoma PC3 cells. In all the 3 cell lines, DHS, 7OM and 7OG demonstrated better growth inhibitory effects and compared to silybin, while other silybin derivatives showed lesser or no efficacy. Next, we prepared the optical isomers (A and B) of silybin, DHS, 7OM and 7OG, and compared their anti-cancer efficacy. Isomers of these three silybin derivatives also showed better efficacy compared with respective silybin isomers, but in each, there was no clear cut silybin A versus B isomer activity preference. Further studies in HTB cells found that DHS, 7OM and 7OG exert better apoptotic activity than silibinin. Clonogenic assays in HTB9 cells further confirmed that both the racemic mixtures as well as pure optical isomers of DHS, 7OM and 7OG were more effective than silybin. Overall, these results clearly suggest that the anti-cancer efficacy of silybin could be significantly enhanced through structural modifications, and identify strong anti-cancer efficacy of silybin derivatives, namely DHS, 7OM, and 7OG, signifying that their efficacy and toxicity should be evaluated in relevant pre-clinical cancer models in rodents. PMID:23555889

Agarwal, Chapla; Wadhwa, Ritambhara; Deep, Gagan; Biedermann, David; Gažák, Radek; K?en, Vladimír; Agarwal, Rajesh

2013-01-01

209

Haloalkylamine-induced renal papillary necrosis: a histopathological study of structure-activity relationships.  

PubMed

The haloalkylamine 2-bromoethanamine (BEA) causes necrosis of renal papillae of rats within 24 h of a single intraperitoneal dose greater than or equal to 100 mg/kg. Nine structural analogues of BEA, differing by halide substitution, alkyl chain elongation or amine substitution, were tested for their ability to induce renal papillary lesions in rats. Three compounds (2-chloroethanamine, 3-bromopropanamine and 2-chloro-N,N-dimethylethanamine) induced lesions which were morphologically indistinguishable from those of BEA. All the molecular structural variations investigated reduced papillotoxicity compared with BEA, the parent compound. A variety of non-renal lesions including hepatic, adrenal, testicular and lymphoid necroses were also encountered. The most toxic compound was 2-fluorethanamine, a 5 mg/kg dose of which was lethal and induced renal corticomedullary mineralization and centrilobular hepatic necrosis. One analogue, 3-bromo-2-hydroxypropanamine, caused rapid and extensive necrosis of the adrenal pars fasciculata and reticularis, simulating human Waterhouse Friderichsen syndrome. The three newly identified renal papillotoxins are all theoretically capable of generating direct-acting alkylating species in solution and their activity as direct-acting mutagens in the Ames bacterial mutagenicity test with TA100 (indicating base pair substitution) closely correlated with their potency as papillotoxins. We therefore hypothesize that non-enzymically formed direct-acting alkylating species mediate these papillary lesions, and that the target selectivity of haloalkylamine toxicity most probably results from the accumulation of these alkylating species in papillary tissue. PMID:1768609

Powell, C J; Grasso, P; Ioannides, C; Wilson, J; Bridges, J W

1991-12-01

210

Acyl sulfonamide anti-proliferatives: benzene substituent structure-activity relationships for a novel class of antitumor agents.  

PubMed

Two closely related diaryl acylsulfonamides were recently reported as potent antitumor agents against a broad spectrum of human tumor xenografts (colon, lung, breast, ovary, and prostate) in nude mice. Especially intriguing was their activity against colorectal cancer xenografts. In this paper, rapid parallel synthesis along with traditional medicinal chemistry techniques were used to quickly delineate the structure-activity relationships of the substitution patterns in both phenyl rings of the acylsufonamide anti-proliferative scaffold. Although the molecular target of the compounds remains unclear, we determined that the vascular endothelial growth factor-dependent human umbilical vein endothelial cells assay in combination with a soft agar disk diffusion assay allowed for optimization of potency in the series. The pharmacokinetic properties and in vivo activity in an HCT116 xenograft model are reported for representative compounds. PMID:15481975

Lobb, Karen L; Hipskind, Philip A; Aikins, James A; Alvarez, Enrique; Cheung, Yiu-Yin; Considine, Eileen L; De Dios, Alfonso; Durst, Gregory L; Ferritto, Rafael; Grossman, Cora Sue; Giera, Deborah D; Hollister, Beth A; Huang, Zhongping; Iversen, Philip W; Law, Kevin L; Li, Tiechao; Lin, Ho-Shen; Lopez, Beatriz; Lopez, Jose E; Cabrejas, Luisa M Martin; McCann, Denis J; Molero, Victoriano; Reilly, John E; Richett, Michael E; Shih, Chuan; Teicher, Beverly; Wikel, James H; White, Wesley T; Mader, Mary M

2004-10-21

211

New imidazo[1,2-b]pyrazoles as anticancer agents: synthesis, biological evaluation and structure activity relationship analysis.  

PubMed

Synthesis and functionalization strategies of the imidazo[1,2-b]pyrazole core were developed giving a rapid access to three series of novel imidazo[1,2-b]pyrazole type derivatives: C-2/C-6/C-7 trisubstituted, C-2/C-3/C-6 tri(hetero)arylated and C-2/C-3/C-6/C-7 tetrasubstituted imidazo[1,2-b]pyrazoles. 39 of the synthetized products were evaluated for in vitro anticancer activity using the MTT colorimetric assay against 5 human and 1 murine cancer cell lines. Promising in vitro growth inhibitory activities were exhibited by some of the target compounds. Of the 39 evaluated products, 4 displayed an IC50 ? 10 ?M in the 6 cell lines analyzed (compounds 4d, 4g, 9a, 11a). A structure activity relationship analysis is also reported in this paper. PMID:25064349

Grosse, Sandrine; Mathieu, Véronique; Pillard, Christelle; Massip, Stéphane; Marchivie, Mathieu; Jarry, Christian; Bernard, Philippe; Kiss, Robert; Guillaumet, Gérald

2014-09-12

212

Structure-activity relationships of antitubercular salicylanilides consistent with disruption of the proton gradient via proton shuttling.  

PubMed

A series of salicylanilides was synthesized based on a high-throughput screening hit against Mycobacterium tuberculosis. A free phenolic hydroxyl on the salicylic acid moeity is required for activity, and the structure-activity relationship of the aniline ring is largely driven by the presence of electron withdrawing groups. We synthesized 94 analogs exploring substitutions of both rings and the linker region in this series and we have identified multiple compounds with low micromolar potency. Unfortunately, cytotoxicity in a murine macrophage cell line trends with antimicrobial activity, suggesting a similar mechanism of action. We propose that salicylanilides function as proton shuttles that kill cells by destroying the cellular proton gradient, limiting their utility as potential therapeutics. PMID:23211970

Lee, Ill-Young; Gruber, Todd D; Samuels, Amanda; Yun, Minhan; Nam, Bora; Kang, Minseo; Crowley, Kathryn; Winterroth, Benjamin; Boshoff, Helena I; Barry, Clifton E

2013-01-01

213

Active Tensegrity Structure  

Microsoft Academic Search

Most active structures involve direct control of single parameters when there is a closed form relationship between the response required and the control parameter. Building on a previous study of an adjustable structure, this paper describes geometric active control of a reusable tensegrity structure that has been enlarged to five modules with improved connections and is equipped with actuators. Closely

Etienne Fest; Kristina Shea; Ian F. C. Smith

2009-01-01

214

Haloalkylamine-induced renal papillary necrosis: a histopathological study of structure-activity relationships.  

PubMed Central

The haloalkylamine 2-bromoethanamine (BEA) causes necrosis of renal papillae of rats within 24 h of a single intraperitoneal dose greater than or equal to 100 mg/kg. Nine structural analogues of BEA, differing by halide substitution, alkyl chain elongation or amine substitution, were tested for their ability to induce renal papillary lesions in rats. Three compounds (2-chloroethanamine, 3-bromopropanamine and 2-chloro-N,N-dimethylethanamine) induced lesions which were morphologically indistinguishable from those of BEA. All the molecular structural variations investigated reduced papillotoxicity compared with BEA, the parent compound. A variety of non-renal lesions including hepatic, adrenal, testicular and lymphoid necroses were also encountered. The most toxic compound was 2-fluorethanamine, a 5 mg/kg dose of which was lethal and induced renal corticomedullary mineralization and centrilobular hepatic necrosis. One analogue, 3-bromo-2-hydroxypropanamine, caused rapid and extensive necrosis of the adrenal pars fasciculata and reticularis, simulating human Waterhouse Friderichsen syndrome. The three newly identified renal papillotoxins are all theoretically capable of generating direct-acting alkylating species in solution and their activity as direct-acting mutagens in the Ames bacterial mutagenicity test with TA100 (indicating base pair substitution) closely correlated with their potency as papillotoxins. We therefore hypothesize that non-enzymically formed direct-acting alkylating species mediate these papillary lesions, and that the target selectivity of haloalkylamine toxicity most probably results from the accumulation of these alkylating species in papillary tissue. Images Fig. 3 Fig. 4 Fig. 5 Fig. 6 Fig. 7 Fig. 8 PMID:1768609

Powell, C. J.; Grasso, P.; Ioannides, C.; Wilson, J.; Bridges, J. W.

1991-01-01

215

Type AII lantibiotic bovicin HJ50 with a rare disulfide bond: structure, structure-activity relationships and mode of action.  

PubMed

Lantibiotics are ribosomally synthesized antimicrobial peptides containing unusual amino acids. As promising alternatives to conventional antibiotics, they have a high potential for alleviating the problem of emergent antibiotic resistance, with possible applications in many industries that have antibacterial demand. Bovicin HJ50 is a type AII lantibiotic, the largest group of lantibiotics, comprising a linear N-terminal region and a globular C-terminal region. Interestingly, bovicin H50 has a disulfide bond that is rare in this group. Owing to limited information about the spatial structures of type AII lantibiotics, the functional regions of this type and the role of the disulfide bond are still unknown. In the present study, we resolved the solution structure of bovicin HJ50 using NMR spectroscopy. This is the first spatial structure of a type AII lantibiotic. Bovicin HJ50 exhibited high flexibility in aqueous solution, whereas varied rigidities were observed in the different rings with the conserved ring A being the most rigid. The charged residues Lys¹¹, Asp¹² and Lys³?, as well as the essential disulfide bond were critical for antimicrobial activity. Importantly, bovicin HJ50 showed not only peptidoglycan precursor lipid II-binding ability, but also pore-forming activity, which is significantly different from other bacteriostatic type AII lantibiotics, suggesting a novel antimicrobial mechanism. PMID:24814218

Zhang, Jie; Feng, Yingang; Teng, Kunling; Lin, Yuheng; Gao, Yong; Wang, Jinfeng; Zhong, Jin

2014-08-01

216

Structure-Activity Relationships of Novel Salicylaldehyde Isonicotinoyl Hydrazone (SIH) Analogs: Iron Chelation, Anti-Oxidant and Cytotoxic Properties  

PubMed Central

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. PMID:25393531

Pot??ková, Eliška; Hrušková, Kate?ina; Bureš, Jan; Kova?íková, Petra; Špirková, Iva A.; Pravdíková, Kate?ina; Kolbabová, Lucie; Hergeselová, Tereza; Hašková, Pavlína; Jansová, Hana; Machá?ek, Miloslav; Jirkovská, Anna; Richardson, Vera; Lane, Darius J. R.; Kalinowski, Danuta S.; Richardson, Des R.; Vávrová, Kate?ina; Šim?nek, Tomáš

2014-01-01

217

Synthesis and structure-activity relationship study of chemical probes as hypoxia induced factor-1?/malate dehydrogenase 2 inhibitors.  

PubMed

A structure-activity relationship study of hypoxia inducible factor-1? inhibitor 3-aminobenzoic acid-based chemical probes, which were previously identified to bind to mitochondrial malate dehydrogenase 2, was performed to provide a better understanding of the pharmacological effects of LW6 and its relation to hypoxia inducible factor-1? (HIF-1?) and malate dehydrogenase 2 (MDH2). A variety of multifunctional probes including the benzophenone or the trifluoromethyl diazirine for photoaffinity labeling and click reaction were prepared and evaluated for their biological activity using a cell-based HRE-luciferase assay as well as a MDH2 assay in human colorectal cancer HCT116 cells. Among them, the diazirine probe 4a showed strong inhibitory activity against both HIF-1? and MDH2. Significantly, the inhibitory effect of the probes on HIF-1? activity was consistent with that of the MDH2 enzyme assay, which was further confirmed by the effect on in vitro binding activity to recombinant human MDH2, oxygen consumption, ATP production, and AMP activated protein kinase (AMPK) activation. Competitive binding modes of LW6 and probe 4a to MDH2 were also demonstrated. PMID:25356789

Naik, Ravi; Won, Misun; Ban, Hyun Seung; Bhattarai, Deepak; Xu, Xuezhen; Eo, Yumi; Hong, Ye Seul; Singh, Sarbjit; Choi, Yongseok; Ahn, Hee-Chul; Lee, Kyeong

2014-11-26

218

Structure-activity relationships of synthetic cordycepin analogues as experimental therapeutics for African trypanosomiasis.  

PubMed

Novel methods for treatment of African trypanosomiasis, caused by infection with Trypanosoma brucei are needed. Cordycepin (3'-deoxyadenosine, 1a) is a powerful trypanocidal compound in vitro but is ineffective in vivo because of rapid metabolic degradation by adenosine deaminase (ADA). We elucidated the structural moieties of cordycepin required for trypanocidal activity and designed analogues that retained trypanotoxicity while gaining resistance to ADA-mediated metabolism. 2-Fluorocordycepin (2-fluoro-3'-deoxyadenosine, 1b) was identified as a selective, potent, and ADA-resistant trypanocidal compound that cured T. brucei infection in mice. Compound 1b is transported through the high affinity TbAT1/P2 adenosine transporter and is a substrate of T. b. brucei adenosine kinase. 1b has good preclinical properties suitable for an oral drug, albeit a relatively short plasma half-life. We present a rapid and efficient synthesis of 2-halogenated cordycepins, also useful synthons for the development of additional novel C2-substituted 3'-deoxyadenosine analogues to be evaluated in development of experimental therapeutics. PMID:24283924

Vodnala, Suman K; Lundbäck, Thomas; Yeheskieli, Esther; Sjöberg, Birger; Gustavsson, Anna-Lena; Svensson, Richard; Olivera, Gabriela C; Eze, Anthonius A; de Koning, Harry P; Hammarström, Lars G J; Rottenberg, Martin E

2013-12-27

219

Structure-activity relationship of C5-curcuminoids and synthesis of their molecular probes thereof.  

PubMed

A series of novel analogues of 1,5-bis(4-hydroxy-3-methoxyphenyl)-penta-(1E,4E)-1,4-dien-3-one (C(5)-curcumin), which is a natural analogue of curcumin isolated from the rhizomes of Curcuma domestica Val. (Zingiberacea), were synthesized and evaluated for their cytotoxicities against human colon cancer cell line HCT-116 to conclude the SAR of C(5)-curcuminoids for further development of their use in cancer chemotherapy: (1) Bis(arylmethylidene)acetone serves as a promising skeleton for eliciting cytotoxicity. (2) The 3-oxo-1,4-pentadiene structure is essential for eliciting cytotoxicity. (3) As for the extent of the aromatic substituents, hexasubstituted compounds exhibit strong activities, in which 3,4,5-hexasubstitution results in the highest potency. (5) The symmetry between two aryl rings is not an essential requirement for bis(arylmethylidene)acetones to elicit cytotoxicity. (6) para-Positions allows the installation of additional functional groups for use as molecular probes. By taking advantage of the SAR diagram, we have elaborated several advanced derivatives having GI(50) of single-digit micromolar potencies that will function as molecular probes to target and/or report key biomolecules interacting with curcumin and C(5)-curcumin. PMID:20060305

Yamakoshi, Hiroyuki; Ohori, Hisatsugu; Kudo, Chieko; Sato, Atsuko; Kanoh, Naoki; Ishioka, Chikashi; Shibata, Hiroyuki; Iwabuchi, Yoshiharu

2010-02-01

220

Amide-Modified Prenylcysteine based Icmt Inhibitors: Structure Activity Relationships, Kinetic Analysis and Cellular Characterization  

PubMed Central

Human protein isoprenylcysteine carboxyl methyltransferase (hIcmt) is the enzyme responsible for the ?-carboxyl methylation of the C-termimal isoprenylated cysteine of CaaX proteins, including Ras proteins. This specific posttranslational methylation event has been shown to be important for cellular transformation by oncogenic Ras isoforms. This finding led to interest in hIcmt inhibitors as potential anti-cancer agents. Previous analog studies based on N-acetyl-S-farnesylcysteine identified two prenylcysteine-based low micromolar inhibitors (1a and 1b) of hIcmt, each bearing a phenoxyphenyl amide modification. In this study, a focused library of analogs of 1a and 1b was synthesized and screened versus hIcmt, delineating structural features important for inhibition. Kinetic characterization of the most potent analogs 1a and 1b established that both inhibitors exhibited mixed-mode inhibition and that the competitive component predominated. Using the Cheng – Prusoff method, the Ki values were determined from the IC50 values. Analog 1a has a KIC of 1.4 ± 0.2 ?M and a KIU of 4.8 ± 0.5 ?M while 1b has a KIC of 0.5 ± 0.07 ?M and a KIU of 1.9 ± 0.2 ?M. Cellular evaluation of 1b revealed that it alters the subcellular localization of GFP-KRas, and also inhibits both Ras activation and Erk phosphorylation in Jurkat cells. PMID:22142613

Majmudar, Jaimeen D.; Hodges-Loaiza, Heather B.; Hahne, Kalub; Donelson, James L.; Song, Jiao; Shrestha, Liza; Harrison, Marietta L.; Hrycyna, Christine A.; Gibbs, Richard A.

2012-01-01

221

Quantitative structure-activity relationship modeling of polycyclic aromatic hydrocarbon mutagenicity by classification methods based on holistic theoretical molecular descriptors.  

PubMed

Various polycyclic aromatic hydrocarbons (PAHs), ubiquitous environmental pollutants, are recognized mutagens and carcinogens. A homogeneous set of mutagenicity data (TA98 and TA100,+S9) for 32 benzocyclopentaphenanthrenes/chrysenes was modeled by the quantitative structure-activity relationship classification methods k-nearest neighbor and classification and regression tree, using theoretical holistic molecular descriptors. Genetic algorithm provided the selection of the best subset of variables for modeling mutagenicity. The models were validated by leave-one-out and leave-50%-out approaches and have good performance, with sensitivity and specificity ranges of 90-100%. Mutagenicity assessment for these PAHs requires only a few theoretical descriptors of their molecular structure. PMID:16616369

Gramatica, Paola; Papa, Ester; Marrocchi, Assunta; Minuti, Lucio; Taticchi, Aldo

2007-03-01

222

Cyclotide Structure-Activity Relationships: Qualitative and Quantitative Approaches Linking Cytotoxic and Anthelmintic Activity to the Clustering of Physicochemical Forces  

PubMed Central

Cyclotides are a family of plant-derived proteins that are characterized by a cyclic backbone and a knotted disulfide topology. Their cyclic cystine knot (CCK) motif makes them exceptionally resistant to thermal, chemical, and enzymatic degradation. Cyclotides exert much of their biological activity via interactions with cell membranes. In this work, we qualitatively and quantitatively analyze the cytotoxic and anthelmintic membrane activities of cyclotides. The qualitative and quantitative models describe the potency of cyclotides using four simple physicochemical terms relevant to membrane contact. Specifically, surface areas of the cyclotides representing lipophilic and hydrogen bond donating properties were quantified and their distribution across the molecular surface was determined. The resulting quantitative structure-activity relation (QSAR) models suggest that the activity of the cyclotides is proportional to their lipophilic and positively charged surface areas, provided that the distribution of these surfaces is asymmetric. In addition, we qualitatively analyzed the physicochemical differences between the various cyclotide subfamilies and their effects on the cyclotides' orientation on the membrane and membrane activity. PMID:24682019

Park, Sungkyu; Stromstedt, Adam A.; Goransson, Ulf

2014-01-01

223

Synthesis and structure-activity relationships of novel THF 1?-methylcarbapenems  

Microsoft Academic Search

A series of twelve highly active aminomethyl-THF 1?-methylcarbapenems 3a-1 were synthesized. Of these, carbapenems 3a-f demonstrated a spectrum of antimicrobial activity comparable to those of imipenem and meropenem with the exception of only moderate anti-pseudomonal activity. Most importantly, they demonstrated moderate intrinsic oral activity against an E. coli infection in mice.

Yang-I Lin; Panayota Bitha; Subas M. Sakya; Timothy W. Strohmeyer; Zhong Li; Ving J. Lee; Stanley A. Lang; Youjun Yang; Niraja Bhachech; William J. Weiss; Peter J. Petersen; Nilda V. Jacobus; Karen Bush; Raymond T. Testa; Francis P. Tally

1997-01-01

224

Kinetics and quantitative structure-activity relationship study on the degradation reaction from perfluorooctanoic acid to trifluoroacetic acid.  

PubMed

Investigation of the degradation kinetics of perfluorooctanoic acid (PFOA) has been carried out to calculate rate constants of the main elementary reactions using the multichannel Rice-Ramsperger-Kassel-Marcus theory and canonical variational transition state theory with small-curvature tunneling correction over a temperature range of 200~500 K. The Arrhenius equations of rate constants of elementary reactions are fitted. The decarboxylation is role step in the degradation mechanism of PFOA. For the perfluorinated carboxylic acids from perfluorooctanoic acid to trifluoroacetic acid, the quantitative structure-activity relationship of the decarboxylation was analyzed with the genetic function approximation method and the structure-activity model was constructed. The main parameters governing rate constants of the decarboxylation reaction from the eight-carbon chain to the two-carbon chain were obtained. As the structure-activity model shows, the bond length and energy of C1-C2 (RC1-C2 and EC1-C2) are positively correlated to rate constants, while the volume (V), the energy difference between EHOMO and ELUMO (?E), and the net atomic charges on atom C2 (QC2) are negatively correlated. PMID:25196516

Gong, Chen; Sun, Xiaomin; Zhang, Chenxi; Zhang, Xue; Niu, Junfeng

2014-01-01

225

Synthesis and structure-activity relationships of 2-amino-3-carboxy-4-phenylthiophenes as novel atypical protein kinase C inhibitors  

PubMed Central

Recent evidence suggests atypical protein kinase C (aPKC) isoforms are required for both TNF- and VEGF-induced breakdown of the blood-retinal barrier (BRB) and endothelial permeability to 70kDa dextran or albumin. A chemical library screen revealed a series of novel small molecule phenylthiophene based inhibitors of aPKC isoforms that effectively block permeability in cell culture and in vivo. In an effort to further elucidate the structural requirements of this series of inhibitors, we detail in this study a structure-activity relationship (SAR) built on screening hit 1, which expands on our initial pharmacophore model. The biological activity of our analogues was evaluated in models of bona fide aPKC-dependent signaling including NF?B driven-gene transcription as a marker for an inflammatory response and VEGF/TNF-induced vascular endothelial permeability. The EC50 for the most efficacious inhibitors (6, 32) was in the low nanomolar range in these two cellular assays. Our study demonstrates the key structural elements that confer inhibitory activity and highlights the requirement for electron-donating moieties off the C-4 aryl moiety of the 2-amino-3-carboxy-4-phenylthiophene backbone. These studies suggest that this class has potential for further development into small molecule aPKC inhibitors with therapeutic efficacy in a host of diseases involving increased vascular permeability and inflammation. PMID:23566515

Titchenell, Paul M.; Hollis Showalter, H. D.; Pons, Jean-François; Barber, Alistair J.; Jin, Yafei

2013-01-01

226

Structure-activity relationships of saponins enhancing the cytotoxicity of ribosome-inactivating proteins type I (RIP-I).  

PubMed

Saponins are amphiphilic secondary plant compounds able to interfere with surfaces and permeabilize membranes. In addition to antimicrobial and anti-inflammatory features, anti-neoplastic activities are described which base on various mechanisms. A very promising anti-cancer strategy is the synergistic enhancement of the cytotoxicity of ribosome-inactivating proteins type I (RIP-I) by suitable saponins. The cytotoxicity of the naturally low cytotoxic activity showing RIP-I can be augmented up to 100,000-fold, if they are applied in combination with appropriate saponins. These saponins have to hold certain structural features. We analyzed 56 different saponins for their non-synergistic, as well as their synergistic cytotoxicity with the RIP-I saporin from Saponaria officinalis L. (Caryophyllaceae). The saponins were assorted into categories, according to their structural features and their cytotoxic behavior, to build up structure-activity relationships. A non-synergistic cytotoxicity as low as possible and a synergistic cytotoxicity as high as possible were desired. The investigations suggest that ideal saponins consist of an oleanane-type scaffold, preferably gypsogenin or quillaic acid, three branched sugars at the C-3-OH-group including glucuronic acid, galactose, xylose and four branched sugars at the C-28-OH-group, including deoxy-sugars and acetyl-residues. PMID:23891686

Böttger, Stefan; Westhof, Elena; Siems, Karsten; Melzig, Matthias F

2013-10-01

227

Muscarinic agonists with antipsychotic-like activity: structure-activity relationships of 1,2,5-thiadiazole analogues with functional dopamine antagonist activity.  

PubMed

Muscarinic agonists were tested in two models indicative of clinical antipsychotic activity: conditioned avoidance responding (CAR) in rats and inhibition of apomorphine-induced climbing in mice. The standard muscarinic agonists oxotremorine and pilocarpine were both active in these tests but showed little separation between efficacy and cholinergic side effects. Structure-activity relationships of the alkylthio-1,2,5-thiadiazole azacyclic type muscarinic partial agonists are shown, revealing the exo-6-(3-propyl/butylthio-1,2, 5-thiadiazol-4-yl)-1-azabicyclo[3.2.1]octane analogues (4a,b and 9a, b) to be the most potent antipsychotic agents with large separation between efficacy and cholinergic side effects. The lack of enantiomeric selectivity suggests the pharmacophoric elements are in the mirror plane of the compounds. A model explaining the potency differences of closely related compounds is offered. The data suggest that muscarinic agonists act as functional dopamine antagonists and that they could become a novel treatment of psychotic patients. PMID:9784113

Sauerberg, P; Jeppesen, L; Olesen, P H; Rasmussen, T; Swedberg, M D; Sheardown, M J; Fink-Jensen, A; Thomsen, C; Thøgersen, H; Rimvall, K; Ward, J S; Calligaro, D O; DeLapp, N W; Bymaster, F P; Shannon, H E

1998-10-22

228

Substituted 4-(Thiazol-5-yl)-2-(phenylamino)pyrimidines Are Highly Active CDK9 Inhibitors: Synthesis, X-ray Crystal Structures, Structure–Activity Relationship, and Anticancer Activities  

PubMed Central

Cancer cells often have a high demand for antiapoptotic proteins in order to resist programmed cell death. CDK9 inhibition selectively targets survival proteins and reinstates apoptosis in cancer cells. We designed a series of 4-thiazol-2-anilinopyrimidine derivatives with functional groups attached to the C5-position of the pyrimidine or to the C4-thiazol moiety and investigated their effects on CDK9 potency and selectivity. One of the most selective compounds, 12u inhibits CDK9 with IC50 = 7 nM and shows over 80-fold selectivity for CDK9 versus CDK2. X-ray crystal structures of 12u bound to CDK9 and CDK2 provide insights into the binding modes. This work, together with crystal structures of selected inhibitors in complex with both enzymes described in a companion paper,34 provides a rationale for the observed SAR. 12u demonstrates potent anticancer activity against primary chronic lymphocytic leukemia cells with a therapeutic window 31- and 107-fold over those of normal B- and T-cells. PMID:23301767

2013-01-01

229

Antioxidant capacity of curcumin-directed analogues: Structure–activity relationship and influence of microenvironment  

Microsoft Academic Search

Curcumin is the active ingredient of turmeric powder with a variety of biological activities including antioxidative activity. In order to find more active antioxidants with curcumin as the lead compound we synthesised a series of enone analogues of curcumin. The present work studied and compared the capacity of curcumin-directed analogues to scavenge 2,2-diphenyl-1-picrylhydrazyl (DPPH) and protect human red blood cells

Ya-Jing Shang; Xiao-Ling Jin; Xian-Ling Shang; Jiang-Jiang Tang; Guo-Yun Liu; Fang Dai; Yi-Ping Qian; Gui-Juan Fan; Qiang Liu; Bo Zhou

2010-01-01

230

Designing Anti-Influenza Aptamers: Novel Quantitative Structure Activity Relationship Approach Gives Insights into Aptamer - Virus Interaction  

PubMed Central

This study describes the development of aptamers as a therapy against influenza virus infection. Aptamers are oligonucleotides (like ssDNA or RNA) that are capable of binding to a variety of molecular targets with high affinity and specificity. We have studied the ssDNA aptamer BV02, which was designed to inhibit influenza infection by targeting the hemagglutinin viral protein, a protein that facilitates the first stage of the virus’ infection. While testing other aptamers and during lead optimization, we realized that the dominant characteristics that determine the aptamer’s binding to the influenza virus may not necessarily be sequence-specific, as with other known aptamers, but rather depend on general 2D structural motifs. We adopted QSAR (quantitative structure activity relationship) tool and developed computational algorithm that correlate six calculated structural and physicochemical properties to the aptamers’ binding affinity to the virus. The QSAR study provided us with a predictive tool of the binding potential of an aptamer to the influenza virus. The correlation between the calculated and actual binding was R2?=?0.702 for the training set, and R2?=?0.66 for the independent test set. Moreover, in the test set the model’s sensitivity was 89%, and the specificity was 87%, in selecting aptamers with enhanced viral binding. The most important properties that positively correlated with the aptamer’s binding were the aptamer length, 2D-loops and repeating sequences of C nucleotides. Based on the structure-activity study, we have managed to produce aptamers having viral affinity that was more than 20 times higher than that of the original BV02 aptamer. Further testing of influenza infection in cell culture and animal models yielded aptamers with 10 to 15 times greater anti-viral activity than the BV02 aptamer. Our insights concerning the mechanism of action and the structural and physicochemical properties that govern the interaction with the influenza virus are discussed. PMID:24846127

Musafia, Boaz; Oren-Banaroya, Rony; Noiman, Silvia

2014-01-01

231

Designing anti-influenza aptamers: novel quantitative structure activity relationship approach gives insights into aptamer-virus interaction.  

PubMed

This study describes the development of aptamers as a therapy against influenza virus infection. Aptamers are oligonucleotides (like ssDNA or RNA) that are capable of binding to a variety of molecular targets with high affinity and specificity. We have studied the ssDNA aptamer BV02, which was designed to inhibit influenza infection by targeting the hemagglutinin viral protein, a protein that facilitates the first stage of the virus' infection. While testing other aptamers and during lead optimization, we realized that the dominant characteristics that determine the aptamer's binding to the influenza virus may not necessarily be sequence-specific, as with other known aptamers, but rather depend on general 2D structural motifs. We adopted QSAR (quantitative structure activity relationship) tool and developed computational algorithm that correlate six calculated structural and physicochemical properties to the aptamers' binding affinity to the virus. The QSAR study provided us with a predictive tool of the binding potential of an aptamer to the influenza virus. The correlation between the calculated and actual binding was R2?=?0.702 for the training set, and R2?=?0.66 for the independent test set. Moreover, in the test set the model's sensitivity was 89%, and the specificity was 87%, in selecting aptamers with enhanced viral binding. The most important properties that positively correlated with the aptamer's binding were the aptamer length, 2D-loops and repeating sequences of C nucleotides. Based on the structure-activity study, we have managed to produce aptamers having viral affinity that was more than 20 times higher than that of the original BV02 aptamer. Further testing of influenza infection in cell culture and animal models yielded aptamers with 10 to 15 times greater anti-viral activity than the BV02 aptamer. Our insights concerning the mechanism of action and the structural and physicochemical properties that govern the interaction with the influenza virus are discussed. PMID:24846127

Musafia, Boaz; Oren-Banaroya, Rony; Noiman, Silvia

2014-01-01

232

Structure-Activity Relationship Study Reveals ML240 and ML241 as Potent and Selective Inhibitors of p97 ATPase  

PubMed Central

To discover more potent p97 inhibitors, we carried out a structure–activity relationship study of the quinazoline scaffold previously identified from our HTS campaigns. Two improved inhibitors, ML240 and ML241, inhibit p97 ATPase with IC50 values of 100 nm. Both compounds inhibited degradation of a p97-dependent but not a p97-independent proteasome substrate in a dual-reporter cell line. They also impaired the endoplasmic-reticulum-associated degradation (ERAD) pathway. Unexpectedly, ML240 potently stimulated accumulation of LC3-II within minutes, inhibited cancer cell growth, and rapidly mobilized the executioner caspases 3 and 7, whereas ML241 did not. The behavior of ML240 suggests that disruption of the protein homeostasis function of p97 leads to more rapid activation of apoptosis than is observed with a proteasome inhibitor. Further characterization revealed that ML240 has broad antiproliferative activity toward the NCI-60 panel of cancer cell lines, but slightly lower activity toward normal cells. ML240 also synergizes with the proteasome inhibitor MG132 to kill multiple colon cancer cell lines. Meanwhile, both probes have low off-target activity toward a panel of protein kinases and central nervous system targets. Our results nominate ML240 as a promising starting point for the development of a novel agent for the chemotherapy of cancer, and provide a rationale for developing pathway-specific p97 inhibitors. PMID:23316025

Chou, Tsui-Fen; Li, Kelin; Frankowski, Kevin J; Schoenen, Frank J; Deshaies, Raymond J

2013-01-01

233

Structure-activity relationships in ultrashort cationic lipopeptides: the effects of amino acid ring constraint on antibacterial activity.  

PubMed

Taking a minimalistic approach in efforts to lower the cost for the development of new synthetic antimicrobial peptides, ultrashort cationic lipopeptides were designed to mimic the amphiphilic nature crucial for their activity but with only a very short peptide sequence ligated to a lipidic acid. Nine ultrashort cationic lipopeptides were prepared to study the effects of ring constraint in the amino acid side chain of the peptide component. USCL-PCat1, consisting of only four L-4R-aminoproline residues and acylated with palmitic acid at the N-terminus, was found to populate a polyproline II helical secondary conformation that is stable to different pHs and temperatures using circular dichroism. The synthesized lipopeptides were found to have a micellar structure in water using negative staining transmission electron microscopy. We found that constraining the side chain of the amino acid component is not beneficial to the antimicrobial activity. USCL-Dab1, USCL-Dab3 and USCL-K1 showed promising activity against a panel of laboratory reference and clinically isolated Gram-positive and Gram-negative bacterial strains, some of which are multidrug resistant. No appreciable cytotoxicity against human monocytic THP-1 cells was observed up to concentrations of 20-40 µM for all synthesized compounds. Moreover, all USCLs did not induce the production of either pro-inflammatory cytokines or chemokines up to 40 µM. PMID:25069750

Domalaon, Ronald; Yang, Xuan; O'Neil, Joe; Zhanel, George G; Mookherjee, Neeloffer; Schweizer, Frank

2014-11-01

234

Structure-activity relationships of milrinone analogues determined in vitro in a rabbit heart membrane Ca(2+)-ATPase model.  

PubMed

The cardiac activity of a series of analogues of the positive inotropic bipyridines amrinone (5-amino-[3,4'-bipyridin]-6(1H)-one) and milrinone (2-methyl-5-cyano-[3,4'-bipyridin]-6(1H)-one) was evaluated in vitro in a rabbit myocardial membrane Mg(2+)-dependent, Ca(2+)-stimulable adenosine triphosphatase (Ca(2+)-ATPase) model and structure-activity relationships were compared for nine closely related derivatives. In the present studies, a 5-bromo analogue of milrinone stimulated myocardial membrane Ca(2+)-ATPase significantly (10(-7) M; P < 0.001 vs control, with 67% of the activity of milrinone), whereas a 2'-methyl-2H-milrinone derivative was inactive. Although amrinone was inactive in this assay, its 2-methyl analogue was stimulatory. However, analogues lacking a 2-substituent (with or without a 5-cyano group) or with the 3-N position blocked by a methyl group did not stimulate myocardial membrane Ca(2+)-ATPase activity. Structural data for these bipyridines show that those with either a 2- or 2'-methyl substituent have a twist conformation, whereas those without are nearly planar. Activity data reveal that those bipyridines with a nonplanar conformation are more active in the Ca(2+)-ATPase assay. Further study of milrinone analogues with a 2'-methyl substituent shows that even though the effect on the twist angle is equivalent to that of 2-methyl substitution, these analogues are less potent. Data for this series reveal that the prerequisites for Ca(2+)-ATPase stimulation include not only a 2-methyl to maintain a twist conformation but also a free 3-N position and a 5-substituent. This model for optimal activity in the myocardial membrane Ca(2+)-ATPase system differs from those proposed for phosphodiesterase enzyme receptor recognition only in the requirement for a nonplanar molecule. We have previously shown that milrinone, but not amrinone, shares structural homology with thyroxine and was able to stimulate myocardial membrane Ca(2+)-ATPase activity in a manner similar to the thyroid hormone. Additionally, milrinone, but not amrinone, was an effective competitor for thyroxine binding to the serum transport protein transthyretin. Analysis of the milrinone-transthyretin crystal complex confirms the structural homology between milrinone and thyroid hormone which is not shared by amrinone. Modeling studies of the binding interactions of milrinone analogues indicate that the 2-desmethylmilrinone analogue, the most inhibitory analogue, lacks the hydrophobic contacts present in milrinone in its transthyretin-bound complex.(ABSTRACT TRUNCATED AT 400 WORDS) PMID:7783130

Cody, V; Wojtczak, A; Davis, F B; Davis, P J; Blas, S D

1995-05-26

235

Synthesis and Structure-Activity Relationship Studies of HIV-1 Virion Infectivity Factor (Vif) Inhibitors that Block Viral Replication  

PubMed Central

The HIV-1 Vif protein, essential for in vivo viral replication, protects the virus from innate antiviral cellular factor APOBEC3G (A3G), and is an attractive target for developing antiviral therapeutics. Here we have evaluated the structure-activity relationships of RN18, a small molecule recently identified as an inhibitor of Vif function that blocks viral replication only in non-permissive cells expressing A3G, by inhibiting Vif-A3G interactions. Microwave-assisted cross-coupling reactions were developed to prepare a series of RN18 analogues with diverse linkages and substitutions on the phenyl rings. A dual cell-based assay system was used to assess antiviral activity against wild-type HIV-1 in both non-permissive (H9) and permissive (MT-4) cells that also allowed evaluation of specificity. In general, variations of phenyl substitutions were detrimental for antiviral potency and specificity, but isosteric replacements of amide and ether linkages were relatively well tolerated. These SAR data define structural requirements for Vif-specific activity, identify new compounds with improved antiviral potency and specificity, and provide leads for further exploration to develop new antiviral therapeutics. PMID:22555953

Ali, Akbar; Wang, Jinhua; Nathans, Robin S.; Cao, Hong; Sharova, Natalia; Stevenson, Mario; Rana, Tariq M.

2012-01-01

236

Jatrophane diterpenes as inhibitors of chikungunya virus replication: structure-activity relationship and discovery of a potent lead.  

PubMed

Bioassay-guided purification of an EtOAc extract of the whole plant of Euphorbia amygdaloides ssp. semiperfoliata using a chikungunya virus-cell-based assay led to the isolation of six new (1-4, 9, and 10) and six known (5-7, 8, 11, and 12) jatrophane esters. Their planar structures and relative configurations were determined by extensive spectroscopic analysis, and their absolute configurations by X-ray analysis. These compounds were investigated for selective antiviral activity against chikungunya virus (CHIKV), Semliki Forest virus, Sindbis virus, and HIV-1 and HIV-2 viruses. Compound 3 was found to be the most potent and selective inhibitor of the replication of CHIKV and of HIV-1 and HIV-2 (EC50 = 0.76, IC50 = 0.34 and 0.043 ?M, respectively). A preliminary structure-activity relationship study demonstrated that potency and selectivity are very sensitive to the substitution pattern on the jatrophane skeleton. Although replication strategies of CHIK and HIV viruses are quite different, the mechanism of action by which these compounds act may involve a similar target for both viruses. The present results provide additional support for a previous hypothesis that the anti-CHIKV activity could involve a PKC-dependent mechanism. PMID:24926807

Nothias-Scaglia, Louis-Félix; Retailleau, Pascal; Paolini, Julien; Pannecouque, Christophe; Neyts, Johan; Dumontet, Vincent; Roussi, Fanny; Leyssen, Pieter; Costa, Jean; Litaudon, Marc

2014-06-27

237

Drug structure-transport relationships  

PubMed Central

Malcolm Rowland has greatly facilitated an understanding of drug structure–pharmacokinetic relationships using a physiological perspective. His view points, covering a wide range of activities, have impacted on my own work and on my appreciation and understanding of our science. This overview summarises some of our parallel activities, beginning with Malcolm’s work on the pH control of amphetamine excretion, his work on the disposition of aspirin and on the application of clearance concepts in describing the disposition of lidocaine. Malcolm also spent a considerable amount of time developing principles that define solute structure and transport/pharmacokinetic relationships using in situ organ studies, which he then extended to involve the whole body. Together, we developed a physiological approach to studying hepatic clearance, introducing the convection–dispersion model in which there was a spread in blood transit times through the liver accompanied by permeation into hepatocytes and removal by metabolism or excretion into the bile. With a range of colleagues, we then further developed the model and applied it to various organs in the body. One of Malcolm’s special interests was in being able to apply this knowledge, together with an understanding of physiological differences in scaling up pharmacokinetics from animals to man. The description of his many other activities, such as the development of clearance concepts, application of pharmacokinetics to the clinical situation and using pharmacokinetics to develop new compounds and delivery systems, has been left to others. PMID:21107662

2010-01-01

238

Structure-activity relationships for DT-diaphorase reduction of hypoxic cell directed agents: indoloquinones and diaziridinyl benzoquinones.  

PubMed

The flavoenzyme DT-diaphorase has the potential either to bioactivate or to detoxify different bioreductive cytotoxins. Elucidation of structural features governing the ability to act as a substrate for DT-diaphorase should facilitate rational optimization or elimination of this reductive pathway for a particular class of bioreductive drug. We have examined structure-activity relationships governing both the cytotoxicity and the DT-diaphorase mediated reduction of two groups of bioreductive alkylating agents: (1) Indoloquinones related to EO9 [3-hydroxy-methyl-5-aziridinyl-1-methyl-2-(1H-indole-4,7-dione)prop-beta - en-alpha-ol]; and (2) derivatives of diaziridinyl benzoquinone or diaziquone [2,5-bis(carboethoxyamino)-3,6-diaziridinyl-1,4-benzoquinone]. The rat U.K. 256 Walker tumor cell line and the human HT29 colon carcinoma line were studied because of their high DT-diaphorase content. Enzyme activity was measured spectrophotometrically by dicoumarol inhibitable cytochrome c reduction in the presence of drug, and aerobic cytotoxicity was assessed by the MTT assay. EO9 acted as a good substrate for both enzyme preparations and was highly potent in each cell line, especially in Walker tumor cells (ID50 0.039 nM). AZQ was also reduced efficiently and gave an ID50 of 6 nM in the Walker tumor line. Slight modifications in structure resulted in large variations in both DT-diaphorase metabolism and toxicity for both types of agent. There was a clear tendency for the most efficiently reduced analogues to exhibit greater cytotoxic potency. Inclusion of an aziridine moiety in the structure appears to be desirable, but not essential, for both rapid reduction and cytotoxicity. There was no evidence of active site-directed enzyme inhibition. PMID:1544832

Bailey, S M; Suggett, N; Walton, M I; Workman, P

1992-01-01

239

Synthesis, antimicrobial evaluation, and structure-activity relationship of ?-pinene derivatives.  

PubMed

Several (+)- and (-)-?-pinene derivatives were synthesized and evaluated for their antimicrobial activity toward Gram-positive bacteria Micrococcus luteus and Staphylococcus aureus, Gram-negative bacterium Escherichia coli, and the unicellular fungus Candida albicans using bioautographic assays. (+)-?-Pinene 1a showed modest activity against the test organisms, whereas (-)-?-pinene 1b showed no activity at the tested concentration. Of all the ?-pinene derivatives evaluated, the ?-lactam derivatives (10a and 10b) were the most antimicrobial. The increase in the antimicrobial activity of 10a compared to 1a ranged from nearly 3.5-fold (C. albicans) to 43-fold (S. aureus). The mean ± standard deviation for the zone of inhibition (mm) for 10a (C. albicans) was 31.9 ± 4.3 and that for S. aureus was 51.1 ± 2.9. Although (-)-?-pinene 1b was not active toward the test microorganisms, the corresponding ?-lactam 10b, amino ester 13b, and amino alcohol 14b showed antimicrobial activity toward the test microorganisms. The increase in the antimicrobial activity of 10b compared to 1b ranged from 32-fold (S. aureus) to 73-fold (M. luteus). The mean ± standard deviation for the zone of inhibition (mm) for 10b (S. aureus) was 32.0 ± 0.60 and that for M. luteus was 73.2 ± 0.30. PMID:24716724

Dhar, Preeti; Chan, PuiYee; Cohen, Daniel T; Khawam, Fadi; Gibbons, Sarah; Snyder-Leiby, Teresa; Dickstein, Ellen; Rai, Prashant Kumar; Watal, Geeta

2014-04-23

240

Relationship of Chemical Structure and Antimicrobial Activity of Alkyl Amides and Amines  

PubMed Central

Contrary to the limited effects of alkyl amides and their corresponding N-derivatives, alkyl amines affected both gram-positive and gram-negative organisms. As with other alkyl derivatives the most sensitive gram-negative bacteria were usually more resistant than the most resistant gram-positive bacteria. Compounds with a chain-length of 11 to 15 are most active. Although some of the general properties relating the activity of fatty acids to their antimicrobial action are similar to those of amine compounds, the amines are unique in that monounsaturation does not increase compound activity. The possible modes of action of these compounds are discussed. PMID:4670442

Kabara, Jon J.; Conley, Anthony J.; Truant, Joseph P.

1972-01-01

241

Structure-activity relationships of C-17-substituted estratriene-3-O-sulfamates as anticancer agents.  

PubMed

The synthesis and antiproliferative activities of analogues of 2-substituted estradiol-3,17-O,O-bis-sulfamates (E2bisMATEs) are discussed. Modifications of the C-17 substituent confirm that an H-bond acceptor is essential for high activity; its optimal linkage to C-17 and the local environment in which it resides are defined. In the non-sulfamoylated series 17?-acyl substitution delivers 48b, the most potent compound identified to date. In the sulfamate series a number of permutations of linker and H-bond acceptor deliver excellent activity, with 55, 61, 65, 49a, and 49b proving especially promising. The in vivo potential of these compounds was explored in the NCI hollow fiber assay and also in a mouse Matrigel model of antiangiogenesis in which 49 and 55 show significant inhibitory activity. PMID:21604672

Jourdan, Fabrice; Leese, Mathew P; Dohle, Wolfgang; Ferrandis, Eric; Newman, Simon P; Chander, Surinder; Purohit, Atul; Potter, Barry V L

2011-07-14

242

Synthesis and quantitative structure-activity relationships of analeptic agents related to dimefline.  

PubMed

Some new dimefline-type derivatives have been synthesized and their pharmacological activity, as well as their distribution coefficients have been determined. The distribution coefficients of a number of previously published analogue compounds have also been measured and the QSAR analysis of the whole set has been carried out. The results of such analysis allow to point out which factors are influencing the biological activity of this group of compounds. PMID:2569302

Recanatini, M; Valenti, P; Da Re, P; Giusti, P

1989-05-01

243

Virulence Factor-activity Relationships: Workshop Summary  

EPA Science Inventory

The concept or notion of virulence factor?activity relationships (VFAR) is an approach for identifying an analogous process to the use of qualitative structure?activity relationships (QSAR) for identifying new microbial contaminants. In QSAR, it is hypothesized that, for new chem...

244

Structure-Activity Relationship Exploration of Kv1.3 Blockers Based on Diphenoxylate  

PubMed Central

Diphenoxylate, a well-known opioid agonist and anti-diarrhoeal agent, was recently found to block Kv1.3 potassium channels, which have been proposed as potential therapeutic targets for a range of autoimmune diseases. The molecular basis for this Kv1.3 blockade was assessed by the selective removal of functional groups from the structure of diphenoxylate as well as a number of other structural variations. Removal of the nitrile functional group and replacement of the C-4 piperidinyl substituents resulted in several compounds with submicromolar IC50 values. PMID:23084278

Nguyen, William; Howard, Brittany L.; Jenkins, David P.; Wulff, Heike; Thompson, Philip E.; Manallack, David T.

2013-01-01

245

Quantitative structure-activity relationship (QSAR) study of toxicity of quaternary ammonium compounds on Chlorella pyrenoidosa and Scenedesmus quadricauda.  

PubMed

The acute toxicity of 13 quaternary ammonium compounds (QACs) to Chlorella pyrenoidosa and Scenedesmus quadricauda was investigated in the present study. Significant inhibition on algae biomass was observed and 96 h EC(50)-value of 13 QACs was tested. Sixteen physicochemical and quantum chemical parameters of the QACs were calculated using the semi-empirical MOPAC AMI method. The multiple linear regression (MLR) was employed to derive the quantitative structure-activity relationship (QSAR) models, by which the calculated parameters were correlated to the toxicity of QACs on the two green algaes. Results showed that the alkyl chain lengths (CL) and total connectivity (T(Con)) were the main descriptors in governing the log (1/EC(50)) values of the QACs in the two QSAR models. The two models had high predictive ability and stability, and two parameters were proved to have the general applicability in QSAR study of QACs congeners. PMID:22014469

Jing, Guohua; Zhou, Zuoming; Zhuo, Jing

2012-01-01

246

Structure-activity relationship study of sesquiterpene lactones and their semi-synthetic amino derivatives as potential antitrypanosomal products.  

PubMed

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 ?-methylene-?-lactone moiety is necessary for both antitrypanosomal effects and cytotoxicity. Antitrypanosomal selectivity is facilitated by 2-(hydroxymethyl)acrylate 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. PMID:24662071

Zimmermann, Stefanie; Fouché, Gerda; De Mieri, Maria; Yoshimoto, Yukiko; Usuki, Toyonobu; Nthambeleni, Rudzani; Parkinson, Christopher J; van der Westhuyzen, Christiaan; Kaiser, Marcel; Hamburger, Matthias; Adams, Michael

2014-01-01

247

Computational Structure-Activity Relationship Analysis of Non-peptide Inducers of Macrophage Tumor Necrosis Factor-? Production  

PubMed Central

Previously, we screened a series of arylcarboxylic acid hydrazide derivatives for their ability to induce macrophage tumor necrosis factor ? (TNF-?) production and identified 16 such compounds. In the present study, we evaluated 23 additional arylcarboxylic acid hydrazides and found that seven of these compounds also induced macrophage TNF-? production, representing novel compounds with this activity. The total set of active compounds was then used for computational structure–activity relationship (SAR) analysis to further optimize lead molecules. A sequence of 1) linear discriminant analysis, 2) classification tree analysis with linear combination, and 3) univariate splits based on atom pair descriptors led to the derivation of SAR rule-based algorithms with fittng accuracy of 96.5, 91.9, and 84.9%, respectively. The SAR rules obtained from classification tree analysis with univariate splits, which was based on three atom pair descriptors only, revealed that the main factors influencing agonist activity of arylcarboxylic acid hydrazide derivatives were the presence of a methyl or trifluoromethyl group in the benzene ring attached to the furan moiety, an alkoxy group in the aromatic ring near the methylenehydrazide linker, and two or more halogen atoms (chlorine or bromine) on one side of the dumbbell-shaped hydrazide molecule opposed by an aromatic moiety on the opposite side of the molecule. Thus, these rules represent a relatively simple classification approach for de novo design of small molecule inducers of macrophage TNF-? production. PMID:18815052

Khlebnikov, Andrei I.; Schepetkin, Igor A.; Kirpotina, Liliya N.; Quinn, Mark T.

2008-01-01

248

In Silico Screening, Structure-Activity Relationship, and Biologic Evaluation of Selective Pteridine Reductase Inhibitors Targeting Visceral Leishmaniasis? †  

PubMed Central

In this study we utilized the concept of rational drug design to identify novel compounds with optimal selectivity, efficacy and safety, which would bind to the target enzyme pteridine reductase 1 (PTR1) in Leishmania parasites. Twelve compounds afforded from Baylis-Hillman chemistry were docked by using the QUANTUM program into the active site of Leishmania donovani PTR1 homology model. The biological activity for these compounds was estimated in green fluorescent protein-transfected L. donovani promastigotes, and the most potential analogue was further investigated in intracellular amastigotes. Structure-activity relationship based on homology model drawn on our recombinant enzyme was substantiated by recombinant enzyme inhibition assay and growth of the cell culture. Flow cytometry results indicated that 7-(4-chlorobenzyl)-3-methyl-4-(4-trifluoromethyl-phenyl)-3,4,6,7,8,9-hexahydro-pyrimido[1,2-a]pyrimidin-2-one (compound 7) was 10 times more active on L. donovani amastigotes (50% inhibitory concentration [IC50] = 3 ?M) than on promastigotes (IC50 = 29 ?M). Compound 7 exhibited a Ki value of 0.72 ?M in a recombinant enzyme inhibition assay. We discovered that novel pyrimido[1,2-a]pyrimidin-2-one systems generated from the allyl amines afforded from the Baylis-Hillman acetates could have potential as a valuable pharmacological tool against the neglected disease visceral leishmaniasis. PMID:21115787

Kaur, Jaspreet; Kumar, Pranav; Tyagi, Sargam; Pathak, Richa; Batra, Sanjay; Singh, Prashant; Singh, Neeloo

2011-01-01

249

Antileishmanial chalcones: statistical design, synthesis, and three-dimensional quantitative structure-activity relationship analysis.  

PubMed

A large number of substituted chalcones have been synthesized and tested for antileishmanial and lymphocyte-suppressing activities. A subset of the chalcones was designed by using statistical methods. 3D-QSAR analyses using 67 (antileishmanial activity) and 63 (lymphocyte-suppressing activity) of the compounds for the training sets and 9 compounds as an external validation set were performed by using the GRID/GOLPE methodology. The Smart Region Definition procedure with subsequent region selection as implemented in GOLPE reduced the number of variables to approximately 1300 yielding 3D-QSAR models of high quality (lymphocyte-suppressing model, R2 = 0. 90, Q2 = 0.80; antileishmanial model, R2 = 0.73, Q2 = 0.63). The coefficient plots indicate that steric interactions between the chalcones and the target are of major importance for the potencies of the compounds. A comparison of the coefficient plots for the antileishmanial effect and the lymphocyte-suppressing activity discloses significant differences which should make it possible to design chalcones having a high antileishmanial activity without suppressing the proliferation of lymphocytes. PMID:9822551

Nielsen, S F; Christensen, S B; Cruciani, G; Kharazmi, A; Liljefors, T

1998-11-19

250

Synthesis, structure-activity relationships, and biological studies of chromenochalcones as potential antileishmanial agents.  

PubMed

Antileishmanial activities of a library of synthetic chalcone analogues have been examined. Among them, five compounds (11, 14, 16, 17, 22, and 24) exhibited better activity than the marketed drug miltefosine in in vitro studies against the intracellular amastigotes form of Leishmania donovani. Three promising compounds, 16, 17, and 22, were tested in a L. donovani/hamster model. Oral administration of chalcone 16, at a concentration of 100 mg/kg of body weight per day for 5 consecutive days, resulted in >84% parasite inhibition at day 7 post-treatment and it retained the activity until day 28. The molecular and immunological studies revealed that compound 16 has a dual nature to act as a direct parasite killing agent and as a host immunostimulant. Pharmacokinetics and serum albumin binding studies also suggest that compound 16 has the potential to be a candidate for the treatment of the nonhealing form of leishmaniasis. PMID:24635539

Shivahare, Rahul; Korthikunta, Venkateswarlu; Chandasana, Hardik; Suthar, Manish K; Agnihotri, Pragati; Vishwakarma, Preeti; Chaitanya, Telaprolu K; Kancharla, Papireddy; Khaliq, Tanvir; Gupta, Shweta; Bhatta, Rabi Sankar; Pratap, J Venkatesh; Saxena, Jitendra K; Gupta, Suman; Tadigoppula, Narender

2014-04-24

251

Structure-activity relationships of the hypertrehalosemic hormone from the cockroach Blaberus discoidalis Serville  

E-print Network

chromatophores (54). AKH from locust was also active in this bioassay. When 10 AKH was tested in a lipid mobilisation bioassay, the N-terminal octapeptide, a C- terminal threonine amide, and an N-terminal L-pyroglutamic acid are required for activity... was used for the synthesis of HTH acid. 4- Methylbenzylhydrylamine resin (0. 26 MEq/gm) was used for the synthesis of the rest of the analogs which were peptide amides. The amino group on the MBHA resin was in the form of a salt and had to be converted...

Ford, Mary Stahlschmidt

2012-06-07

252

Flavonoids as Opioid Receptor Ligands: Identification and Preliminary Structure-Activity Relationships  

PubMed Central

Flavonoids have been recognized as the active ingredients of many medicinal plant extracts due to interactions with proteins via phenolic groups and low toxicity. Here, we report the investigation of the flavonoid core as a potential new scaffold for the development of opioid receptor ligands. Biological results suggest that stereochemistry of the C2 and C3 positions is important for antagonist activity and selectivity. Our results also suggest that the actions of Hypericum perforatum may be mediated in part by opioid receptors. PMID:17685652

Katavic, Peter L.; Lamb, Kenneth; Navarro, Hernan; Prisinzano, Thomas E.

2008-01-01

253

Insights into structure-activity relationship of GABAA receptor modulating coumarins and furanocoumarins  

PubMed Central

The coumarins imperatorin and osthole are known to exert anticonvulsant activity. We have therefore analyzed the modulation of GABA-induced chloride currents (IGABA) by a selection of 18 coumarin derivatives on recombinant ?1?2?2S GABAA receptors expressed in Xenopus laevis oocytes by means of the two-microelectrode voltage clamp technique. Osthole (EC50=14±1 ?M) and oxypeucedanin (EC50=25±8 ?M) displayed the highest efficiency with IGABA potentiation of 116±4% and 547±56%, respectively. IGABA enhancement by osthole and oxypeucedanin was not inhibited by flumazenil (1 ?M) indicating an interaction with a binding site distinct from the benzodiazepine binding site. In general, prenyl residues are essential for the positive modulatory activity, while longer side chains or bulkier residues (e.g. geranyl residues) diminish IGABA modulation. Generation of a binary classification tree revealed the importance of polarisability, which is sufficient to distinguish actives from inactives. A 4-point pharmacophore model based on oxypeucedanin – comprising three hydrophobic and one aromatic feature – identified 6 out of 7 actives as hits. In summary, (oxy-)prenylated coumarin derivatives from natural origin represent new GABAA receptor modulators. PMID:21749864

Singhuber, Judith; Baburin, Igor; Ecker, Gerhard F.; Kopp, Brigitte; Hering, Steffen

2011-01-01

254

Insights into structure-activity relationship of GABAA receptor modulating coumarins and furanocoumarins.  

PubMed

The coumarins imperatorin and osthole are known to exert anticonvulsant activity. We have therefore analyzed the modulation of GABA-induced chloride currents (I(GABA)) by a selection of 18 coumarin derivatives on recombinant ?(1)?(2)?(2S) GABA(A) receptors expressed in Xenopus laevis oocytes by means of the two-microelectrode voltage clamp technique. Osthole (EC(50)=14 ± 1 ?M) and oxypeucedanin (EC(50)=25 ± 8 ?M) displayed the highest efficiency with I(GABA) potentiation of 116 ± 4 % and 547 ± 56 %, respectively. I(GABA) enhancement by osthole and oxypeucedanin was not inhibited by flumazenil (1 ?M) indicating an interaction with a binding site distinct from the benzodiazepine binding site. In general, prenyl residues are essential for the positive modulatory activity, while longer side chains or bulkier residues (e.g. geranyl residues) diminish I(GABA) modulation. Generation of a binary classification tree revealed the importance of polarisability, which is sufficient to distinguish actives from inactives. A 4-point pharmacophore model based on oxypeucedanin - comprising three hydrophobic and one aromatic feature - identified 6 out of 7 actives as hits. In summary, (oxy-)prenylated coumarin derivatives from natural origin represent new GABA(A) receptor modulators. PMID:21749864

Singhuber, Judith; Baburin, Igor; Ecker, Gerhard F; Kopp, Brigitte; Hering, Steffen

2011-10-01

255

Evolved neural networks for quantitative structure-activity relationships of anti-HIV compounds  

Microsoft Academic Search

This paper compares the utility of an evolved neural network to a linear model to describe the activity of a set of anti-HIV compounds. The results indicate that significant nonlinearity exists within the descriptors for these molecules. This nonlinearity can be captured in a neural network architecture for significantly increased predictive performance

Dana Landavazo; Gary B. Fogel

2002-01-01

256

Structure-activity relationships among the kanamycin aminoglycosides: role of ring I hydroxyl and amino groups.  

PubMed

The kanamycins form an important subgroup of the 4,6-disubstituted 2-deoxystreptamine aminoglycoside antibiotics, comprising kanamycin A, kanamycin B, tobramycin, and dibekacin. These compounds interfere with protein synthesis by targeting the ribosomal decoding A site, and they differ in the numbers and locations of amino and hydroxy groups of the glucopyranosyl moiety (ring I). We synthesized kanamycin analogues characterized by subtle variations of the 2' and 6' substituents of ring I. The functional activities of the kanamycins and the synthesized analogues were investigated (i) in cell-free translation assays on wild-type and mutant bacterial ribosomes to study drug-target interaction, (ii) in MIC assays to assess antibacterial activity, and (iii) in rabbit reticulocyte translation assays to determine activity on eukaryotic ribosomes. Position 2' forms an intramolecular H bond with O5 of ring II, helping the relative orientations of the two rings with respect to each other. This bond becomes critical for drug activity when a 6'-OH substituent is present. PMID:22948879

Salian, Sumantha; Matt, Tanja; Akbergenov, Rashid; Harish, Shinde; Meyer, Martin; Duscha, Stefan; Shcherbakov, Dmitri; Bernet, Bruno B; Vasella, Andrea; Westhof, Eric; Böttger, Erik C

2012-12-01

257

Structure-Activity Relationships among the Kanamycin Aminoglycosides: Role of Ring I Hydroxyl and Amino Groups  

PubMed Central

The kanamycins form an important subgroup of the 4,6-disubstituted 2-deoxystreptamine aminoglycoside antibiotics, comprising kanamycin A, kanamycin B, tobramycin, and dibekacin. These compounds interfere with protein synthesis by targeting the ribosomal decoding A site, and they differ in the numbers and locations of amino and hydroxy groups of the glucopyranosyl moiety (ring I). We synthesized kanamycin analogues characterized by subtle variations of the 2? and 6? substituents of ring I. The functional activities of the kanamycins and the synthesized analogues were investigated (i) in cell-free translation assays on wild-type and mutant bacterial ribosomes to study drug-target interaction, (ii) in MIC assays to assess antibacterial activity, and (iii) in rabbit reticulocyte translation assays to determine activity on eukaryotic ribosomes. Position 2? forms an intramolecular H bond with O5 of ring II, helping the relative orientations of the two rings with respect to each other. This bond becomes critical for drug activity when a 6?-OH substituent is present. PMID:22948879

Salian, Sumantha; Matt, Tanja; Akbergenov, Rashid; Harish, Shinde; Meyer, Martin; Duscha, Stefan; Shcherbakov, Dmitri; Bernet, Bruno B.; Vasella, Andrea; Westhof, Eric

2012-01-01

258

Pimarane Cyclooxygenase 2 (COX-2) Inhibitor and its StructureActivity Relationship  

E-print Network

activities, although the inhibitory potency was not satisfactory. Our docking study9 revealed that the COX-2. *Corresponding author. Tel.: +82-02-880-7875; fax: +82-02-888- 0649; e-mail: ygsuh@plaza.snu.ac.kr #12

Suh, Young-Ger

259

[Glycopolymers of microorganisms: molecular relationship between structure, function, and biological activity].  

PubMed

The results of the Department of Biochemistry investigations during the recent 5 years are presented. For the first time the structures of O-specific polysaccharides of lipopolysaccharides of representatives of Enterobacteriaceae new genus--Rahnella aquatilis have been established. The structures are represented by linear or branched mono-, tri- and hexasaccharides. As well as in other Enterobacteriaceae representatives only one hydrohylated acid--3-hydroxytetradecanoic has been established in lipids A of R. aquatilis. It was shown that toxicity and pyrogeneity of lipopolysaccharides R. aquatilis and Ralstonia solanacearum are due to the acyl-, phosphoryl- and free hydroxylic groups of lipids A. Physico-chemical properties and substrated specificity of enzymes-glycoproteins (alpha-L-rhmanosidase, a-N-acetylgalactosaminidase, collagenase and keratinase) have been studied. On the basis of the data concerning substrate specificity of the above enzymes the possible trends of their practical usage are considered. PMID:18663920

Varbanets', L D

2008-01-01

260

Structure-activity relationships of vanilloid receptor agonists for arteriolar TRPV1  

PubMed Central

BACKGROUND AND PURPOSE The transient receptor potential vanilloid 1 (TRPV1) plays a role in the activation of sensory neurons by various painful stimuli and is a therapeutic target. However, functional TRPV1 that affect microvascular diameter are also expressed in peripheral arteries and we attempted to characterize this receptor. EXPERIMENTAL APPROACH Sensory TRPV1 activation was measured in rats by use of an eye wiping assay. Arteriolar TRPV1-mediated smooth muscle specific responses (arteriolar diameter, changes in intracellular Ca2+) were determined in isolated, pressurized skeletal muscle arterioles obtained from the rat and wild-type or TRPV1?/? mice and in canine isolated smooth muscle cells. The vascular pharmacology of the TRPV1 agonists (potency, efficacy, kinetics of action and receptor desensitization) was determined in rat isolated skeletal muscle arteries. KEY RESULTS Capsaicin evoked a constrictor response in isolated arteries similar to that mediated by noradrenaline, this was absent in arteries from TRPV1 knockout mice and competitively inhibited by TRPV1 antagonist AMG9810. Capsaicin increased intracellular Ca2+ in the arteriolar wall and in isolated smooth muscle cells. The TRPV1 agonists evoked similar vascular constrictions (MSK-195 and JYL-79) or were without effect (resiniferatoxin and JYL-273), although all increased the number of responses (sensory activation) in the eye wiping assay. Maximal doses of all agonists induced complete desensitization (tachyphylaxis) of arteriolar TRPV1 (with the exception of capsaicin). Responses to the partial agonist JYL-1511 suggested 10% TRPV1 activation is sufficient to evoke vascular tachyphylaxis without sensory activation. CONCLUSIONS AND IMPLICATIONS Arteriolar TRPV1 have different pharmacological properties from those located on sensory neurons in the rat. PMID:21883148

Czikora, Á; Lizanecz, E; Bakó, P; Rutkai, I; Ruzsnavszky, F; Magyar, J; Pórszász, R; Kark, T; Facskó, A; Papp, Z; Édes, I; Tóth, A

2012-01-01

261

Structure-activity relationship of S-trityl-L-cysteine analogues as inhibitors of the human mitotic kinesin Eg5.  

PubMed

The human kinesin Eg5 is a potential drug target for cancer chemotherapy. Eg5 specific inhibitors cause cells to block in mitosis with a characteristic monoastral spindle phenotype. Prolonged metaphase block eventually leads to apoptotic cell death. S-trityl-L-cysteine (STLC) is a tight-binding inhibitor of Eg5 that prevents mitotic progression. It has proven antitumor activity as shown in the NCI 60 tumor cell line screen. It is of considerable interest to define the minimum chemical structure that is essential for Eg5 inhibition and to develop more potent STLC analogues. An initial structure-activity relationship study on a series of STLC analogues reveals the minimal skeleton necessary for Eg5 inhibition as well as indications of how to obtain more potent analogues. The most effective compounds investigated with substitutions at the para-position of one phenyl ring have an estimated K i (app) of 100 nM in vitro and induce mitotic arrest with an EC 50 of 200 nM. PMID:18266314

Debonis, Salvatore; Skoufias, Dimitrios A; Indorato, Rose-Laure; Liger, François; Marquet, Bernard; Laggner, Christian; Joseph, Benoît; Kozielski, Frank

2008-03-13

262

Structure-activity relationships of bisphenol A analogs at estrogen receptors (ERs): discovery of an ER?-selective antagonist.  

PubMed

Our multi-template approach for drug discovery, focusing on protein targets with similar fold structures, has yielded lead compounds for various targets. We have also shown that a diphenylmethane skeleton can serve as a surrogate for a steroid skeleton. Here, on the basis of those ideas, we hypothesized that the diphenylmethane derivative bisphenol A (BPA) would bind to the ligand-binding domain of estrogen receptors (ERs) in a similar manner to estradiol and act as a steroid surrogate. To test this idea, we synthesized a series of BPA analogs and evaluated their structure-activity relationships, focusing on agonistic/antagonistic activities at ERs and ER?/ER? subtype selectivity. Among the compounds examined, 18 was found to be a potent ER?-antagonist with high selectivity over ER? and androgen receptor under our assay conditions. A computational docking study suggested that 18 would bind to the antagonistic conformation of ER?. ER?-selective antagonists, such as 18, are candidate agents for treatment of breast cancer. PMID:23768907

Maruyama, Keisuke; Nakamura, Masaharu; Tomoshige, Shusuke; Sugita, Kazuyuki; Makishima, Makoto; Hashimoto, Yuichi; Ishikawa, Minoru

2013-07-15

263

Synthesis, antibacterial activity, and quantitative structure-activity relationships of new (Z)-2-(nitroimidazolylmethylene)-3(2H)-benzofuranone derivatives.  

PubMed

A new series of (Z)-2-(1-methyl-5-nitroimidazole-2-ylmethylene)-3(2H)-benzofuranones (11a-p) and (Z)-2-(1-methyl-4-nitroimidazole-5-ylmethylene)-3(2H)-benzofuranones (12a-m) were synthesized and assayed for their antibacterial activity against Gram-positive and Gram-negative bacteria. Most of the 5-nitroimidazole analogues (11a-p) showed a remarkable inhibition of a wide spectrum of Gram-positive bacteria (Staphylococcus aureus, Streptococcus epidermidis, MRSA, and Bacillus subtilis) and Gram-negative Klebsiella pneumoniae, whereas 4-nitroimidazole analogues (12a-m) were not effective against selected bacteria. The quantitative structure-activity relationship investigations were applied to find out the correlation between the experimentally evaluated activities with various parameters of the compounds studied. The QSAR models built in this work had reasonable predictive power and could be explained by the observed trends in activities. PMID:17919903

Hadj-esfandiari, Narges; Navidpour, Latifeh; Shadnia, Hooman; Amini, Mohsen; Samadi, Nasrin; Faramarzi, Mohammad Ali; Shafiee, Abbas

2007-11-15

264

Structure-activity relationships among antifungal nylon-3 polymers: identification of materials active against drug-resistant strains of Candida albicans.  

PubMed

Fungal infections are a major challenge to human health that is heightened by pathogen resistance to current therapeutic agents. Previously, we were inspired by host-defense peptides to develop nylon-3 polymers (poly-?-peptides) that are toxic toward the fungal pathogen Candida albicans but exert little effect on mammalian cells. Based on subsequent analysis of structure-activity relationships among antifungal nylon-3 polymers, we have now identified readily prepared cationic homopolymers active against strains of C. albicans that are resistant to the antifungal drugs fluconazole and amphotericin B. These nylon-3 polymers are nonhemolytic. In addition, we have identified cationic-hydrophobic copolymers that are highly active against a second fungal pathogen, Cryptococcus neoformans, and moderately active against a third pathogen, Aspergillus fumigatus. PMID:24606327

Liu, Runhui; Chen, Xinyu; Falk, Shaun P; Mowery, Brendan P; Karlsson, Amy J; Weisblum, Bernard; Palecek, Sean P; Masters, Kristyn S; Gellman, Samuel H

2014-03-19

265

Structure activity relationship of phenolic diterpenes from Salvia officinalis as activators of the nuclear factor E2-related factor 2 pathway  

PubMed Central

Nuclear factor E2-related factor 2 (Nrf2) is a transcription factor known to activate cytoprotective genes which may be useful in the treatment of neurodegenerative disease. In order to better understand the structure activity relationship of phenolic diterpenes from Salvia officinalis L., we isolated carnosic acid, carnosol, epirosmanol, rosmanol, 12-methoxy-carnosic acid, sageone, and carnosaldehyde using polyamide column, centrifugal partition chromatography, and semi-preparative high performance liquid chromatography. Isolated compounds were screened in-vitro for their ability to active the Nrf2 and general cellular toxicity using mouse primary cortical cultures. All compounds except 12-methoxy-carnosic acid were able to activate the antioxidant response element. Furthermore both carnosol and carnoasldehyde were able to induce Nrf2-dependent gene expression as well as protect mouse primary cortical neuronal cultures from H2O2 induced cell death. PMID:23507152

Fischedick, Justin T; Standiford, Miranda; Johnson, Delinda A.; Johnson, Jeffrey A.

2013-01-01

266

Structure activity relationship of phenolic diterpenes from Salvia officinalis as activators of the nuclear factor E2-related factor 2 pathway.  

PubMed

Nuclear factor E2-related factor 2 (Nrf2) is a transcription factor known to activate cytoprotective genes which may be useful in the treatment of neurodegenerative disease. In order to better understand the structure activity relationship of phenolic diterpenes from Salvia officinalis L., we isolated carnosic acid, carnosol, epirosmanol, rosmanol, 12-methoxy-carnosic acid, sageone, and carnosaldehyde using polyamide column, centrifugal partition chromatography, and semi-preparative high performance liquid chromatography. Isolated compounds were screened in vitro for their ability to active the Nrf2 and general cellular toxicity using mouse primary cortical cultures. All compounds except 12-methoxy-carnosic acid were able to activate the antioxidant response element. Furthermore both carnosol and carnoasldehyde were able to induce Nrf2-dependent gene expression as well as protect mouse primary cortical neuronal cultures from H(2)O(2) induced cell death. PMID:23507152

Fischedick, Justin T; Standiford, Miranda; Johnson, Delinda A; Johnson, Jeffrey A

2013-05-01

267

Structure/function/activity relationships in marine snow. Current understanding and suggested research thrusts.  

PubMed

Marine snow and marine snow components contribute to the mucilage phenomenon in the northern Adriatic Sea. Of special relevance is the matrix material, composed of extracellular polymeric substances, which are packaged into fibrils of colloidal dimensions. These 0.005 micron diameter fibrils are physical units of mucilage which can be visualized by transmission electron microscopy (TEM). They form polymer bridges between the various biotic and mineral components of marine snow, creating three-dimensional networks which affect floc porosity, density and settling behaviour. Recent observations of the matrix by TEM reveal complex fibril-delimited channels and capillary systems which partially traverse marine snow flocs and which are postulated to play roles in anomalous settling. Considering the marine snow floc as a microecosystem, the relationships between ultrastructure, chemistry and environmental properties are being explored. On the assumption that colloidal matrix materials, including those released into the bulk water, might provide advance information on anomalous floc behaviour, two new methods are recommended for monitoring the northern Adriatic Sea. One is a technique for chemical quantification of colloidal organic carbon. The other uses TEM, applied to water fractions derived from cascade ultracentrifugation, to estimate fibril quantities as a proportion of colloidal organic carbon. PMID:10721203

Leppard, G G

1999-01-01

268

Structure/antileishmanial activity relationship study of naphthoquinones and dependency of the mode of action on the substitution patterns.  

PubMed

A series of naphthoquinones was tested for activity against both extracellular promastigote and intracellular amastigote Leishmania major GFP in vitro. In parallel, the compounds were evaluated for cytotoxic effects against bone marrow-derived macrophages (BMM ?) as a mammalian host cell control. Most of the compounds noticeably inhibited the growth of extracellular parasites (IC (50) 0.5 to 6?µM) and the intracellular survival of L. major GFP amastigotes (IC (50) 1 to 7?µM) when compared with the antileishmanial drug amphotericin B (IC (50) of 2.5 and 0.2?µM, respectively). In general, antiprotozoal activity and host cell cytotoxicity seemed to increase in parallel. Conspicuously, the cytotoxic effect was less pronounced on infected host cells when compared with that on noninfected cells. Concerning structure/activity relationships for the tested naphthoquinones, some interesting structural features emerged from this study. Introduction of a methyl or methoxyl group at C-2 of the parent 1,4-naphthoquinone slightly increased the antileishmanial activity against clinically relevant amastigotes, while the presence of a hydroxyl function in this position dramatically reduced the effectiveness. In contrast, hydroxylation at C-5 and dihydroxy substitution at C-5 and C-8 significantly enhanced the antiprotozoal activity. Similarly, the presence of a side chain hydroxyl group PERI to a carbonyl function as represented in the series of shikonin/alkannin derivatives increased the activity when compared with substituted analogs. Within the series of naphthoquinones tested, the dimeric mixture of vaforhizin and isovaforhizin showed the highest activity IN VITRO against the clinically relevant intracellular amastigote with an IC (50) of 1.1?µM. With IC (50) values mostly in the range of 1-3?µM, the shikonin/alkannin derivatives proved to be similarly considerably leishmanicidal. None of the compounds tested was capable to induce NO production known to play a crucial role in the host resistance against intracellular pathogens, excluding activation of microbicidal mechanisms in macrophages. The mode of action apparently depended on the substitution pattern, associated with the electrophilicity of the naphthoquinone or the efficiency of redox cycling. Conspicuously, members oxygenated in the quinone ring proved to be leishmanicidal when coincubated with glutathione, while the majority of the remaining compounds lost activity. PMID:21800278

Ali, Ahmad; Assimopoulou, Andreana Nikolaos; Papageorgiou, Vassilios Peter; Kolodziej, Herbert

2011-12-01

269

Thinking in Terms of Structure-Activity-Relationships (T-SAR): A Tool to Better Understand Nanofiltration Membranes  

PubMed Central

A frontier to be conquered in the field of membrane technology is related to the very limited scientific base for the rational and task-specific design of membranes. This is especially true for nanofiltration membranes with properties that are based on several solute-membrane interaction mechanisms. “Thinking in terms of Structure-Activity-Relationships” (T-SAR) is a methodology which applies a systematic analysis of a chemical entity based on its structural formula. However, the analysis become more complex with increasing size of the molecules considered. In this study, T-SAR was combined with classical membrane characterization methods, resulting in a new methodology which allowed us not only to explain membrane characteristics, but also provides evidence for the importance of the chemical structure for separation performance. We demonstrate an application of the combined approach and its potential to discover stereochemistry, molecular interaction potentials, and reactivity of two FilmTec nanofiltration membranes (NF-90 and NF-270). Based on these results, it was possible to predict both properties and performance in the recovery of hydrophobic ionic liquids from aqueous solution. PMID:24957730

Fernández, José F.; Jastorff, Bernd; Störmann, Reinhold; Stolte, Stefan; Thöming, Jorg

2011-01-01

270

Applying quantitative structure-activity relationship (QSAR) methodology for modeling postmortem redistribution of benzodiazepines and tricyclic antidepressants.  

PubMed

Postmortem redistribution (PMR) constitutes a multifaceted process, which complicates the interpretation of drug concentrations by forensic toxicologists. The present study aimed to apply quantitative structure-activity relationship (QSAR) analysis for modeling PMR data of structurally related drugs, 10 benzodiazepines and 10 tricyclic antidepressants. For benzodiazepines, an adequate QSAR model was obtained (R(2) = 0.98, Q(2) = 0.88, RMSEE = 0.12), in which energy, ionization and molecular size exerted significant impact. For tricyclic antidepressants, an adequate QSAR model with slightly inferior statistics (R(2) = 0.95, Q(2) = 0.87, RMSEE = 0.29) was established after exclusion of maprotiline, in which energy parameters, basicity character and lipophilicity exerted significant contribution. Thus, QSAR analysis could be used as a complementary tool to provide an informative illustration of the contributing molecular, physicochemical and structural properties in PMR process. However, the complexity, non-static and time-dependent nature of PMR endpoints raises serious concerns whether QSAR methodology could predict the degree of redistribution, highlighting the need for animal-derived PMR data. PMID:24682110

Giaginis, Constantinos; Tsantili-Kakoulidou, Anna; Theocharis, Stamatios

2014-06-01

271

Synthesis and structure-activity relationships of a novel oral carbapenem, CS-834.  

PubMed

We have studied an ester prodrug of a carbapenem to develop a potent orally active beta-lactam antibiotic. A variety of 1 beta-methylcarbapenem derivatives have been synthesized. We have found that some derivatives having an amide group in the C-2 side chain show potent and well balanced antibacterial activities as well as high stability against dehydropeptidase-I. Oral absorption of derivatives has been optimized by modifying the C-3 ester promoiety. Pivaloyloxymethyl (1R, 5S, 6S)-6-[(R)-1-hydroxyethyl]-l-methyl-2-[(R)-5-oxopyrrolidin-3-yl thio]- l-carbapen-2-em-3-carboxylate, CS-834, has been selected as the most promising compound for further evaluation. PMID:9207914

Miyauchi, M; Endo, R; Hisaoka, M; Yasuda, H; Kawamoto, I

1997-05-01

272

Synthesis and structure-activity relationships of new second-generation taxoids.  

PubMed

A series of second-generation taxoids bearing a substituent on the C-2-benzoyl group and modifications at C-3'/C-10 positions was synthesized. These taxoids exhibited 2-3 orders of magnitude higher potency than that of paclitaxel against drug-resistant human breast cancer cell lines. It is also noteworthy that three taxoids showed almost no difference in activity against drug-resistant and drug-sensitive cell lines, which are categorized as "advanced second generation taxoids". PMID:10617084

Ojima, I; Wang, T; Miller, M L; Lin, S; Borella, C P; Geng, X; Pera, P; Bernacki, R J

1999-12-20

273

Discovery and structure–activity relationship analysis of Staphylococcus aureus sortase A inhibitors  

Microsoft Academic Search

Methicillin resistant Staphylococcus aureus (MRSA) is a major health problem that has created a pressing need for new antibiotics. Compounds that inhibit the S. aureus SrtA sortase may function as potent anti-infective agents as this enzyme attaches virulence factors to the cell wall. Using high-throughput screening, we have identified several compounds that inhibit the enzymatic activity of the SrtA. A

Nuttee Suree; Sung Wook Yi; William Thieu; Melanie Marohn; Robert Damoiseaux; Albert Chan; Michael E. Jung; Robert T. Clubb

2009-01-01

274

Insights into Structure-Activity Relationships in the C-Terminal Region of Divercin V41, a Class IIa Bacteriocin with High-Level Antilisterial Activity?  

PubMed Central

Divercin V41 (DvnV41) is a class IIa bacteriocin with potent antilisterial activity isolated from Carnobacterium divergens V41. Previously, we expressed from a synthetic gene, in Escherichia coli Origami, a recombinant DvnV41 designated DvnRV41, which possesses four additional amino acids (AMDP) in the N-terminal region that result from enzymatic cleavage and retains the initial DvnV41 activity. To unravel the relationship between the structure of DvnRV41 and its particularly elevated activity, we produced by site-directed mutagenesis eight variants in which a single amino acid replacement was specifically introduced into the sequence. The point mutations were designed to change either conserved residues in class IIa bacteriocins or residues specific to DvnV41 located mainly in the C-terminal region. The fusion proteins were purified from the cytosoluble fractions by immobilized affinity chromatography. DvnRV41 and its variants were released from the fusion proteins by enzymatic cleavage, using enterokinase. The purity of DvnRV41 and of the variants was checked by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, high-performance liquid chromatography, and mass spectrometry. The antibacterial activity of DvnRV41 and its variants was assessed using different indicator strains, including Listeria monocytogenes EGDe and Enterococcus faecalis JH2-2. The activity of all of the variants appeared to be less than the activity of DvnRV41. The decrease in activity did not appear to be related to a global conformational change, as determined by circular dichroism. Overall, the variants of DvnRV41 produced in the present study provide interesting insights into structure-activity relationships of class IIa bacteriocins. PMID:19181835

Rihakova, Jitka; Petit, Vanessa W.; Demnerova, Katerina; Prevost, Herve; Rebuffat, Sylvie; Drider, Djamel

2009-01-01

275

Structure-Activity Relationships of Benzbromarone Metabolites and Derivatives as EYA Inhibitory Anti-Angiogenic Agents  

PubMed Central

The tyrosine phosphatase activity of the phosphatase-transactivator protein Eyes Absent (EYA) is angiogenic through its roles in endothelial cell migration and tube formation. Benzbromarone, a known anti-gout agent, was previously identified as an inhibitor of EYA with anti-angiogenic properties. Here we show that the major metabolite of BBR, 6-hydroxy benzbromarone, is a significantly more potent inhibitor of cell migration, tubulogenesis and angiogenic sprouting. In contrast, other postulated metabolites of BBR such as 5-hydroxy benzbromaorne and 1’-hydroxy benzbromarone are less potent inhibitors of EYA tyrosine phosphatase activity as well as being less effective in cellular assays for endothelial cell migration and angiogenesis. Longer substituents at the 2 position of the benzofuran ring promoted EYA3 binding and inhibition, but were less effective in cellular assays, likely reflecting non-specific protein binding and a resulting reduction in free, bio-available inhibitor. The observed potency of 6-hydroxy benzbromarone is relevant in the context of the potential re-purposing of benzbromarone and its derivatives as anti-angiogenic agents. 6-hydroxy benzbromarone represents a metabolite with a longer half-life and greater pharmacological potency than the parent compound, suggesting that biotransformation of benzbromarone could contribute to its therapeutic activity. PMID:24367676

Pandey, Ram Naresh; Wang, Tim Sen; Tadjuidje, Emmanuel; McDonald, Matthew G.; Rettie, Allan E.; Hegde, Rashmi S.

2013-01-01

276

Synthesis, structure and structure-activity relationship analysis of 3-tert-butoxycarbonyl-2-arylthiazolidine-4-carboxylic acid derivatives as potential antibacterial agents.  

PubMed

Nine 2-arylthiazolidine-4-carboxylic acid derivatives and nine 3-tert-butoxycarbonyl-2-arylthiazolidine-4-carboxylic acid derivatives were synthesized to screen for their antibacterial activities. Compounds 5, 14-18 were first reported. Their chemical structures were clearly determined by (1)H NMR, (13)C NMR, ESI mass spectra and elemental analyses, coupled with one selected single-crystal structure. All the compounds were assayed for antibacterial activities against two Gram-positive bacterial strains (Bacillus subtilis ATCC 6633 and Staphylococcus aureus ATCC 6538) and two Gram-negative bacterial strains (Escherichia coli ATCC 35218 and Pseudomonas aeruginosa ATCC 13525) by MTT method. Most of the 3-tert-butoxycarbonyl-2-arylthiazolidine-4-carboxylic acid derivatives exhibited better antibacterial activities against the four bacterial strains than relative 2-arylthiazolidine-4-carboxylic acid derivatives. Compound (2RS,4R)-3-(tert-butoxycarbonyl)-2-(5-fluoro-2-hydroxyphenyl)thiazolidine-4-carboxylic acid (14) showed powerful antibacterial activities against P. aeruginosa with IC(50) value of 0.195 microg/mL, which was superior to the positive controls Penicillin G and Kanamycin B, respectively. On the basis of the biological results, structure-activity relationships were discussed. PMID:19423200

Song, Zhong-Cheng; Ma, Gao-Yuan; Lv, Peng-Cheng; Li, Huan-Qiu; Xiao, Zhu-Ping; Zhu, Hai-Liang

2009-10-01

277

Structure-activity relationship of ibogaine analogs interacting with nicotinic acetylcholine receptors in different conformational states.  

PubMed

The interaction of ibogaine analogs with nicotinic acetylcholine receptors (AChRs) in different conformational states was studied by functional and structural approaches. The results established that ibogaine analogs: (a) inhibit (±)-epibatidine-induced Ca²? influx in human embryonic muscle AChRs with the following potency sequence (IC(50) in ?M): (±)-18-methylaminocoronaridine (5.9±0.3)?(±)-18-methoxycoronaridine (18-MC) (6.8±0.8)>(-)-ibogaine (17±3)?(+)-catharanthine (20±1)>(±)-albifloranine (46±13), (b) bind to the [³H]TCP binding site with higher affinity when the Torpedo AChR is in the desensitized state compared to that in the resting state. Similar results were obtained using [³H]18-MC. These and docking results suggest a steric interaction between TCP and ibogaine analogs for the same site, (c) enhance [³H]cytisine binding to resting but not to desensitized AChRs, with desensitizing potencies (apparent EC??) that correlate very well with the pK(i) values in the desensitized state, and (d) there are good bilinear correlations between the ligand molecular volumes and their affinities in the desensitized and resting states, with an optimal volume of ?345 ?³ for the ibogaine site. These results indicate that the size of the binding sites for ibogaine analogs, located between the serine and nonpolar rings and shared with TCP, is an important structural feature for binding and for inducing desensitization. PMID:21642011

Arias, Hugo R; Feuerbach, Dominik; Targowska-Duda, Katarzyna M; Jozwiak, Krzysztof

2011-09-01

278

Cationic dendron-bearing lipids: investigating structure-activity relationships for small interfering RNA delivery.  

PubMed

A new family of cationic dendron-bearing lipids (CDLs) with poly(amidoamine) dendrons of first to third generation (named as A1, A2, and A3, respectively) was synthesized through a synthesis approach that permits facile variation of chemical structures. All CDLs could effectively bind small interfering RNA (siRNA) to form complexes confirmed by gel retardation analysis. In in vitro transfection experiments, A1/siRNA complexes exhibited significant gene silencing efficiency close to Lipofectamine 2000/siRNA complexes and much higher than A2/siRNA and A3/siRNA complexes. To reveal the underlying reason, we performed a series of experimental methods. The results suggested that the CDLs with smaller dendron sizes and higher proportion of hydrophobic segments could bind siRNA to form dendriplex aggregates with more compact structures and higher surface potentials. Therefore, they could be internalized via endocytosis more easily, which was believed to be the main reason for higher gene silencing efficiency. This paper provides an efficient CDL (A1) for siRNA delivery and indicates great potential for gene therapy. PMID:24144000

Zhang, Yu; Chen, Jie; Xiao, Chunsheng; Li, Mingqiang; Tian, Huayu; Chen, Xuesi

2013-12-01

279

Aedes aegypti (Diptera: Culicidae) biting deterrence: structure-activity relationship of saturated and unsaturated fatty acids.  

PubMed

In this study we evaluated the biting deterrent effects of a series of saturated and unsaturated fatty acids against Aedes aegypti (L), yellow fever mosquito (Diptera: Culicidae) using the K & Dbioassay module system. Saturated (C6:0 to C16:0 and C18:0) and unsaturated fatty acids (C11:1 to C14:1, C16:1, C18:1, and C18:2) showed biting deterrence index (BDI) values significantly greater than ethanol, the negative control. Among the saturated fatty acids, mid chain length acids (C10:0 to C13:0) showed higher biting deterrence than short (C6:0 to C9:0) and long chain length acids (C14:0 to C18:0), except for C8:0 and C16:0 that were more active than the other short and long chain acids. The BDI values of mid chain length acids (C10:0 to C13:0) were not significantly less than N, N-diethyl-meta-toluamide (DEET), the positive control. Among the unsaturated fatty acids, C11:1 showed the highest activity (BDI = 1.05) and C18:2 had the lowest activity (BDI = 0.7). In C11:1, C12:1, and C14:1 BDI values were not significantly less than DEET. After the preliminary observations, residual activity bioassays were performed on C11:0, C12:0, C11:1, and C12:1 over a 24-h period. All the fatty acids (C11:0, C12:0, C11:1, and C12:1) and DEET showed significantly higher activity at all test intervals than the solvent control. At treatment and 1-h posttreatment, all fatty acids showed proportion not biting (PNB) values not significantly less than DEET. At 3-, 6-, and 12-h posttreatment, all fatty acids showed PNB values significantly greater than DEET. At 24-h posttreatment, only the PNB value for C12:0 was significantly higher than DEET. The dose-responses of C12:0 and DEET were determined at concentrations of 5-25 nmol/cm2. As in the residual activity bioassays, the PNB values for C12:0 and DEET at 25 nmol/cm(2) were not significantly different. However, at lower concentrations, the PNB values for C12:0 were significantly greater than DEET. These results clearly indicate that mid chain length fatty acids not only have levels of biting deterrence similar to DEET at 25 nmnol/cm(2) in our test system, but also appeared to be more persistent than DEET. In contrast, in vivo cloth patch assay system showed that the mid-chain length fatty acids, C11:0, C11:1, C12:0, and C12:1 had minimum effective dose (MED) values greater than DEET against Ae. aegypti and their relative repellency varied according to species tested. The MED values of 120 (C11:0), 145 (C12:0) and 116 (C11:1) nmol/cm(2) against Anopheles quadrimaculatus Say, indicated that these acids were not as potent as DEET with a MED of 54 nmol/cm(2). The MED ratio of the C11:0 and C11:1 for all three mosquito species indicated the C11 saturated and unsaturated acids as more repellent than their corresponding C12:0 and C12:1 homologues. PMID:23270165

Ali, Abbas; Cantrell, Charles L; Bernier, Ulrich R; Duke, Stephen O; Schneider, John C; Agramonte, Natasha M; Khan, Ikhlas

2012-11-01

280

Structure-activity relationships of tea compounds against human cancer cells.  

PubMed

The content of the biologically active amino acid theanine in 15 commercial black, green, specialty, and herbal tea leaves was determined as the 2,4-dinitrophenyltheanine derivative (DNP-theanine) by a validated HPLC method. To define relative anticarcinogenic potencies of tea compounds and teas, nine green tea catechins, three black tea theaflavins, and theanine as well as aqueous and 80% ethanol/water extracts of the same tea leaves were evaluated for their ability to induce cell death in human cancer and normal cells using a tetrazolium microculture (MTT) assay. Compared to untreated controls, most catechins, theaflavins, theanine, and all tea extracts reduced the numbers of the following human cancer cell lines: breast (MCF-7), colon (HT-29), hepatoma (liver) (HepG2), and prostate (PC-3) as well as normal human liver cells (Chang). The growth of normal human lung (HEL299) cells was not inhibited. The destruction of cancer cells was also observed visually by reverse phase microscopy. Statistical analysis of the data showed that (a) the anticarcinogenic effects of tea compounds and of tea leaf extracts varied widely and were concentration dependent over the ranges from 50 to 400 microg/mL of tea compound and from 50 to 400 microg/g of tea solids; (b) the different cancer cells varied in their susceptibilities to destruction; (c) 80% ethanol/water extracts with higher levels of flavonoids determined by HPLC were in most cases more active than the corresponding water extracts; and (d) flavonoid levels of the teas did not directly correlate with anticarcinogenic activities. The findings extend related observations on the anticarcinogenic potential of tea ingredients and suggest that consumers may benefit more by drinking both green and black teas. PMID:17227049

Friedman, Mendel; Mackey, Bruce E; Kim, Hyun-Jeong; Lee, In-Seon; Lee, Kap-Rang; Lee, Seung-Un; Kozukue, Etsuko; Kozukue, Nobuyuki

2007-01-24

281

CLEFMA- An Anti-Proliferative Curcuminoid from Structure Activity Relationship Studies on 3,5-bis(benzylidene)-4-piperidones  

PubMed Central

3,5-bis(benzylidene)-4-piperidones are being advanced as synthetic analogs of curcumin for anticancer and anti-inflammatory properties. We performed structure-activity relationship studies, by testing several synthesized 3,5-bis(benzylidene)-4-piperidones for anti-proliferative activity in lung adenocarcinoma H441 cells. Compared to the lead compound 1, or 3,5-bis(2-fluorobenzylidene)-4-piperidone, five compounds were found to be more potent (IC50 < 30 ?M), and sixteen compounds possessed reduced cell-killing efficacy (IC50 > 50 ?M). Based on the observations, we synthesized 4-[3,5-bis(2-chlorobenzylidene-4-oxo-piperidine-1-yl)-4-oxo-2-butenoic acid] (29 or CLEFMA) as a novel analog of 1. CLEFMA was evaluated for anti-proliferative activity in H441 cells, and was found to be several folds more potent than compound 1. We did not find apoptotic cell population in flow cytometry, and the absence of apoptosis was confirmed by the lack of caspase cleavage. The electron microscopy of H441cells indicated that CLEFMA and compound 1 induce autophagic cell death that was inhibited by specific autophagy inhibitor 3-methyladenine. The results suggest that the potent and novel curcuminoid, CLEFMA, offers an alternative mode of cell death in apoptosis-resistant cancers. PMID:20638855

Lagisetty, Pallavi; Vilekar, Prachi; Sahoo, Kaustuv; Anant, Shrikant; Awasthi, Vibhudutta

2010-01-01

282

Antiproliferative constituents in plants 10. Flavones from the leaves of Lantana montevidensis Briq. and consideration of structure-activity relationship.  

PubMed

The flavonoid fraction from the leaves of Lantana montevidensis Briq. (Verbenaceae) showed antiproliferative activity against human gastric adenocarcinoma (MK-1, GI50: 12 microg/ml), human uterus carcinoma (HeLa, 5 microg/ml), and murine melanoma (B16F10, 5 microg/ml) cells in vitro. Bioactivity-guided chemical investigation of the fraction has resulted in the isolation of apigenin (10) and ten 5,6,7-oxygenated flavones: cirsilineol (1), eupatorin (2), 5,4'-dihydroxy-6,7,3',5'-tetramethoxyflavone (3), 5,6-dihydroxy-7,3',4'-trimethoxyflavone (4), 5,6,4'-trihydroxy-7,3',5'-trimethoxyflavone (5), 5,6,3'-trihydroxy-7,4'-dimethoxyflavone (6), 5,3',4'-trihydroxy-6,7,5'-trimethoxyflavone (7), cirsiliol (8), hispidulin (9), and eupafolin (11). Antiproliferative activity of the isolated flavones, some other related flavones (luteolin, baicalein, 6-hydroxyluteolin, pectolinarigenin, jaceosidin, desmethoxycentaureidin, eupatilin, and chrysin) from other plant materials, and synthetic 6- and 7-methoxyflavones was evaluated, and the structure-activity relationships were examined. PMID:12132661

Nagao, Tsuneatsu; Abe, Fumiko; Kinjo, Junei; Okabe, Hikaru

2002-07-01

283

Novel hinge-binding motifs for janus kinase?3 inhibitors: a comprehensive structure-activity relationship study on tofacitinib bioisosteres.  

PubMed

The Janus kinases (JAKs) are a family of cytosolic tyrosine kinases crucially involved in cytokine signaling. JAKs have been demonstrated to be valid targets in the treatment of inflammatory and myeloproliferative disorders, and two inhibitors, tofacitinib and ruxolitinib, recently received their marketing authorization. Despite this success, selectivity within the JAK family remains a major issue. Both approved compounds share a common 7H-pyrrolo[2,3-d]pyrimidine hinge binding motif, and little is known about modifications tolerated at this heterocyclic core. In the current study, a library of tofacitinib bioisosteres was prepared and tested against JAK3. The compounds possessed the tofacitinib piperidinyl side chain, whereas the hinge binding motif was replaced by a variety of heterocycles mimicking its pharmacophore. In view of the promising expectations obtained from molecular modeling, most of the compounds proved to be poorly active. However, strategies for restoring activity within this series of novel chemotypes were discovered and crucial structure-activity relationships were deduced. The compounds presented may serve as starting point for developing novel JAK inhibitors and as a valuable training set for in?silico models. PMID:25139757

Gehringer, Matthias; Forster, Michael; Pfaffenrot, Ellen; Bauer, Silke M; Laufer, Stefan A

2014-11-01

284

Structure-activity relationships for vitamin D3-based aromatic a-ring analogues as hedgehog pathway inhibitors.  

PubMed

A structure-activity relationship study for a series of vitamin D3-based (VD3) analogues that incorporate aromatic A-ring mimics with varying functionality has provided key insight into scaffold features that result in potent, selective Hedgehog (Hh) pathway inhibition. Three analogue subclasses containing (1) a single substitution at the ortho or para position of the aromatic A-ring, (2) a heteroaryl or biaryl moiety, or (3) multiple substituents on the aromatic A-ring were prepared and evaluated. Aromatic A-ring mimics incorporating either single or multiple hydrophilic moieties on a six-membered ring inhibited the Hh pathway in both Hh-dependent mouse embryonic fibroblasts and cultured cancer cells (IC50 values 0.74-10 ?M). Preliminary studies were conducted to probe the cellular mechanisms through which VD3 and 5, the most active analogue, inhibit Hh signaling. These studies suggested that the anti-Hh activity of VD3 is primarily attributed to the vitamin D receptor, whereas 5 affects Hh inhibition through a separate mechanism. PMID:24730984

Deberardinis, Albert M; Madden, Daniel J; Banerjee, Upasana; Sail, Vibhavari; Raccuia, Daniel S; De Carlo, Daniel; Lemieux, Steven M; Meares, Adam; Hadden, M Kyle

2014-05-01

285

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

PubMed

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. PMID:24339424

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

2014-02-01

286

The design, synthesis and structure-activity relationships of novel isoindoline-based histone deacetylase inhibitors.  

PubMed

The design, synthesis and biological evaluation of a novel series of isoindoline-based hydroxamates is described. Several analogs were shown to inhibit HDAC1 with IC(50) values in the low nanomolar range and inhibit cellular proliferation of HCT116 human colon cancer cells in the sub-micromolar range. The cellular potency of compound 17e was found to have greater in vitro anti-proliferative activity than several compounds in late stage clinical trials for the treatment of cancer. The in vitro safety profiles of selected compounds were assessed and shown to be suitable for further lead optimization. PMID:21742496

Shultz, Michael; Fan, Jianmei; Chen, Christine; Cho, Young Shin; Davis, Nicole; Bickford, Sheri; Buteau, Kristen; Cao, Xueying; Holmqvist, Mats; Hsu, Meier; Jiang, Lei; Liu, Gang; Lu, Qiang; Patel, Chetan; Suresh, Joghee Raju; Selvaraj, Mannangatti; Urban, Laszlo; Wang, Ping; Yan-Neale, Yan; Whitehead, Lewis; Zhang, Haiyan; Zhou, Liping; Atadja, Peter

2011-08-15

287

Toxicity of substituted anilines to Pseudokirchneriella subcapitata and quantitative structure-activity relationship analysis for polar narcotics.  

PubMed

This study evaluated the toxic effects of substituted anilines on Pseudokirchneriella subcapitata with the use of a closed algal toxicity testing technique with no headspace. Two response endpoints (i.e., dissolved oxygen production [DO] and algal growth rate) were used to evaluate the toxicity of anilines. Both DO and growth rate endpoints revealed similar sensitivity to the effects of anilines. However, trichloroanilines showed stronger inhibitory effects on microalgal photosynthetic reactions than that on algal growth. For various aquatic organisms, the relative sensitivity relationship for anilines is Daphnia magna > luminescent bacteria (Microtox) > or = Pocelia reticulata > or = Pseudokirchneriella subcapitata > or = fathead minnow > Tetrahymena pyriformis. The susceptibility of P. subcapitata to anilines is similar to fish, but P. subcapitata is apparently less sensitive than the water flea. The lack of correlation between the toxicity revealed by different aquatic organisms (microalgae, D. magna, luminescent bacteria, and P. reticulata) suggests that anilines might have different metabolic routes in these organisms. Both hydrogen bonding donor capacity (the lowest unoccupied molecular orbital energy, Elumo) and hydrophobicity (1-octanol:water partition coefficient, Kow) were found to provide satisfactory descriptions for the toxicity of polar narcotics (substituted anilines and chlorophenols). Quantitative structure-activity relationships (QSARs) based on Elumo, log Kow, or both values were established with r2 values varying from 0.75 to 0.92. The predictive power for the QSAR models were found to be satisfactory through leave-one-out cross-validation. Such relationships could provide useful information for the estimation of toxicity for other polar narcotic compounds. PMID:17571680

Chen, Chung-Yuan; Ko, Chia-Wen; Lee, Po-I

2007-06-01

288

Structure-Activity Relationships in Tripodal Transmembrane Anion Transporters: The Effect of Fluorination  

PubMed Central

A series of easy-to-make fluorinated tripodal anion transporters containing urea and thiourea groups have been prepared and their anion transport properties studied. Vesicle anion transport assays using ion-selective electrodes show that this class of compound is capable of transporting chloride through a lipid bilayer via a variety of mechanisms, including chloride/H+ cotransport and chloride/nitrate, chloride/bicarbonate, and to a lesser extent an unusual chloride/sulfate antiport process. Calculations indicate that increasing the degree of fluorination of the tripodal transmembrane transporters increases the lipophilicity of the transporter and this is shown to be the major contributing factor in the superior transport activity of the fluorinated compounds, with a maximum transport rate achieved for clog P = 8. The most active transporter 5 contained a urea functionality appended with a 3,5-bis(trifluoromethyl)phenyl group and was able to mediate transmembrane chloride transport at receptor to lipid ratios as low as 1:250000. Proton NMR titration and single crystal X-ray diffraction revealed the ability of the tripodal receptors to bind different anions with varying affinities in a 1:1 or 2:1 stoichiometry in solution and in the solid state. We also provide evidence that the most potent anion transporters are able to induce apoptosis in human cancer cells by using a selection of in vitro viability and fluorescence assays. PMID:21846096

2011-01-01

289

Structure-activity relationships in tripodal transmembrane anion transporters: the effect of fluorination.  

PubMed

A series of easy-to-make fluorinated tripodal anion transporters containing urea and thiourea groups have been prepared and their anion transport properties studied. Vesicle anion transport assays using ion-selective electrodes show that this class of compound is capable of transporting chloride through a lipid bilayer via a variety of mechanisms, including chloride/H(+) cotransport and chloride/nitrate, chloride/bicarbonate, and to a lesser extent an unusual chloride/sulfate antiport process. Calculations indicate that increasing the degree of fluorination of the tripodal transmembrane transporters increases the lipophilicity of the transporter and this is shown to be the major contributing factor in the superior transport activity of the fluorinated compounds, with a maximum transport rate achieved for clog P = 8. The most active transporter 5 contained a urea functionality appended with a 3,5-bis(trifluoromethyl)phenyl group and was able to mediate transmembrane chloride transport at receptor to lipid ratios as low as 1:250000. Proton NMR titration and single crystal X-ray diffraction revealed the ability of the tripodal receptors to bind different anions with varying affinities in a 1:1 or 2:1 stoichiometry in solution and in the solid state. We also provide evidence that the most potent anion transporters are able to induce apoptosis in human cancer cells by using a selection of in vitro viability and fluorescence assays. PMID:21846096

Busschaert, Nathalie; Wenzel, Marco; Light, Mark E; Iglesias-Hernández, Paulina; Pérez-Tomás, Ricardo; Gale, Philip A

2011-09-01

290

In Vitro Structure-Activity Relationship of Re-cyclized Octreotide Analogues  

PubMed Central

Introduction Development of radiolabeled octreotide analogues is of interest for targeting somatostatin receptor-positive tumors for diagnostic and therapeutic purposes. We are investigating a direct labeling approach for incorporation of a Re ion into octreotide analogues, where the peptide sequences are cyclized via coordination to Re rather than through a disulfide bridge. Methods Various octreotide analogue sequences and coordination systems (e.g., S2N2 and S3N) were synthesized and cyclized with non-radioactive Re. In vitro competitive binding assays with 111In-DOTA-Tyr3-octreotide in AR42J rat pancreatic tumor cells yielded IC50 values as a measure of somatostatin receptor affinity of the Re-cyclized analogues. Three-dimensional structures of Re-cyclized Tyr3-octreotate and its disulfide-bridged analogue were calculated from two-dimensional NMR experiments to visualize the effect of metal cyclization on the analogue’s pharmacophore. Results Only two of the eleven Re-cyclized analogues investigated showed moderate in vitro binding affinity toward somatostatin subtype 2 receptors. Three-dimensional molecular structures of Re- and disulfide-cyclized Tyr3-octreotate were calculated, and both of their pharmacophore turns appear to be very similar with minor differences due to metal coordination to the amide nitrogen of one of the pharmacophore amino acids. Conclusions Various Re-cyclized analogues were developed and analogue 4 had moderate affinity toward somatostatin subtype 2 receptors. In vitro stable studies that are in progress showed stable radiometal-cyclization of octreotide analogues via NS3 and N2S2 coordination forming 5- and 6- membered chelate rings. In vivo biodistribution studies are underway of 99m Tc- cyclized analogue 4. PMID:20610157

Dannoon, Shorouk F.; Bigott-Hennkens, Heather M.; Ma, Lixin; Gallazzi, Fabio; Lewis, Michael R.; Jurisson, Silvia S.

2010-01-01

291

Quantitative structure–activity relationships for estimating the aryl hydrocarbon receptor binding affinities of resveratrol derivatives and the antioxidant activities of hydroxystilbenes  

Microsoft Academic Search

Quantitative structure–activity relationships (QSARs) were developed for the aryl hydrocarbon receptor (AhR) binding affinity\\u000a of non-fluorinated and fluorinated cis and trans 3,4?,5-substituted resveratrol derivatives. Lower quality QSAR fits were found when all compounds were modeled together,\\u000a in contrast to strong correlations with Hammett substituent constants and atomic charges for separate non-fluorinated\\/fluorinated\\u000a and cis\\/trans groupings. The collective findings suggest little promise

Sierra Rayne; Charles D. Goss; Kaya Forest; Ken J. Friesen

2010-01-01

292

Structures, Biological Activities and Phylogenetic Relationships of Terpenoids from Marine Ciliates of the Genus Euplotes  

PubMed Central

In the last two decades, large scale axenic cell cultures of the marine species comprising the family Euplotidae have resulted in the isolation of several new classes of terpenoids with unprecedented carbon skeletons including the (i) euplotins, highly strained acetylated sesquiterpene hemiacetals; (ii) raikovenals, built on the bicyclo[3.2.0]heptane ring system; (iii) rarisetenolides and focardins containing an octahydroazulene moiety; and (iv) vannusals, with a unique C30 backbone. Their complex structures have been elucidated through a combination of nuclear magnetic resonance spectroscopy, mass spectrometry, molecular mechanics and quantum chemical calculations. Despite the limited number of biosynthetic experiments having been performed, the large diversity of ciliate terpenoids has facilitated the proposal of biosynthetic pathways whereby they are produced from classical linear precursors. Herein, the similarities and differences emerging from the comparison of the classical chemotaxonomy approach based on secondary metabolites, with species phylogenesis based on genetic descriptors (SSU-rDNA), will be discussed. Results on the interesting ecological and biological properties of ciliate terpenoids are also reported. PMID:20714425

Guella, Graziano; Skropeta, Danielle; Di Giuseppe, Graziano; Dini, Fernando

2010-01-01

293

Structure-activity relationships of polyphenols to prevent lipid oxidation in pelagic fish muscle.  

PubMed

The influence of polymerization (number of monomers) and galloylation (content of esterified gallates) of oligomeric catechins (proanthocyanidins) on their effectiveness to prevent lipid oxidation in pelagic fish muscle was evaluated. Non-galloylated oligomers of catechin with diverse mean polymerization (1.9-3.4 monomeric units) were extracted from pine (Pinus pinaster) bark. Homologous fractions with galloylation ranging from 0.25 to <1 gallate group per molecule were obtained from grape (Vitis vinifera) and witch hazel (Hamamelis virginiana). The results showed the convenience of proanthocyanidins with medium size (2-3 monomeric units) and low galloylation degree (0.15-0.25 gallate group/molecule) to inhibit lipid oxidation in pelagic fish muscle. These optimal structural characteristics of proanthocyanidins were similar to those lately reported in fish oil-in-water emulsions using phosphatidylcholine as emulsifier. This finding suggests that the antioxidant behavior of polyphenols in muscle-based foods can be mimicked in emulsions prepared with phospholipids as emulsifier agents. The present data give relevant information to achieve an optimum use of polyphenols in pelagic fish muscle. PMID:20925315

Pazos, Manuel; Iglesias, Jacobo; Maestre, Rodrigo; Medina, Isabel

2010-10-27

294

Cardenolides as oviposition deterrents to twoPieris species: Structure-activity relationships.  

PubMed

Oviposition responses ofPieris rapae andP. napi oleracea to 18 cardenolides were compared under the same conditions. Effects of different concentrations of selected cardenolides were also tested. Most of the compounds were deterrent to oviposition by both insects, but to significantly different degrees.P. rapae were strongly deterred by K-strophanthoside, K-strophanthin-?, cymarin, convallatoxin, oleandrin, erysimoside, erychroside, and gitoxigenin. The most deterrent compounds forP. napi oleracea were erychroside, cymarin, erysimoside, convallatoxin, and K-strophanthoside. Strophanthidin-based glycosides were more deterrent than digitoxigenin-based ones, and the number and type of sugar substitutions can have profound effects on activity. Both similarities and contrasts were found in responses ofP. rapae andP. napi oleracea to these cardenolides. Cymarin was equally deterrent to bothPieris species at all concentrations tested. However, when compared withP. rapae, P. napi oleracea was less sensitive to most of the cardenolides.P. napi oleracea was insensitive to K-strophanthin-? and oleandrin at 0.5 × 10(-4) M, which were highly deterrent toP. rapae. PMID:24242301

Huang, X; Renwick, J A

1994-05-01

295

Structure-activity relationships of 2-aminothiazoles effective against Mycobacterium tuberculosis  

PubMed Central

A series of 2-aminothiazoles was synthesized based on a HTS scaffold from a whole-cell screen against Mycobacterium tuberculosis (Mtb). The SAR shows the central thiazole moiety and the 2-pyridyl moiety at C-4 of the thiazole are intolerant to modification. However, the N-2 position of the aminothiazole exhibits high flexibility and we successfully improved the antitubercular activity of the initial hit by more than 128-fold through introduction of substituted benzoyl groups at this position. N-(3-Chlorobenzoyl)-4-(2-pyridinyl)-1,3-thiazol-2-amine (55) emerged as one of the most promising analogues with a MIC of 0.024 ?M or 0.008 ?g/mL in 7H9 media and therapeutic index of nearly ~300. However, 55 is rapidly metabolized by human liver microsomes (t1/2 = 28 min) with metabolism occurring at the invariant aminothiazole moiety and Mtb develops spontaneous resistance with a high frequency of ~10?5. PMID:24075144

Meissner, Anja; Boshoff, Helena I.; Vasan, Mahalakshmi; Duckworth, Benjamin P.; Barry, Clifton E.; Aldrich, Courtney C.

2013-01-01

296

A quantitative structure-activity relationship for predicting metabolic biotransformation rates for organic chemicals in fish.  

PubMed

An evaluated database of whole body in vivo biotransformation rate estimates in fish was used to develop a model for predicting the primary biotransformation half-lives of organic chemicals. The estimated biotransformation rates were converted to half-lives and divided into a model development set (n=421) and an external validation set (n=211) to test the model. The model uses molecular substructures similar to those of other biodegradation models. The biotransformation half-life predictions were calculated based on multiple linear regressions of development set data against counts of 57 molecular substructures, the octanol-water partition coefficient, and molar mass. The coefficient of determination (r2) for the development set was 0.82, the cross-validation (leave-one-out coefficient of determination, q2) was 0.75, and the mean absolute error (MAE) was 0.38 log units (factor of 2.4). Results for the external validation of the model using an independent test set were r2 = 0.73 and MAE = 0.45 log units (factor of 2.8). For the development set, 68 and 95% of the predicted values were within a factor of 3 and a factor of 10 of the expected values, respectively. For the test (or validation) set, 63 and 90% of the predicted values were within a factor of 3 and a factor of 10 of the expected values, respectively. Reasons for discrepancies between model predictions and expected values are discussed and recommendations are made for improving the model. This model can predict biotransformation rate constants from chemical structure for screening level bioaccumulation hazard assessments, exposure and risk assessments, comparisons with other in vivo and in vitro estimates, and as a contribution to testing strategies that reduce animal usage. PMID:19152232

Arnot, Jon A; Meylan, William; Tunkel, Jay; Howard, Phil H; Mackay, Don; Bonnell, Mark; Boethling, Robert S

2009-06-01

297

In vitro toxicological effects of estrogenic mycotoxins on human placental cells: Structure activity relationships  

SciTech Connect

Zearalenone (ZEN) is a non-steroid estrogen mycotoxin produced by numerous strains of Fusarium which commonly contaminate cereals. After oral administration, ZEN is reduced via intestinal and hepatic metabolism to ?- and ?-zearalenol (?ZEL and ?ZEL). These reduced metabolites possess estrogenic properties, ?ZEL showing the highest affinity for ERs. ZEN and reduced metabolites cause hormonal effects in animals, such as abnormalities in the development of the reproductive tract and mammary gland in female offspring, suggesting a fetal exposure to these contaminants. In our previous work, we have suggested the potential impact of ZEN on placental cells considering this organ as a potential target of xenobiotics. In this work, we first compared the in vitro effects of ?ZEL and ???L on cell differentiation to their parental molecule on human trophoblast (BeWo cells). Secondly, we investigated their molecular mechanisms of action by investigating the expression of main differentiation biomarkers and the implication of nuclear receptor by docking prediction. Conversely to ZEN, reduced metabolites did not induce trophoblast differentiation. They also induced significant changes in ABC transporter expression by potential interaction with nuclear receptors (LXR, PXR, PR) that could modify the transport function of placental cells. Finally, the mechanism of ZEN differentiation induction seemed not to involve nuclear receptor commonly involved in the differentiation process (PPAR?). Our results demonstrated that in spite of structure similarities between ZEN, ?ZEL and ?ZEL, toxicological effects and toxicity mechanisms were significantly different for the three molecules. -- Highlights: ? ZEN and metabolites have differential effect on trophoblast differentiation. ? ZEN and metabolites have differential effect on ABC transporter expression. ? ZEN and metabolites effects involved nuclear receptors interaction.

Prouillac, Caroline, E-mail: c.prouillac@vetagro-sup.fr [Université Lyon, US/C 1233 INRA VetAgroSup, Métabolisme et Toxicologie Comparée des Xénobiotiques, 1 avenue Bourgelat, BP 83, 69280 Marcy l'Etoile (France)] [Université Lyon, US/C 1233 INRA VetAgroSup, Métabolisme et Toxicologie Comparée des Xénobiotiques, 1 avenue Bourgelat, BP 83, 69280 Marcy l'Etoile (France); Koraichi, Farah; Videmann, Bernadette; Mazallon, Michelle [Université Lyon, US/C 1233 INRA VetAgroSup, Métabolisme et Toxicologie Comparée des Xénobiotiques, 1 avenue Bourgelat, BP 83, 69280 Marcy l'Etoile (France)] [Université Lyon, US/C 1233 INRA VetAgroSup, Métabolisme et Toxicologie Comparée des Xénobiotiques, 1 avenue Bourgelat, BP 83, 69280 Marcy l'Etoile (France); Rodriguez, Frédéric; Baltas, Michel [Université Paul Sabatier, SPCMIB-UMR5068, Laboratoire de Synthèse et de Physicochimie des Molécules d'Intérêt Biologique, 118 route de Narbonne, 31062 TOULOUSE cedex 9 (France)] [Université Paul Sabatier, SPCMIB-UMR5068, Laboratoire de Synthèse et de Physicochimie des Molécules d'Intérêt Biologique, 118 route de Narbonne, 31062 TOULOUSE cedex 9 (France); Lecoeur, Sylvaine [Université Lyon, US/C 1233 INRA VetAgroSup, Métabolisme et Toxicologie Comparée des Xénobiotiques, 1 avenue Bourgelat, BP 83, 69280 Marcy l'Etoile (France)] [Université Lyon, US/C 1233 INRA VetAgroSup, Métabolisme et Toxicologie Comparée des Xénobiotiques, 1 avenue Bourgelat, BP 83, 69280 Marcy l'Etoile (France)

2012-03-15

298

Structure activity relationships in alkylammonium C12-gemini surfactants used as dermal permeation enhancers.  

PubMed

The purpose of this study was to determine the ability and the safety of a series of alkylammonium C12-gemini surfactants to act as permeation enhancers for three model drugs, namely lidocaine HCl, caffeine, and ketoprofen. In vitro permeation studies across dermatomed porcine skin were performed over 24 h, after pretreating the skin for 1 h with an enhancer solution 0.16 M dissolved in propylene glycol. The highest enhancement ratio (enhancement ratio (ER)=5.1) was obtained using G12-6-12, resulting in a cumulative amount of permeated lidocaine HCl of 156.5 ?g cm?2. The studies with caffeine and ketoprofen revealed that the most effective gemini surfactant was the one with the shorter spacer, G12-2-12. The use of the latter resulted in an ER of 2.4 and 2.2 in the passive permeation of caffeine and ketoprofen, respectively. However, Azone was found to be the most effective permeation enhancer for ketoprofen, attaining a total of 138.4 ?g cm?2 permeated, 2.7-fold over controls. This work demonstrates that gemini surfactants are effective in terms of increasing the permeation of drugs, especially in the case of hydrophilic ionized compounds, that do not easily cross the stratum corneum. Skin integrity evaluation studies did not indicate the existence of relevant changes in the skin structure after the use of the permeation enhancers, while the cytotoxicity studies allowed establishing a relative cytotoxicity profile including this class of compounds, single chain surfactants, and Azone. A dependence of the toxicity to HEK and to HDF cell lines on the spacer length of the various gemini molecules was found. PMID:23959685

Silva, Sérgio M C; Sousa, João J S; Marques, Eduardo F; Pais, Alberto A C C; Michniak-Kohn, Bozena B

2013-10-01

299

Quantitative structure-activity relationships for the developmental toxicity of haloacetic acids in mammalian whole embryo culture.  

PubMed

Developmental toxicity in mouse whole embryo culture assay has been reported for acetic acid (AA) and a series of ten haloacetic acids, including mono-, di-, tri-fluoro (MFA, DFA, TFA), chloro (MCA, DCA, TCA), bromo (MBA, DBA, TBA), and monoiodo (MIA) acetic acids. Benchmark concentrations (BCm), calculated as the lower 95% confidence limit of molar acid concentration producing a 5% increase in embryos with neural tube defects, provided potency estimates for development of quantitative structure-activity relationships (QSARs). The best overall regression was obtained for the ten halo-acids (excluding AA) and related log (1/BCm) to the energy of the lowest unoccupied molecular orbital (Elumo) and acid dissociation constant (pKa) with a correlation coefficient of r = 0.97, and a sample size-adjusted r2 = 0.92. This QSAR suggested a common basis for the mechanism of HA activity, which would imply additivity for mixtures of these acids. Examination of QSARs for subsets of the total data set (e.g., monohaloacids) highlighted parameter relationships embedded in the total QSAR, helping to unravel the separate contributions of Elumo and pKa to the overall potency. The relevance of these parameters is discussed in terms of postulated mechanisms of developmental toxicity involving changes in intercellular pH and redox metabolism. The whole embryo assay results pertain to direct embryo exposure and toxicity without the confounding influence of maternal factors. The resulting QSAR model offers possible insight into the mechanism of embryo toxicity that will hopefully contribute to understanding of the more complex, in vivo teratogenicity problem. PMID:8910981

Richard, A M; Hunter, E S

1996-06-01

300

The solution structure of Bacillus anthracis dihydrofolate reductase yields insight into the analysis of structure-activity relationships for novel inhibitors.  

PubMed

There is a significant need for new therapeutics to treat infections caused by the biodefense agent Bacillus anthracis. In pursuit of drug discovery against this organism, we have developed novel propargyl-linked inhibitors that target the essential enzyme dihydrofolate reductase (DHFR) from B. anthracis. Previously, we reported an initial series of these inhibitors and a high-resolution crystal structure of the ternary complex of the enzyme bound to its cofactor and one of the most potent inhibitors, UCP120B [Beierlein, J., Frey, K., Bolstad, D., Pelphrey, P., Joska, T., Smith, A., Priestley, N., Wright, D., and Anderson, A. (2008) J. Med. Chem. 51, 7532-7540]. Herein, we describe a three-dimensional solution structure of the ternary complex as determined by NMR. A comparison of this solution structure to the crystal structure reveals a general conservation of the DHFR fold and cofactor interactions as well as differences in the location of an active site helix and specific ligand interactions. In addition to data for the fully assigned ternary complex, data for the binary (enzyme-cofactor) complex were collected, providing chemical shift comparisons and revealing perturbations in residues that accommodate ligand binding. Dynamics of the protein, measured using (15)N T(1) and T(2) relaxation times and {(1)H}-(15)N heteronuclear NOEs, reveal residue flexibility at the active site that explains enzyme inhibition and structure-activity relationships for two different series of these propargyl-linked inhibitors. The information obtained from the solution structure regarding active site flexibility will be especially valuable in the design of inhibitors with increased potency. PMID:19323450

Beierlein, Jennifer M; Deshmukh, Lalit; Frey, Kathleen M; Vinogradova, Olga; Anderson, Amy C

2009-05-19

301

Prediction of the health effects of polychlorinated biphenyls (PCBs) and their metabolites using quantitative structure-activity relationship (QSAR).  

PubMed

Polychlorinated biphenyls (PCBs) are a group of 209 persistent environmental contaminants that are slightly different but structurally related. PCBs are known to induce a variety of health effects and often have been toxicologically tested as complex commercial mixtures (Aroclors) but environmental exposure occurs separately to a small number of specific congeners. Recently, the Third National Report on Human Exposures to Environmental Chemicals, an assessment of exposure data of the National Health and Nutrition Examination Survey (NHANES), identified 35 individual PCB congeners in the U.S. population. These types of findings necessitate the toxicity evaluation of individual congeners but adequate toxicity data for most individual PCB congeners are not available. Due to this, a quantitative structure-activity relationship (QSAR) approach was used to assess the potential mutagenesis and carcinogenesis of individual congeners and their possible metabolites. The predictions were analyzed to define the underlying generalizations between the parent PCBs, their metabolites, and some important toxicological endpoints. This analysis reveals that (1) mono and di-chlorinated PCBs and their metabolites can be potential mutagens; (2) PCB benzoquinone metabolites could be carcinogenic but the weight of evidence is poor. These results support the hypothesis that environmental exposure to some PCBs and/or their metabolites could produce mutagenicity and/or carcinogenicity. Hence, these data should be considered as priority toxicological testing data needs. As with all computational toxicology analytical findings, these conclusions must yield to empirical data as they become available. PMID:18662755

Ruiz, P; Faroon, O; Moudgal, C J; Hansen, H; De Rosa, C T; Mumtaz, M

2008-09-01

302

Structure—Activity Relationships in the Binding of Chemically Derivatized CD4 to gp120 from Human Immunodeficiency Virus  

PubMed Central

The first step in HIV infection is the binding of the envelope glycoprotein gp120 to the host cell receptor CD4. An interfacial “Phe43 cavity” in gp120, adjacent to residue Phe43 of gp120-bound CD4, has been suggested as a potential target for therapeutic intervention. We designed a CD4 mutant (D1D2F43C) for site-specific coupling of compounds for screening against the cavity. Altogether, 81 cysteine-reactive compounds were designed, synthesized, and tested. Eight derivatives exceeded the affinity of native D1D2 for gp120. Structure–activity relationships (SAR) for derivatized CD4 binding to gp120 revealed significant plasticity of the Phe43 cavity and a narrow entrance. The primary contacts for compound recognition inside the cavity were found to be van der Waals interactions, whereas hydrophilic interactions were detected in the entrance. This first SAR on ligand binding to an interior cavity of gp120 may provide a starting point for structure-based assembly of small molecules targeting gp120-CD4 interaction. PMID:17803292

Xie, Hui; Ng, Danny; Savinov, Sergey N.; Dey, Barna; Kwong, Peter D.; Wyatt, Richard; Smith, Amos B.; Hendrickson, Wayne A.

2008-01-01

303

Global structure-activity relationship model for nonmutagenic carcinogens using virtual ligand-protein interactions as model descriptors.  

PubMed

Structure-activity relationship (SAR) models are powerful tools to investigate the mechanisms of action of chemical carcinogens and to predict the potential carcinogenicity of untested compounds. We describe the use of a traditional fragment-based SAR approach along with a new virtual ligand-protein interaction-based approach for modeling of nonmutagenic carcinogens. The ligand-based SAR models used descriptors derived from computationally calculated ligand-binding affinities for learning set agents to 5495 proteins. Two learning sets were developed. One set was from the Carcinogenic Potency Database, where chemicals tested for rat carcinogenesis along with Salmonella mutagenicity data were provided. The second was from Malacarne et al. who developed a learning set of nonalerting compounds based on rodent cancer bioassay data and Ashby's structural alerts. When the rat cancer models were categorized based on mutagenicity, the traditional fragment model outperformed the ligand-based model. However, when the learning sets were composed solely of nonmutagenic or nonalerting carcinogens and noncarcinogens, the fragment model demonstrated a concordance of near 50%, whereas the ligand-based models demonstrated a concordance of 71% for nonmutagenic carcinogens and 74% for nonalerting carcinogens. Overall, these findings suggest that expert system analysis of virtual chemical protein interactions may be useful for developing predictive SAR models for nonmutagenic carcinogens. Moreover, a more practical approach for developing SAR models for carcinogenesis may include fragment-based models for chemicals testing positive for mutagenicity and ligand-based models for chemicals devoid of DNA reactivity. PMID:22678118

Cunningham, Albert R; Carrasquer, C Alex; Qamar, Shahid; Maguire, Jon M; Cunningham, Suzanne L; Trent, John O

2012-10-01

304

Structure-activity relationships of anthraquinone derivatives derived from bromaminic acid as inhibitors of ectonucleoside triphosphate diphosphohydrolases (E-NTPDases).  

PubMed

Reactive blue 2 (RB-2) had been characterized as a relatively potent ectonucleoside triphosphate diphosphohydrolase (E-NTPDase) inhibitor with some selectivity for NTPDase3. In search for the pharmacophore and to analyze structure-activity relationships we synthesized a series of truncated derivatives and analogs of RB-2, including 1-amino-2-sulfo-4-ar(alk)ylaminoanthraquinones, 1-amino-2-methyl-4-arylaminoanthraquinones, 1-amino-4-bromoanthraquinone 2-sulfonic acid esters and sulfonamides, and bis-(1-amino-4-bromoanthraquinone) sulfonamides, and investigated them in preparations of rat NTPDase1, 2, and 3 using a capillary electrophoresis assay. Several 1-amino-2-sulfo-4-ar(alk)ylaminoanthraquinone derivatives inhibited E-NTPDases in a concentration-dependent manner. The 2-sulfonate group was found to be required for inhibitory activity, since 2-methyl-substituted derivatives were inactive. 1-Amino-2-sulfo-4-p-chloroanilinoanthraquinone (18) was identified as a nonselective competitive blocker of NTPDases1, 2, and 3 (K(i) 16-18 muM), while 1-amino-2-sulfo-4-(2-naphthylamino)anthraquinone (21) was a potent inhibitor with preference for NTPDase1 (K(i) 0.328 muM) and NTPDase3 (K(i) 2.22 muM). Its isomer, 1-amino-2-sulfo-4-(1-naphthylamino)anthraquinone (20), was a potent and selective inhibitor of rat NTPDase3 (K(i) 1.5 muM). PMID:18528783

Baqi, Younis; Weyler, Stefanie; Iqbal, Jamshed; Zimmermann, Herbert; Müller, Christa E

2009-03-01

305

Acaricidal toxicity of 2'-hydroxy-4'-methylacetophenone isolated from Angelicae koreana roots and structure-activity relationships of its derivatives.  

PubMed

The acaricidal activities of 2'-hydroxy-4'-methylacetophenone derived from Angelica koreana roots and its derivatives against Dermatophagoides farinae, Dermatophagoides pteronyssinus, and Tyrophagus putrescentiae were examined by vapor phase and contact toxicity bioassays. In the vapor phase toxicity bioassay, 2'-methylacetophenone (1.25 ?g/cm(2)) was 8.0 times more toxic against D. farinae than benzyl benzoate (10.00 ?g/cm(2)), followed by 3'-methylacetophenone (1.26 ?g/cm(2)), 4'-methylacetophenone (1.29 ?g/cm(2)), 2'-hydroxy-4'-methylacetophenone (1.75 ?g/cm(2)), and 2'-hydroxy-5'-methylacetophenone (1.96 ?g/cm(2)). In the contact toxicity bioassay, 3'-methylacetophenone (0.58 ?g/cm(2)) was 17.24 times more effective against D. farinae than benzyl benzoate (7.52 ?g/cm(2)), followed by 2'-methylacetophenone (0.64 ?g/cm(2)), 2'-hydroxy-4'-methylacetophenone (0.76 ?g/cm(2)), 4'-methylacetophenone (0.77 ?g/cm(2)), and 2'-hydroxy-5'-methylacetophenone (1.16 ?g/cm(2)). The acaricidal activities of 2'-hydroxy-4'-methylacetophenone derivatives against D. pteronyssinus and T. putrescentiae were similar to those against D. farinae. In terms of structure-activity relationships, acaricidal activity against the three mite species changed with the introduction of hydroxyl and methyl functional groups onto the acetophenone skeleton. Furthermore, some of 2'-hydroxy-4'-methylacetophenone derivatives could be useful for natural acaricides against three mite species. PMID:22429095

Oh, Min Seok; Yang, Ji-Yeon; Lee, Hoi Seon

2012-04-11

306

Ethionamide boosters: synthesis, biological activity, and structure-activity relationships of a series of 1,2,4-oxadiazole EthR inhibitors.  

PubMed

We report in this article an extensive structure-activity relationships (SAR) study with 58 thiophen-2-yl-1,2,4-oxadiazoles as inhibitors of EthR, a transcriptional regulator controling ethionamide bioactivation in Mycobacterium tuberculosis. We explored the replacement of two key fragments of the starting lead BDM31343. We investigated the potency of all analogues to boost subactive doses of ethionamide on a phenotypic assay involving M. tuberculosis infected macrophages and then ascertained the mode of action of the most active compounds using a functional target-based surface plasmon resonance assay. This process revealed that introduction of 4,4,4-trifluorobutyryl chain instead of cyanoacetyl group was crucial for intracellular activity. Replacement of 1,4-piperidyl by (R)-1,3-pyrrolidyl scaffold did not enhance activity but led to improved pharmacokinetic properties. Furthermore, the crystal structures of ligand-EthR complexes were consistent with the observed SAR. In conclusion, we identified EthR inhibitors that boost antibacterial activity of ethionamide with nanomolar potency while improving solubility and metabolic stability. PMID:21417236

Flipo, Marion; Desroses, Matthieu; Lecat-Guillet, Nathalie; Dirié, Bertrand; Carette, Xavier; Leroux, Florence; Piveteau, Catherine; Demirkaya, Fatma; Lens, Zoé; Rucktooa, Prakash; Villeret, Vincent; Christophe, Thierry; Jeon, Hee Kyoung; Locht, Camille; Brodin, Priscille; Déprez, Benoit; Baulard, Alain R; Willand, Nicolas

2011-04-28

307

A structure-activity relationship study on multi-heterocyclic molecules: two linked thiazoles are required for cytotoxic activity  

PubMed Central

We report the synthesis, cytotoxicity, and phenotypic analysis of oxazole and thiazole containing fragments. Evaluating the optimal size and heterocycle for growth inhibition and apoptosis showed that activity required at least two thiazoles sequentially connected. This is the first detailed comparison of biological activity between multi-heterocyclic containing fragments. PMID:23524379

Kim, Seong Jong; Lin, Chun Chieh; Pan, Chung-Mao; Rananaware, Dimple P.; Ramsey, Deborah M.

2013-01-01

308

Synthesis, structure-activity, and structure-stability relationships of 2-substituted-N-(4-oxo-3-oxetanyl) N-acylethanolamine acid amidase (NAAA) inhibitors.  

PubMed

N-Acylethanolamine acid amidase (NAAA) is a cysteine amidase that preferentially hydrolyzes saturated or monounsaturated fatty acid ethanolamides (FAEs), such as palmitoylethanolamide (PEA) and oleoylethanolamide (OEA), which are endogenous agonists of nuclear peroxisome proliferator-activated receptor-? (PPAR-?). Compounds that feature an ?-amino-?-lactone ring have been identified as potent and selective NAAA inhibitors and have been shown to exert marked anti-inflammatory effects that are mediated through FAE-dependent activation of PPAR-?. We synthesized and tested a series of racemic, diastereomerically pure ?-substituted ?-amino-?-lactones, as either carbamate or amide derivatives, investigating the structure-activity and structure-stability relationships (SAR and SSR) following changes in ?-substituent size, relative stereochemistry at the ?- and ?-positions, and ?-amino functionality. Substituted carbamate derivatives emerged as more active and stable than amide analogues, with the cis configuration being generally preferred for stability. Increased steric bulk at the ?-position negatively affected NAAA inhibitory potency, while improving both chemical and plasma stability. PMID:24403170

Vitale, Romina; Ottonello, Giuliana; Petracca, Rita; Bertozzi, Sine Mandrup; Ponzano, Stefano; Armirotti, Andrea; Berteotti, Anna; Dionisi, Mauro; Cavalli, Andrea; Piomelli, Daniele; Bandiera, Tiziano; Bertozzi, Fabio

2014-02-01

309

Application of thin-layer chromatographic data in quantitative structure–activity relationship assay of thiazole and benzothiazole derivatives with H 1-antihistamine activity. I  

Microsoft Academic Search

A quantitative structure–activity relationship analysis of H1-antihistamine activity and chromatographic data of 2-[2-(phenylamino)thiazol-4-yl]ethanamine; 2-(2-benzyl-4-thiazolyl)ethanamine; 2-(2-benzhydrylthiazol-4-yl)ethylamine derivative; 2-(1-piperazinyl- and 2-(hexahydro-1H-1,4-diazepin-1-yl)benzothiazole derivatives was made. The RP2 thin-layer chromatography (TLC) plates (silica gel RP2 60F254 silanised precoated), impregnated with solutions of selected amino acid mixtures (l-Asp, l-Asn, l-Thr and l-Lys), were used in two developing solvents as hH1R antagonistic interaction models. Using regression

El?bieta Brzezi?ska; Gra?yna Ko?ka; Krzysztof Walczy?ski

2003-01-01

310

Application of thin-layer chromatographic data in quantitative structure–activity relationship assay of thiazole and benzothiazole derivatives with H 1-antihistamine activity. II  

Microsoft Academic Search

Quantitative structure–activity relationship (QSAR) analysis of H1-antihistamine activity was carried out and chromatographic data of 2-[2-(phenylamino)thiazol-4-yl]ethanamine, 2-(2-benzyl-4-thiazolyl)ethanamine, 2-(2-benzhydrylthiazol-4-yl)ethylamine derivative, and 2-(1-piperazinyl- and 2-(hexahydro-1H-1,4-diazepin-1-yl)benzothiazole derivatives were obtained. Normal-phase (NP) TLC plates (silica gel 60F254), impregnated with solutions of selected amino acid mixtures (l-Asp, l-Asn, l-Thr and l-Lys) were used in two developing solvents as human histamine H1-receptor (hH1R) antagonistic interaction models.

El?bieta Brzezi?ska; Gra?yna Ko?ka; Alicja K?imczak

2003-01-01

311

In Silico Quantitative Structure-Activity Relationship Studies on P-gp Modulators of Tetrahydroisoquinoline-Ethyl-Phenylamine Series  

PubMed Central

Background Multidrug resistance (MDR) is a major obstacle in cancer chemotherapy. The drug efflux by a transport protein is the main reason for MDR. In humans, MDR mainly occurs when the ATP-binding cassette (ABC) family of proteins is overexpressed simultaneously. P-glycoprotein (P-gp) is most commonly associated with human MDR; it utilizes energy from adenosine triphosphate (ATP) to transport a number of substrates out of cells against concentration gradients. By the active transport of substrates against concentration gradients, intracellular concentrations of substrates are decreased. This leads to the cause of failure in cancer chemotherapy. Results Herein, we report Topomer CoMFA (Comparative Molecular Field Analysis) and HQSAR (Hologram Quantitative Structure Activity Relationship) models for third generation MDR modulators. The Topomer CoMFA model showed good correlation between the actual and predicted values for training set molecules. The developed model showed cross validated correlation coefficient (q2) = 0.536 and non-cross validated correlation coefficient (r2) = 0.975 with eight components. The best HQSAR model (q2 = 0.777, r2 = 0.956) with 5-8 atom counts was used to predict the activity of test set compounds. Both models were validated using test set compounds, and gave a good predictive values of 0.604 and 0.730. Conclusions The contour map near R1 indicates that substitution of a bulkier and polar group to the ortho position of the benzene ring enhances the inhibitory effect. This explains why compounds with a nitro group have good inhibitory potency. Molecular fragment analyses shed light on some essential structural and topological features of third generation MDR modulators. Fragments analysis showed that the presence of tertiary nitrogen, a central phenyl ring and an aromatic dimethoxy group contributed to the inhibitory effect. Based on contour map information and fragment information, five new molecules with variable R1 substituents were designed. The activity of these designed molecules was predicted by the Topomer CoMFA and HQSAR models. The novel compounds showed higher potency than existing compounds. PMID:21269449

2011-01-01

312

Synthesis, anticancer activity and structure-activity relationship of some anticancer agents based on cyclopenta (b) thiophene scaffold.  

PubMed

Methods for the synthesis of new heterocyclic systems of thieno (3,2-d)- (1,2,3)-triazine derivatives and N-(3-cyano-5,6-dihydro-4H-cyclopenta (b) thiophene derivatives have been developed. The newly synthesized compounds were tested in vitro against human breast carcinoma cell line (MCF-7). Compounds 7 and 9 have shown the highest activity among the two synthesized series. The results of this study have led to the identification of two lead compounds with good inhibitory activities that can confirm the design of the next generation inhibitors of tyrosine kinase with fewer side effects such as hepatotoxicity and resistance. PMID:25015456

Said, Mohamed; Elshihawy, Hosam

2014-07-01

313

Exploring the Anti-Cancer Activity of Novel Thiosemicarbazones Generated through the Combination of Retro-Fragments: Dissection of Critical Structure-Activity Relationships.  

PubMed

Thiosemicarbazones (TSCs) are an interesting class of ligands that show a diverse range of biological activity, including anti-fungal, anti-viral and anti-cancer effects. Our previous studies have demonstrated the potent in vivo anti-tumor activity of novel TSCs and their ability to overcome resistance to clinically used chemotherapeutics. In the current study, 35 novel TSCs of 6 different classes were designed using a combination of retro-fragments that appear in other TSCs. Additionally, di-substitution at the terminal N4 atom, which was previously identified to be critical for potent anti-cancer activity, was preserved through the incorporation of an N4-based piperazine or morpholine ring. The anti-proliferative activity of the novel TSCs were examined in a variety of cancer and normal cell-types. In particular, compounds 1d and 3c demonstrated the greatest promise as anti-cancer agents with potent and selective anti-proliferative activity. Structure-activity relationship studies revealed that the chelators that utilized "soft" donor atoms, such as nitrogen and sulfur, resulted in potent anti-cancer activity. Indeed, the N,N,S donor atom set was crucial for the formation of redox active iron complexes that were able to mediate the oxidation of ascorbate. This further highlights the important role of reactive oxygen species generation in mediating potent anti-cancer activity. Significantly, this study identified the potent and selective anti-cancer activity of 1d and 3c that warrants further examination. PMID:25329549

Serda, Maciej; Kalinowski, Danuta S; Rasko, Nathalie; Pot??ková, Eliška; Mrozek-Wilczkiewicz, Anna; Musiol, Robert; Ma?ecki, Jan G; Sajewicz, Mieczys?aw; Ratuszna, Alicja; Muchowicz, Angelika; Go??b, Jakub; Sim?nek, Tomáš; Richardson, Des R; Polanski, Jaroslaw

2014-01-01

314

Exploring the Anti-Cancer Activity of Novel Thiosemicarbazones Generated through the Combination of Retro-Fragments: Dissection of Critical Structure-Activity Relationships  

PubMed Central

Thiosemicarbazones (TSCs) are an interesting class of ligands that show a diverse range of biological activity, including anti-fungal, anti-viral and anti-cancer effects. Our previous studies have demonstrated the potent in vivo anti-tumor activity of novel TSCs and their ability to overcome resistance to clinically used chemotherapeutics. In the current study, 35 novel TSCs of 6 different classes were designed using a combination of retro-fragments that appear in other TSCs. Additionally, di-substitution at the terminal N4 atom, which was previously identified to be critical for potent anti-cancer activity, was preserved through the incorporation of an N4-based piperazine or morpholine ring. The anti-proliferative activity of the novel TSCs were examined in a variety of cancer and normal cell-types. In particular, compounds 1d and 3c demonstrated the greatest promise as anti-cancer agents with potent and selective anti-proliferative activity. Structure-activity relationship studies revealed that the chelators that utilized “soft” donor atoms, such as nitrogen and sulfur, resulted in potent anti-cancer activity. Indeed, the N,N,S donor atom set was crucial for the formation of redox active iron complexes that were able to mediate the oxidation of ascorbate. This further highlights the important role of reactive oxygen species generation in mediating potent anti-cancer activity. Significantly, this study identified the potent and selective anti-cancer activity of 1d and 3c that warrants further examination. PMID:25329549

Rasko, Nathalie; Pot??ková, Eliška; Mrozek-Wilczkiewicz, Anna; Musiol, Robert; Ma?ecki, Jan G.; Sajewicz, Mieczys?aw; Ratuszna, Alicja; Muchowicz, Angelika; Go??b, Jakub; Šim?nek, Tomáš; Richardson, Des R.; Polanski, Jaroslaw

2014-01-01

315

Design, Structure-Activity Relationship, and in Vivo Characterization of the Development Candidate NVP-HSP990.  

PubMed

Utilizing structure-based drug design, a novel dihydropyridopyrimidinone series which exhibited potent Hsp90 inhibition, good pharmacokinetics upon oral administration, and an excellent pharmacokinetic/pharmacodynamic relationship in vivo was developed from a commercial hit. The exploration of this series led to the selection of NVP-HSP990 as a development candidate. PMID:25368984

McBride, Christopher M; Levine, Barry; Xia, Yi; Bellamacina, Cornelia; Machajewski, Timothy; Gao, Zhenhai; Renhowe, Paul; Antonios-McCrea, William; Barsanti, Paul; Brinner, Kristin; Costales, Abran; Doughan, Brandon; Lin, Xiaodong; Louie, Alicia; McKenna, Maureen; Mendenhall, Kris; Poon, Daniel; Rico, Alice; Wang, Michael; Williams, Teresa E; Abrams, Tinya; Fong, Susan; Hendrickson, Thomas; Lei, Dachuan; Lin, Julie; Menezes, Daniel; Pryer, Nancy; Taverna, Pietro; Xu, Yongjin; Zhou, Yasheen; Shafer, Cynthia M

2014-11-13

316

Non-nucleoside Inhibitors of the Measles Virus RNA-dependent RNA Polymerase: Synthesis, Structure-Activity Relationships and Pharmacokinetics  

PubMed Central

The measles virus (MeV), a member of the paramyxovirus family, is an important cause of pediatric morbidity and mortality worldwide. In an effort to provide therapeutic treatments for improved measles management, we previously identified a small, non-nucleoside organic inhibitor of the viral RNA-dependent RNA polymerase (RdRp) by means of high-throughput screening (HTS). Subsequent structure-activity relationship (SAR) studies around the corresponding pyrazole carboxamide scaffold led to the discovery of 2 (AS-136a), a first generation lead with low nanomolar potency against life MeV and attractive physical properties suitable for development. However, its poor water solubility and low oral bioavailability (F) in the rat suggested that the lead could benefit from further SAR studies to improve the biophysical characteristics of the compound. Optimization of in vitro potency and aqueous solubility led to the discovery of 2o (ERDRP-00519), a potent inhibitor of MeV (EC50 = 60 nM) with aqueous solubility of approximately 60 ?g/ml. The agent shows a 10-fold exposure (AUC/Cmax) increase in the rat model relative to 2, displays near dose proportionality in the range of 10 mg/kg to 50 mg/kg, and exhibits good oral bioavailability (F = 39%) in the rat. The significant solubility increase appears linked to the improved oral bioavailability. PMID:22480182

Ndungu, J. Maina; Krumm, Stefanie A.; Yan, Dan; Arrendale, Richard F.; Reddy, G. Prabhakar; Evers, Taylor; Howard, Randy; Natchus, Michael G.; Saindane, Manohar T.; Liotta, Dennis C.; Plemper, Richard K.; Snyder, James P.; Sun, Aiming

2013-01-01

317

Serotonin 5-HT7 receptor agents: structure-activity relationships and potential therapeutic applications in central nervous system disorders  

PubMed Central

Since its discovery in the 1940s in serum, the mammalian intestinal mucosa, and in the central nervous system, serotonin (5-HT) has been shown to be involved in virtually all cognitive and behavioral human functions, and alterations in its neurochemistry have been implicated in the etiology of a plethora of neuropsychiatric disorders. The cloning of 5-HT receptor subtypes has been of importance in enabling them to be classified as specific protein molecules encoded by specific genes. The 5-HT7 receptor is the most recently classified member of the serotonin receptor family. Since its identification, it has been the subject of intense research efforts driven by its presence in functionally relevant regions of the brain. The availability of some selective antagonists and agonists, in combination with genetically modified mice lacking the 5-HT7 receptor, has allowed for a better understanding of the pathophysiological role of this receptor. This paper reviews data on localization and pharmacological properties of the 5-HT7 receptor, and summarizes the results of structure-activity relationship studies aimed at the discovery of selective 5-HT7 receptor ligands. Additionally, an overview of the potential therapeutic applications of 5-HT7 receptor agonists and antagonists in central nervous system disorders is presented. PMID:20923682

Leopoldo, Marcello; Lacivita, Enza; Berardi, Francesco; Perrone, Roberto; Hedlund, Peter B.

2010-01-01

318

Determination of boiling point of petrochemicals by gas chromatography-mass spectrometry and multivariate regression analysis of structural activity relationship.  

PubMed

Accurate understanding of analyte boiling points (BP) is of critical importance in gas chromatographic (GC) separation and crude oil refinery operation in petrochemical industries. This study reported the first combined use of GC separation and partial-least-square (PLS1) multivariate regression analysis of petrochemical structural activity relationship (SAR) for accurate BP determination of two commercially available (D3710 and MA VHP) calibration gas mix samples. The results of the BP determination using PLS1 multivariate regression were further compared with the results of traditional simulated distillation method of BP determination. The developed PLS1 regression was able to correctly predict analytes BP in D3710 and MA VHP calibration gas mix samples, with a root-mean-square-%-relative-error (RMS%RE) of 6.4%, and 10.8% respectively. In contrast, the overall RMS%RE of 32.9% and 40.4%, respectively obtained for BP determination in D3710 and MA VHP using a traditional simulated distillation method were approximately four times larger than the corresponding RMS%RE of BP prediction using MRA, demonstrating the better predictive ability of MRA. The reported method is rapid, robust, and promising, and can be potentially used routinely for fast analysis, pattern recognition, and analyte BP determination in petrochemical industries. PMID:24881546

Fakayode, Sayo O; Mitchell, Breanna S; Pollard, David A

2014-08-01

319

Defining RNA motif-aminoglycoside interactions via two-dimensional combinatorial screening and structure-activity relationships through sequencing.  

PubMed

RNA is an extremely important target for the development of chemical probes of function or small molecule therapeutics. Aminoglycosides are the most well studied class of small molecules to target RNA. However, the RNA motifs outside of the bacterial rRNA A-site that are likely to be bound by these compounds in biological systems is largely unknown. If such information were known, it could allow for aminoglycosides to be exploited to target other RNAs and, in addition, could provide invaluable insights into potential bystander targets of these clinically used drugs. We utilized two-dimensional combinatorial screening (2DCS), a library-versus-library screening approach, to select the motifs displayed in a 3×3 nucleotide internal loop library and in a 6-nucleotide hairpin library that bind with high affinity and selectivity to six aminoglycoside derivatives. The selected RNA motifs were then analyzed using structure-activity relationships through sequencing (StARTS), a statistical approach that defines the privileged RNA motif space that binds a small molecule. StARTS allowed for the facile annotation of the selected RNA motif-aminoglycoside interactions in terms of affinity and selectivity. The interactions selected by 2DCS generally have nanomolar affinities, which is higher affinity than the binding of aminoglycosides to a mimic of their therapeutic target, the bacterial rRNA A-site. PMID:23719281

Velagapudi, Sai Pradeep; Disney, Matthew D

2013-10-15

320

Structure-activity relationship for the estimation of OH-oxidation rate constants of carbonyl compounds in the aqueous phase  

NASA Astrophysics Data System (ADS)

In the atmosphere, one important class of reactions occurs in the aqueous phase in which organic compounds are known to undergo oxidation towards a number of radicals, among which OH radicals are the most reactive oxidants. In 2008, Monod and Doussin have proposed a new structure-activity relationship (SAR) to calculate OH-oxidation rate constants in the aqueous phase. This estimation method is based on the group-additivity principle and was until now limited to alkanes, alcohols, acids, bases and related polyfunctional compounds. In this work, the initial SAR is extended to carbonyl compounds, including aldehydes, ketones, dicarbonyls, hydroxy carbonyls, acidic carbonyls, their conjugated bases, and the hydrated form of all these compounds. To do so, only five descriptors have been added and none of the previously attributed descriptors were modified. This extension leads now to a SAR which is based on a database of 102 distinct compounds for which 252 experimental kinetic rate constants have been gathered and reviewed. The efficiency of this updated SAR is such that 58% of the rate constants could be calculated within ±20% of the experimental data and 76% within ±40% (respectively 41 and 72% for the carbonyl compounds alone).

Doussin, J.-F.; Monod, A.

2013-12-01

321

Structure-activity relationship for the estimation of OH-oxidation rate constants of carbonyl compounds in the aqueous phase  

NASA Astrophysics Data System (ADS)

In the atmosphere, one important class of reactions occurs in the aqueous phase in which organic compounds are known to undertake oxidation towards a number of radicals, among which OH radicals are the most reactive oxidants. In 2008, Monod and Doussin have proposed a new structure activity relationship (SAR) to calculate OH-oxidation rate constants in the aqueous phase. This estimation method is based on the group-additivity principle and was until now limited to alkanes, alcohols, acids, bases and related polyfunctional compounds. In this work, the initial SAR is extended to carbonyl compounds, including aldehydes, ketones, dicarbonyls, hydroxy-carbonyls, acidic carbonyls, their conjugated bases, and the hydrated form of all these compounds. To do so, only five descriptors have been added and none of the previously attributed descriptors were modified. This extension leads now to a SAR which is based on a database of 102 distinct compounds for which 252 experimental kinetic rate constants have been gathered and reviewed. The efficiency of this updated SAR is such that 58% of the rate constants could be calculated within ±20% of the experimental data and 76% within ±40%.

Doussin, J. F.; Monod, A.

2013-06-01

322

Determination of key structure-activity relationships in siRNA delivery with a mixed micelle system.  

PubMed

Short interfering ribonucleic acids (siRNAs) offer a highly specific and selective form of therapy for diseases with a genetic component; however the poor pharmacokinetic properties of the molecule have impeded its development into a therapeutic for use in vivo. Several different approaches have been taken to develop a successful siRNA delivery system but these systems lack the flexibility for easy optimisation. Here, we propose a polymeric nanoparticle (PNP) system consisting of two amphiphilic diblock copolymers which allow for the rapid determination of structure-activity relationships involving gene knockdown and toxicity. The diblock copolymers self-assemble into monodisperse micelles of defined hydrodynamic diameters ranging from 30 to 100 nm dependent on the copolymer ratio. A luciferase-based high throughput assay varying PNP composition, concentration and siRNA concentration allowed the rapid identification of efficient PNP formulations for adherent and suspension cell lines. Optimised PNPs efficiently knocked down a fusion oncogene in hard to transfect human leukaemic cells raising the possibility of targeting malignant cells in a cancer-specific fashion. This approach allows the optimum PNP formulation to be identified for different cell types and conditions. PMID:24140749

Omedes Pujol, Marta; Coleman, Daniel J L; Allen, Christopher D; Heidenreich, Olaf; Fulton, David A

2013-12-28

323

Defining RNA motif-aminoglycoside interactions via two-dimensional combinatorial screening and structure-activity relationships through sequencing  

PubMed Central

RNA is an extremely important target for the development of chemical probes of function or small molecule therapeutics. Aminoglycosides are the most well studied class of small molecules to target RNA. However, the RNA motifs outside of the bacterial rRNA A-site that are likely to be bound by these compounds in biological systems is largely unknown. If such information were known, it could allow for aminoglycosides to be exploited to target other RNAs and, in addition, could provide invaluable insights into potential bystander targets of these clinically used drugs. We utilized two-dimensional combinatorial screening (2DCS), a library-versus-library screening approach, to select the motifs displayed in a 3 × 3 nucleotide internal loop library and in a 6-nucleotide hairpin library that bind with high affinity and selectivity to six aminoglycoside derivatives. The selected RNA motifs were then analyzed using structure–activity relationships through sequencing (StARTS), a statistical approach that defines the privileged RNA motif space that binds a small molecule. StARTS allowed for the facile annotation of the selected RNA motif–aminoglycoside interactions in terms of affinity and selectivity. The interactions selected by 2DCS generally have nanomolar affinities, which is higher affinity than the binding of aminoglycosides to a mimic of their therapeutic target, the bacterial rRNA A-site. PMID:23719281

Velagapudi, Sai Pradeep; Disney, Matthew D.

2013-01-01

324

Determination of key structure-activity relationships in siRNA delivery with a mixed micelle system???  

PubMed Central

Short interfering ribonucleic acids (siRNAs) offer a highly specific and selective form of therapy for diseases with a genetic component; however the poor pharmacokinetic properties of the molecule have impeded its development into a therapeutic for use in vivo. Several different approaches have been taken to develop a successful siRNA delivery system but these systems lack the flexibility for easy optimisation. Here, we propose a polymeric nanoparticle (PNP) system consisting of two amphiphilic diblock copolymers which allow for the rapid determination of structure–activity relationships involving gene knockdown and toxicity. The diblock copolymers self-assemble into monodisperse micelles of defined hydrodynamic diameters ranging from 30 to 100 nm dependent on the copolymer ratio. A luciferase-based high throughput assay varying PNP composition, concentration and siRNA concentration allowed the rapid identification of efficient PNP formulations for adherent and suspension cell lines. Optimised PNPs efficiently knocked down a fusion oncogene in hard to transfect human leukaemic cells raising the possibility of targeting malignant cells in a cancer-specific fashion. This approach allows the optimum PNP formulation to be identified for different cell types and conditions. PMID:24140749

Omedes Pujol, Marta; Coleman, Daniel J.L.; Allen, Christopher D.; Heidenreich, Olaf; Fulton, David A.

2013-01-01

325

Derivation of Structure-Activity Relationships from the Anticancer Properties of Ruthenium(II) Arene Complexes with 2-Aryldiazole Ligands.  

PubMed

The ligands 2-pyridin-2-yl-1H-benzimidazole (HL(1)), 1-methyl-2-pyridin-2-ylbenzimidazole (HL(2)), and 2-(1H-imidazol-2-yl)pyridine (HL(3)) and the proligand 2-phenyl-1H-benzimidazole (HL(4)) have been used to prepare five different types of new ruthenium(II) arene compounds: (i) monocationic complexes with the general formula [(?(6)-arene)RuCl(?(2)-N,N-HL)]Y [HL = HL(1), HL(2), or HL(3); Y = Cl or BF4; arene = 2-phenoxyethanol (phoxet), benzene (bz), or p-cymene (p-cym)]; (ii) dicationic aqua complexes of the formula [(?(6)-arene)Ru(OH2)(?(2)-N,N-HL(1))](Y)2 (Y = Cl or TfO; arene = phoxet, bz, or p-cym); (iii) the nucleobase derivative [(?(6)-arene)Ru(9-MeG)(?(2)-N,N-HL(1))](PF6)2 (9-MeG = 9-methylguanine); (iv) neutral complexes consistent with the formulation [(?(6)-arene)RuCl(?(2)-N,N-L(1))] (arene = bz or p-cym); (v) the neutral cyclometalated complex [(?(6)-p-cym)RuCl(?(2)-N,C-L(4))]. The cytototoxic activity of the new ruthenium(II) arene compounds has been evaluated in several cell lines (MCR-5, MCF-7, A2780, and A2780cis) in order to establish structure-activity relationships. Three of the compounds with the general formula [(?(6)-arene)RuCl(?(2)-N,N-HL(1))]Cl differing in the arene moiety have been studied in depth in terms of thermodynamic dissociation constants, aquation kinetic constants, and DNA binding measurements. The biologically most active compound is the p-cym derivative, which strongly destabilizes the DNA double helix, whereas those with bz and phoxet have only a small effect on the stability of the DNA double helix. Moreover, the inhibitory activity of several compounds toward CDK1 has also been evaluated. The DNA binding ability of some of the studied compounds and their CDK1 inhibitory effect suggest a multitarget mechanism for their biological activity. PMID:25302401

Martínez-Alonso, Marta; Busto, Natalia; Jalón, Félix A; Manzano, Blanca R; Leal, José M; Rodríguez, Ana M; García, Begoña; Espino, Gustavo

2014-10-20

326

Structural characterization and cytotoxic properties of a 4-O-methylglucuronoxylan from castanea sativa. 2. Evidence of a structure-activity relationship.  

PubMed

Xylans were purified from delignified holocellulose alkaline extracts of Castanea sativa (Spanish chestnut) and Argania spinosa (Argan tree) and their structures analyzed by means of GC of their per-trimethylsilylated methylglycoside derivatives and (1)H NMR spectroscopy. The structures deduced were characteristic of a 4-O-methylglucuronoxylan (MGX) and a homoxylan (HX), respectively, with degrees of polymerization ranging from 182 to 360. In the case of MGX, the regular or random distribution of 4-O-methylglucuronic acid along the xylosyl backbone--determined by MALDI mass spectrometry after autohydrolysis of the polysaccharide--varied and depended both on the botanical source from which they were extracted and on the xylan extraction procedure. The MGX also inhibited in different ways the proliferation as well as the migration and invasion capability of A431 human epidermoid carcinoma cells. These biological properties could be correlated with structural features including values of the degree of polymerization, 4-O-MeGlcA to xylose ratios, and distribution of 4-O-MeGlcA along the xylosyl backbone, giving evidence of a defined structure-activity relationship. PMID:18646856

Barbat, Aline; Gloaguen, Vincent; Moine, Charlotte; Sainte-Catherine, Odile; Kraemer, Michel; Rogniaux, Hélène; Ropartz, David; Krausz, Pierre

2008-08-01

327

Characteristics of chemical binding to alpha 2u-globulin in vitro--evaluating structure-activity relationships  

SciTech Connect

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.

Borghoff, S.J.; Miller, A.B.; Bowen, J.P.; Swenberg, J.A. (Chemical Industry Institute of Toxicology, Research Triangle Park, NC (USA))

1991-02-01

328

Synthesis and Quantitative Structure–Activity Relationship of Imidazotetrazine Prodrugs with Activity Independent of O6-Methylguanine-DNA-methyltransferase, DNA Mismatch Repair and p53  

PubMed Central

The antitumor prodrug Temozolomide is compromised by its dependence for activity on DNA mismatch repair (MMR) and the repair of the chemosensitive DNA lesion, O6-methylguanine (O6-MeG), by O6-methylguanine-DNA-methyltransferase (EC 2.1.1.63, MGMT). Tumor response is also dependent on wild-type p53. Novel 3-(2-anilinoethyl)-substituted imidazotetrazines are reported that have activity independent of MGMT, MMR and p53. This is achieved through a switch of mechanism so that bioactivity derives from imidazotetrazine-generated arylaziridinium ions that principally modify guanine-N7 sites on DNA. Mono- and bi-functional analogs are reported and a quantitative structure-activity relationship (QSAR) study identified the p-tolyl-substituted bi-functional congener as optimized for potency, MGMT-independence and MMR-independence. NCI60 data show the tumor cell response is distinct from other imidazotetrazines and DNA-guanine-N7 active agents such as nitrogen mustards and cisplatin. The new imidazotetrazine compounds are promising agents for further development and their improved in vitro activity validates the principles on which they were designed. PMID:23895620

Pletsas, Dimitrios; Garelnabi, Elrashied A.E.; Li, Li; Phillips, Roger M.; Wheelhouse, Richard T.

2014-01-01

329

Evaluation of Cancer Preventive Activity and Structure-Activity Relationships of 3-Demethylubiquinone Q2, Isolated from the Ascidian Aplidium glabrum, and its Synthetic Analogues  

PubMed Central

Purpose 3-Demethylubiquinone Q2 (1) was isolated from the ascidian Aplidium glabrum. The cancer preventive properties and the structure-activity relationship for 3-demethylubiquinone Q2 (1) and 12 of its synthetic analogues (3–14) are reported. Methods Compounds 3–14, having one or several di- or triprenyl substitutions and quinone moieties with methoxyls in different positions, were synthesized. The cancer preventive properties of compounds 1 and 3–14 were tested in JB6 Cl41 mouse skin cells, using a variety of assessments, including the MTS assay, flow cytometry, and soft agar assay. Statistical nonparametric methods were used to confirm statistical significance. Results All quinones tested were shown to inhibit JB6 Cl41 cell transformation, to induce apoptosis, AP-1 and NF-?B activity, and to inhibit p53 activity. The most promising effects were indicated for compounds containing two isoprene units in a side chain and a methoxyl group at the para-position to a polyprenyl substitution. Conclusions Quinones 1 and 3–14 demonstrated cancer preventive activity in JB6 Cl41 cells, which may be attributed to the induction of p53-independent apoptosis. These activities depended on the length of side chains and on the positions of the methoxyl groups in the quinone part of the molecule. PMID:16320003

Fedorov, Sergey N.; Radchenko, Oleg S.; Shubina, Larisa K.; Balaneva, Nadezhda N.; Bode, Ann M.; Stonik, Valentin A.; Dong, Zigang

2006-01-01

330

Effect of hydroxyl substitution of flavone on angiogenesis and free radical scavenging activities: a structure-activity relationship studies using computational tools.  

PubMed

Angiogenesis is a key process needed for the growth and survival of solid tumors. Anti-angiogenesis may arrest the tumor growth and keep check on cancer metastasis. Developing antiangiogenic agents have remained a significant hope in the mainstream of anticancer research. The free radical implications in the initiation of cancers are well established. In the present studies, simple flavone and flavones with hydroxyl substitution in 'A' and 'C' ring at 3, 5, 6, and 7 were studied for antiangiogenic activities using chorioallantoic membrane (CAM) model and kinetics of DPPH (2,2-diphenyl-1-picryl hydrazine) and superoxide anion radical (SOR) scavenging activities. The docking of selected flavones with specific angiogenic targets such as vascular endothelial growth factor (VEGF), hypoxia inducible factor (HIF-1alpha) and vascular endothelial growth factor receptor-2 (VEGFR2) from human origin was carried out to focus the possible underlying mechanism of anti-angiogenesis. The result of the present studies shows that the 3-hydroxy substitution of the flavone was found to be the most promising lead for antiangiogenic activity in CAM model. The same was true for DPPH reduction with greater velocity as compared to other hydroxyl substitutions. However the 7- and 6-hydroxy substitution were observed to be more favourable for SOR scavenging activities as compared to other hydroxyl substitutions. The docking experiments shows that the VEGFR2 seems to be a structurally compatible target for tight binding of the flavones especially with 3-hydroxy substitution (-9.78 kcal/mole) as compared to VEGF (-8.47 kcal/mole) and HIF-1alpha (-8.99 kcal/mole). The quantum chemical descriptors of the test flavones related to free radical scavenging and other biological activities were calculated using computational tools. The data is discussed in the light of structure-activity relationship. PMID:19874890

Rajesh, Gacche; Harshala, Shegokar; Dhananjay, Gond; Jadhav, Archana; Vikram, Ghole

2010-01-31

331

Structure-activity relationship of miltirone, an active central benzodiazepine receptor ligand isolated from Salvia miltiorrhiza Bunge (Danshen)  

SciTech Connect

Twenty one o-quinonoid-type compounds and one coumarin-type compound related to miltirone (1) have been synthesized with the aim to identify the key structural elements involved in miltirone's interaction with the central benzodiazepine receptor. On the basis of their inhibition of ({sup 3}H)flunitrazepam binding to bovine cerebral cortex membranes, it is apparent that ring A of miltirone is essential for affinity. Although increasing the size of ring A from six-membered to seven- and eight-membered is well-tolerated, the introduction of polar hydroxyl groups greatly reduces binding affinity. The presence of 1,1-dimethyl groups on ring A is, however, not essential. On the other hand, the isopropyl group on ring C appears to be critical for binding as its removal decreases affinity by more than 30-fold. It can, however, be replaced with a methyl group with minimal reduction in affinity. Finally, linking ring A and B with a -CH{sub 2}CH{sub 2}- bridge results in analogue 89, which is 6 times more potent than miltirone at the central benzodiazepine receptor (IC50 = 0.05 microM).

Chang, H.M.; Chui, K.Y.; Tan, F.W.; Yang, Y.; Zhong, Z.P.; Lee, C.M.; Sham, H.L.; Wong, H.N. (Chinese Univ. of Hong Kong, Shatin (Hong Kong))

1991-05-01

332

Discovery, synthesis, and structure-activity relationships of 20(S)-protopanaxadiol (PPD) derivatives as a novel class of AMPK?2?1?1 activators.  

PubMed

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 ?2?1?1. 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 ?M) and efficacy (fold: 2.5-3.8). Among them, compounds 12 and 13 exhibited the best potency (EC50: 1.2 and 0.7 ?M) 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. PMID:24747289

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

2014-05-22

333

Anti-Helicobacter pylori activity and Structure-Activity Relationship study of 2-Alkylthio-5-(nitroaryl)-1,3,4-thiadiazole Derivatives  

PubMed Central

Nitro-containing heteroaromatic derivatives structurally related to nitroimidazole (Metronidazole) are being extensively evaluated against Helicobacter pylori isolates. On the other hand, 1,3,4-thiadiazole derivatives have also demonstrated promising antibacterial potential. In present study, we evaluated anti-H. pylori activity of novel hybrid molecules bearing nitroaryl and 1,3,4-thiadiazole moieties. Anti-H. pylori activity of novel 5-(5-nitroaryl)-1,3,4-thiadiazole derivatives bearing different bulky alkylthio side chains at C-2 position of thiadiazole ring, were assessed against three different metronidazole resistant H. pylori isolates by paper disk diffusion method. Most of the compounds demonstrated moderate to strong inhibitory response especially at 25 ?g/disk. The structure-activity relationship study of the compounds demonstrated that introduction of different alkylthio moieties at C-2 position of thiadiazole ring; alter the inhibitory activity which is mainly dependent on the type of C-5 attached nitrohetercyclic ring. The promising compound of this scaffold, bearing 1-methyl-5-nitroimidazole moiety at C-5 and ?-methylbenzylthio side chain at C-2 position of thiadiazole ring, showed strong inhibitory response against metronidazole resistant H. pylori isolates at 12.5 ?g/disk (the inhibition zone diameter at all evaluated concentrations (12.5- 100 ?g/disk) is >50 mm). Novel 5-(5-nitroaryl)-1,3,4-thiadiazole scaffold bearing different C-2 attached thio-pendant moieties with promising anti-H. pylori potential were identified. Among different nitroheterocycles, 5-nitrofuran and 5-nitroimidazole moieties were preferable for the substitution at C-5 position of 1,3,4-thiadiazole ring. Introduction of different alkylthio side chains at C-2 position of central ring alter the inhibitory activity which is mainly dependent on the type of C-5 attached nitrohetercyclic ring. PMID:24250634

Asadipour, Ali; Edraki, Najmeh; Nakhjiri, Maryam; Yahya-Meymandi, Azadeh; Alipour, Eskandar; Saniee, Parastoo; Siavoshi, Farideh; Shafiee, Abbas; Foroumadi, Alireza

2013-01-01

334

Crystal structures of mouse autocrine motility factor in complex with carbohydrate phosphate inhibitors provide insight into structure-activity relationship of the inhibitors.  

PubMed

Autocrine motility factor (AMF), a tumor-secreted cytokine, stimulates cell migration in vitro and metastasis in vivo. AMF is identical to the extracellular cytokines neuroleukin and maturation factor and, interestingly, to the intracellular enzyme phosphoglucose isomerase. The cytokine activity of AMF is inhibited by carbohydrate phosphate compounds as they compete for AMF binding with the carbohydrate moiety of the AMF receptor (AMFR), which is a glycosylated seven transmembrane helix protein. Here, we report the first comprehensive high-resolution crystal structure analyses of the inhibitor-free form and the eight types of inhibitor (phosphate, erythrose 4-phosphate (E4P), arabinose 5-phosphate (A5P), sorbitol 6-phosphate (S6P), 6-phosphogluconic acid (6PGA), fructose 6-phosphate (F6P), glucose 6-phosphate (G6P), or mannose 6-phosphate (M6P)) complexes of mouse AMF (mAMF). We assayed the inhibitory activities of these inhibitors against the cytokine activity of mAMF. The inhibitory activities of the six-carbon sugars (G6P, F6P, M6P, and 6PGA) were found to be significantly higher than those of the four or five-carbon sugars (E4P or A5P). The inhibitory activities clearly depend on the length of the inhibitor molecules. A structural comparison revealed that a water-mediated hydrogen bond between one end of the inhibitor and a rigid portion of the protein surface in the shorter-chain inhibitor (E4P) complex is replaced by a direct hydrogen bond in the longer-chain inhibitor (6PGA) complex. Thus, to obtain a new compound with higher inhibitory activities against AMF, water molecules at the inhibitor binding site of AMF should be replaced by a functional group of inhibitors in order to introduce direct interactions with the protein surface. The present structure-activity relationship studies will be valuable not only for designing more effective AMF inhibitors but also for studying general protein-inhibitor interactions. PMID:16375918

Tanaka, Nobutada; Haga, Arayo; Naba, Noriko; Shiraiwa, Katsura; Kusakabe, Yoshio; Hashimoto, Kazunori; Funasaka, Tatsuyoshi; Nagase, Hisamitsu; Raz, Avraham; Nakamura, Kazuo T

2006-02-17

335

FISH ACUTE TOXICITY SYNDROMES AND THEIR USE IN THE QSAR (QUANTITATIVE STRUCTURE ACTIVITY RELATIONSHIP) APPROACH TO HAZARD ASSESSMENT  

EPA Science Inventory

Implementation of the Toxic Substances Control Act of 1977 creates the need to reliably establish testing priorities because laboratory resources are limited and the number of industrial chemicals requiring evaluation is overwhelming. The use of quantitative structure activity re...

336

Three-dimensional quantitative structure-activity relationship modeling of cocaine binding by a novel human monoclonal antibody.  

PubMed

Human monoclonal antibodies (mAbs) designed for immunotherapy have a high potential for avoiding the complications that may result from human immune system responses to the introduction of nonhuman mAbs into patients. This study presents a characterization of cocaine/antibody interactions that determine the binding properties of the novel human sequence mAb 2E2 using three-dimensional quantitative structure-activity relationship (3D-QSAR) methodology. We have experimentally determined the binding affinities of mAb 2E2 for cocaine and 38 cocaine analogues. The K(d) of mAb 2E2 for cocaine was 4 nM, indicating a high affinity. Also, mAb 2E2 displayed good cocaine specificity, as reflected in its 10-, 1500-, and 25000-fold lower binding affinities for the three physiologically relevant cocaine metabolites benzoylecgonine, ecgonine methyl ester, and ecgonine, respectively. 3D-QSAR models of cocaine binding were developed by comparative molecular similarity index analysis (CoMSIA). A model of high statistical quality was generated showing that cocaine binds to mAb 2E2 in a sterically restricted binding site that leaves the methyl group attached to the ring nitrogen of cocaine solvent-exposed. The methyl ester group of cocaine appears to engage in attractive van der Waals interactions with mAb 2E2, whereas the phenyl group contributes to the binding primarily via hydrophobic interactions. The model further indicated that an increase in partial positive charge near the nitrogen proton and methyl ester carbonyl group enhances binding affinity and that the ester oxygen likely forms an intermolecular hydrogen bond with mAb 2E2. Overall, the cocaine binding properties of mAb 2E2 support its clinical potential for development as a treatment of cocaine overdose and addiction. PMID:14695827

Paula, Stefan; Tabet, Michael R; Farr, Carol D; Norman, Andrew B; Ball, W James

2004-01-01

337

Quantitative structure-activity relationship (QSAR) studies for predicting activation of the ryanodine receptor type 1 channel complex (RyR1) by polychlorinated biphenyl (PCB) congeners.  

PubMed

A quantitative structure-activity relationship (QSAR) was developed to predict the congener specific ryanodine receptor type RyR1 activity of all 209 polychlorinated biphenyl (PCB) congeners. A three-variable QSAR equation was obtained via stepwise forward linear regression on an unsupervised forward selection reduced data set from an initial database. Application of the QSAR towards predicting EC(2x) values for all 209 PCB congeners indicated good agreement in substitution pattern trends between the experimental and estimated data sets. The QSAR model predicts a less than two-fold increase in maximal potency among all congeners outside the experimental database, and it appears that no high-potency PCB congeners with EC(2x) values much less than 0.2 microM exist. Increasing RyR1-neuro toxicity equivalents with increasing homologue number and Aroclor chlorination likely reflect indirect molecular controls on toxicity, since congeners with multiple ortho substituents-the primary structural feature controlling a lack of coplanarity and resulting neurotoxicity-are more likely to be found in higher homologues. PMID:20390877

Rayne, Sierra; Forest, Kaya

2010-01-01

338

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

PubMed

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. PMID:16085416

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

339

C1 domain-targeted isophthalates as protein kinase C modulators: structure-based design, structure-activity relationships and biological activities.  

PubMed

Protein kinase C (PKC) is a serine/threonine kinase belonging to the AGC family. PKC isoenzymes are activated by phospholipid-derived second messengers, transmit their signal by phosphorylating specific substrates and play a pivotal role in the regulation of various cell functions, including metabolism, growth, differentiation and apoptosis. Therefore they represent an interesting molecular target for the treatment of several diseases, such as cancer and Alzheimer's disease. Adopting a structure-based approach on the crystal structure of the PKC? C1B domain, our team has developed isophthalic acid derivatives that are able to modify PKC functions by binding to the C1 domain of the enzyme. Bis[3-(trifluoromethyl)benzyl] 5-(hydroxymethyl)isophthalate (HMI-1a3) and bis(1-ethylpentyl) 5-(hydroxymethyl)isophthalate (HMI-1b11) were selected from a set of compounds for further studies due to their high affinity for the C1 domains of PKC? and PKC?. HMI-1a3 showed marked antiproliferative activity in HeLa cells whereas HMI-1b11 induced differentiation and supported neurite growth in SH-SY5Y cells. Our aim in the future is to improve the selectivity and potency of isophthalate derivatives, to clarify their mechanism of action in the cellular environment and to assess their efficacy in cell-based and in vivo disease models. HMI-1a3 has already been selected for a further project and redesigned to function as a probe immobilized on an affinity chromatography column. It will be used to identify cellular target proteins from cell lysates, providing new insights into the mechanism of action of HMI-1a3. PMID:25399568

Talman, Virpi; Provenzani, Riccardo; Boije Af Gennäs, Gustav; Tuominen, Raimo K; Yli-Kauhaluoma, Jari

2014-12-01

340

The structure-activity relationship study on 2-, 5-, and 6-position of the water soluble 1,4-dihydropyridine derivatives blocking N-type calcium channels.  

PubMed

In order to find an injectable and selective N-type calcium channel blocker, we have performed the structure-activity relationship (SAR) study on the 2-, 5-, and 6-position of 1,4-dihydropyridine-3-carboxylate derivative APJ2708 (2), which is a derivative of Cilnidipine and has L/N-type calcium channel dual inhibitory activities. As a consequence of the optimization, 6-dimethylacetal derivative 7 was found to have an effective inhibitory activity against N-type calcium channels with more than 170-fold lower activity for L-type channel compared to that of APJ2708. PMID:18684623

Yamamoto, Takashi; Niwa, Seiji; Ohno, Seiji; Tokumasu, Munetaka; Masuzawa, Yoko; Nakanishi, Chika; Nakajo, Akira; Onishi, Tomoyuki; Koganei, Hajime; Fujita, Shin-Ichi; Takeda, Tomoko; Kito, Morikazu; Ono, Yukitsugu; Saitou, Yuki; Takahara, Akira; Iwata, Seinosuke; Shoji, Masataka

2008-09-01

341

Structural relationships within medical informatics.  

PubMed Central

This study seeks to increase our understanding of the structure of Medical Informatics. In particular, it focuses on the relationships between information science and information technology on the one hand, and biomedical research, clinical practice, and medical education on the other, that have defined "medical informatics." Using indexing terms and MeSH tree structures assigned to medical informatics literature covered by MEDLINE, co-occurrence analysis provides a "map" of the field. Major research and application focuses arrayed within the map elucidate a finer structure than reported previously. Dimensions "Techniques vs. Systems" and "Signs & Symptoms vs. Processes" form the two axes of the map and relate to the relationships underlying the indexing assignments given to the literature studied. Related studies underway using the INSPEC database will provide a complementary perspective on the structure of medical informatics as a field. PMID:11079952

Morris, T. A.

2000-01-01

342

Relationship between chemical structure and biological activity of alkali metal o-, m- and p-anisates. FT-IR and microbiological studies  

NASA Astrophysics Data System (ADS)

In this work we investigated relationship between molecular structure of alkali metal o-, m-, p-anisate molecules and their antimicrobial activity. For this purpose FT-IR spectra for lithium, sodium, potassium, rubidium and caesium anisates in solid state and solution were recorded, assigned and analysed. Microbial activity of studied compounds was tested against Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus and Proteus vulgaris. In order to evaluate the dependency between chemical structure and biological activity of alkali metal anisates the statistical analysis (multidimensional regression and principal component) was performed for selected wavenumbers from FT-IR spectra and parameters that describe microbial activity of anisates. The obtained statistical equations show the existence of correlation between molecular structure of anisates and their biological properties.

Kalinowska, M.; Piekut, J.; Lewandowski, W.

2011-11-01

343

Toxic and antifeedant activities of prenylated flavonoids isolated from Tephrosia apollinea L. against three major coleopteran pests of stored grains with reference to their structure-activity relationship.  

PubMed

Four prenylated flavonoids, isoglabratephrin, (+)-glabratephrin, tephroapollin-F and lanceolatin-A, were isolated from Tephrosia apollinea L. and tested against three stored grain insects. Using the filter paper bioassay, compounds showed adulticidal activity against Sitophilus oryzae (L), Rhyzopertha dominica (F) and Tribolium castaneum (Herbst) at concentrations of 0.875, 1.75 and 3.5 mg mL(- 1). At 3.5 mg mL(- 1), tephroapollin-F was the most toxic (78.6%, 64.6% and 60.7% mortality was recorded after 10 days exposure of S. oryzae, R. dominica and T. castaneum, respectively). The F1 progeny production of insects was affected after parental exposure to flavonoids, where S. oryzae was the most susceptible. A nutritional bioassay, employing a flour disc and test concentrations of 0.65, 1.3 and 2.6 mg g(- 1), revealed a significant reduction in the relative growth rate, relative consumption rate and efficiency of conversion of ingested food by all insects. The structure-activity relationship among the tested flavonoids was discussed. PMID:24980754

Nenaah, Gomah E

2014-12-01

344

Quantitative structure-activity relationships predict the delayed neurotoxicity potential of a series of O-alkyl-O-methylchloroformimino phenylphosphonates.  

PubMed

Inhibition of acetylcholinesterase (AChE) versus inhibition and aging of neuropathy target esterase (NTE) by organophosphorus (OP) compounds in vivo can give rise to distinct neurological consequences: acute cholinergic toxicity versus OP compound-induced delayed neurotoxicity (OPIDN). Previous work has shown that the relative potency of an OP compound to react with NTE versus AChE in vitro may predict its capability to produce OPIDN. The present study was conducted to evaluate further the validity of such predictions and to enhance them with quantitative structure-activity relationships (QSAR) using a homologous series of alkyl phenylphosphonates (RO)C6H5P(O)ON = CCICH3 (PhP; R = alkyl). Neuropathic potential of PhP was assessed by measuring ki(NTE)ki(AChE) ratios in vitro and comparing these with ED50 ratios in vivo. Selectivity for NTE increased with rising R-group hydrophobicity. The ki(NTE)/ki(AChE) ratios were 0.42 (methyl), 3.6 (ethyl), 15 (isopropyl), 36 (propyl), 69 (isobutyl), 105 (butyl), and 124 (pentyl). Ratios > 1 suggest the potential to produce OPIDN at doses lower than the LD50. Inhibition of NTE and AChE in hen brain in vivo was studied 24 h after i.m. injection of hens with increasing doses of methyl and butyl derivatives. Analysis of dose-response curves yielded ED50(AChE)/ED50(NTE) ratio of 0.86 for methyl PhP and 22.1 for butyl PhP. These results predict that the butyl derivative should be more neuropathic than the methyl analogue. Excellent correspondence between in vivo and in vitro predictions of neuropathic potential indicate that valid predictive QSAR models may be based on the in vitro approach. Adoption of this system would result in reducing experimental animal use, lowering costs, accelerating data production, and enabling standardization of a biochemically based risk assessment of the neuropathic potential of OP compounds. PMID:12746136

Malygin, Vladimir V; Sokolov, Vladimir B; Richardson, Rudy J; Makhaeva, Galina F

2003-04-11

345

Quantitative structure-activity relationship analysis of 4(3H)-quinazolone derivatives as tyrosine kinase inhibitors by multiple linear regression.  

PubMed

Computational chemistry is playing an increasingly important role in drug design and discovery, structural biology, and quantitative structure-activity relationship studies. A series of 4(3H)-quinozolone derivatives were screened for two-dimensional quantitative structure-activity relationship studies and subsequently their absorption, distribution, metabolism, and excretion (ADME) properties with the use of soft modeling techniques after selecting suitable descriptors for molecular structure. Multiple linear regression analysis was performed for this study. The final quantitative structure-property relationship mathematical models were found as follows: Equation [Y= log (1MIC)] [symbol: see the text] pMIC= 1. 0:2165?(1) - 2.082?(3) - 0.3235?T - 0.2185?x - 100.6qN - 35.42. 2. 0:2185?(1) - 2.1575?(3) - 0.3622?T - 0.2142?x - 100.4qN - 31.25. 3. 0:0015? - 2.0822?(3) - 0.1252?T - 0.2180?x - 112.9qN - 36.05. 4. 2:108?(3) - 0.0035ET - 0.2033?x - 3.489qesp - 92.60qN - 33.20. 5. 0:2140?(1) - 2.186?(3) - 0.0036Oxxx - 0.0016Oxyy - 78.02qN - 31.52. PMID:20858057

Srivastava, Vikas; Sinha, Deepa; Tiwari, Anjani K; Sharma, Himanshu; Bala Sharma, Raj; Singh, Vinay K; Mishra, Anil K

2010-10-01

346

Increased ( 3H) Phorbol Ester Binding in Rat Cerebellar Granule Cells by Polychlorinated Biphenyl Mixtures and Congeners: StructureActivity Relationships  

Microsoft Academic Search

Our previous reports indicate that polychlorinated biphenyl (PCB) congeners in vitro perturbed cellular Ca2+ homeostasis and protein kinase C (PKC) translocation. We have now studied the structure-activity relationship (SAR) of 3 PCB mixtures, 24 PCB congeners, and 1 dibenzofuran for their effects on PKC translocation by measuring [3H]phorbol ester ([3H]PDBu) binding in cerebellar granule cells (7 days in culture). All

P. R. S. Kodavanti; T. R. Ward; J. D. Mckinney; H. A. Tilson

1995-01-01

347

Structure-Plant Phytotoxic Activity Relationship of 7,7'-epoxylignanes, (+)- and (-)-verrucosin: Simplification on the aromatic ring substituents.  

PubMed

The synthesized 7-aryl derivatives of (7R,7'S,8S,8'S)-(+)-verrucosin were applied to growth inhibitory activity test against ryegrass at 1mM. 7-(3-Ethoxy-4-hydroxyphenyl) derivative 12 and 7-(2-hydroxyphenyl) derivative 4 showed comparable activity to those of (+)-verrucosin against the root (-95%) and the shoot (-60%), respectively. The growth inhibitory activity test against lettuce using synthesized 7-aryl derivatives of (7S,7'R,8R,8'R)-(-)-verrucosin at 1mM showed that the activities of 7-(3-hydroxyphenyl) derivative 20 and 7-(3-ethoxy-4-hydroxyphenyl) derivative 28 are similar to that of (-)-verrucosin against the root (-95%). Against the shoot, 7-(3-hydroxyphenyl) derivative 20 showed higher activity (-80%) than that of (-)-verrucosin (-60%). As the next step, (7S,7'R,8R,8'R)-7-(3-hydroxyphenyl)-7'-aryl-(-)-verrucosin derivatives, in which the most effective 3-hydroxyphenyl group is employed as 7-aromatic ring, were synthesized for the assay against lettuce. In this experiment, 7'-(2-hydroxyphenyl) derivative 37 and 7'-(3-hydroxyphenyl) derivative 38 showed similar activity to that of derivative 20. The effect of 7- and 7'-aryl structures of 7,7'-epoxylignanes on the plant growth inhibitory activity was clarified. The 7- and 7'-aryl structures were simplified to show comparable activity to or higher activity than that of (-)-verrucosin. The plant growth inhibitory activity of a nutmeg component, (+)-fragransin C3b, was estimated as -80% inhibition at 1mM against ryegrass roots. PMID:25248684

Yamauchi, Satoshi; Nakayama, Kumiko; Nishiwaki, Hisashi; Shuto, Yoshihiro

2014-10-15

348

Synthesis of 2-(thienyl-2-yl or -3-yl)-4-furyl-6-aryl pyridine derivatives and evaluation of their topoisomerase I and II inhibitory activity, cytotoxicity, and structure–activity relationship  

Microsoft Academic Search

A series of 2-(thienyl-2-yl or -3-yl)-4-furyl-6-aryl pyridine derivatives were designed, synthesized, and evaluated for their topoisomerase I and II inhibition and cytotoxic activity against several human cancer cell lines. Compounds 10–19 showed moderate topoisomerase I and II inhibitory activity and 20–29 showed significant topoisomerase II inhibitory activity. Structure–activity relationship study revealed that 4-(5-chlorofuran-2-yl)-2-(thiophen-3-yl) moiety has an important role in displaying

Pritam Thapa; Radha Karki; Hoyoung Choi; Jae Hun Choi; Minho Yun; Byeong-Seon Jeong; Mi-Ja Jung; Jung Min Nam; Younghwa Na; Won-Jea Cho; Youngjoo Kwon; Eung-Seok Lee

2010-01-01

349

Structure determination of glycogen synthase kinase-3 from Leishmania major and comparative inhibitor structure?activity relationships with Trypanosoma brucei GSK-3  

SciTech Connect

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 {angstrom} 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-3{beta} (HsGSK-3{beta}) and LmajGSK-3 short SAR suggest that compounds which selectively inhibit LmajGSK-3 short may be found.

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

350

Structure Determination of Glycogen Synthase Kinase-3 from Leishmania major and Comparative Inhibitor Structure-Activity Relationships with Trypanosoma brucei GSK-3  

PubMed Central

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-3? (HsGSK-3?) and LmajGSK-3 short SAR suggest that compounds which selectively inhibit LmajGSK-3 short may be found. PMID:21195115

Ojo, Kayode K.; Arakaki, Tracy L.; Napuli, Alberto J.; Inampudi, Krishna K.; Keyloun, Katelyn R.; Zhang, Li; Hol, Wim G.J.; Verlinde, Christophe L.M.J.; Merritt, Ethan A.; Van Voorhis, Wesley C.

2011-01-01

351

Polybrominated diphenyl ethers and ortho-substituted polychlorinated biphenyls as neuroendocrine disruptors of vasopressin release: effects during physiological activation in vitro and structure-activity relationships.  

PubMed

The neuropeptide, vasopressin (VP) is synthesized in magnocellular neuroendocrine cells (MNCs) located within the supraoptic (SON) and paraventricular (PVN) nuclei of the mammalian hypothalamus. VP has multiple functions including maintenance of body fluid homeostasis, cardiovascular control, learning and memory, and nervous system development. Polybrominated diphenyl ethers (PBDEs), used as additive flame retardants, have been shown to interfere with hormone metabolism and function. Previously, we demonstrated that the technical polychlorinated biphenyl (PCB) mixture, Aroclor 1254, inhibits somatodendritic VP release from the SON of osmotically stimulated rats. The objectives of the current study were to test whether PBDEs affect central VP release in a similar manner and to determine the potency of several PCB and PBDE congeners in order to identify a common mode of action for these persistent chemicals. The current work shows that the commercial PBDE mixture (DE-71) significantly decreased somatodendritic VP release from rat SON punches in a strain-independent manner. In addition, the specific congeners PBDE 47 and PCB 47 (15 and 5 microM) were also neuroactive in this system. To explore structure/activity relationships, we compared the effects of PBDE 77 with PCB 77. PBDE 77, but not PCB 77 significantly reduced VP release. These results show that like PCBs, PBDEs perturb signaling mechanisms responsible for hormone release, and that environmentally relevant PBDE congeners are more neuroactive than the commercial mixtures with noncoplanarity of these compounds playing a role in promoting neuroactivity. PMID:17434953

Coburn, Cary G; Currás-Collazo, Margarita C; Kodavanti, Prasada Rao S

2007-07-01

352

The relationship between enhanced enzyme activity and structural dynamics in ionic liquids: a combined computational and experimental study.  

PubMed

Candida antarctica lipase B (CALB) is an efficient biocatalyst for hydrolysis, esterification, and polymerization reactions. In order to understand how to control enzyme activity and stability we performed a combined experimental and molecular dynamics simulation study of CALB in organic solvents and ionic liquids (ILs). Our results demonstrate that the conformational changes of the active site cavity are directly related to enzyme activity and decrease in the following order: [Bmim][TfO] > tert-butanol > [Bmim][Cl]. The entrance to the cavity is modulated by two isoleucines, ILE-189 and ILE-285, one of which is located on the ?-10 helix. The ?-10 helix can substantially change its conformation due to specific interactions with solvent molecules. This change is acutely evident in [Bmim][Cl] where interactions of LYS-290 with chlorine anions caused a conformational switch between ?-helix and turn. Disruption of the ?-10 helix structure results in a narrow cavity entrance and, thus, reduced the activity of CALB in [Bmim][Cl]. Finally, our results show that the electrostatic energy between solvents in this study and CALB is correlated with the structural changes leading to differences in enzyme activity. PMID:24424278

Kim, Ho Shin; Ha, Sung Ho; Sethaphong, Latsavongsakda; Koo, Yoon-Mo; Yingling, Yaroslava G

2014-02-21

353

Synthesis and structure-activity relationship studies of N-terminal analogues of the antimicrobial peptide tridecaptin A(1).  

PubMed

Chemical synthesis was used to increase the potency of the antimicrobial lipopeptide tridecaptin A1. Lipid tail modification proved to be an ideal platform for synthesizing structurally simpler analogues that are not readily accessible by isolation. The stereochemical elements of the tridecaptin A1 lipid tail are not essential for antimicrobial activity and could be replaced with hydrophobic aliphatic or aromatic groups. Some simpler analogues displayed potent antimicrobial activity against Gram-negative bacteria, including Campylobacter jejuni, Escherichia coli O157:H7, and multidrug resistant Klebsiella pneumoniae. PMID:24479847

Cochrane, Stephen A; Lohans, Christopher T; Brandelli, Jeremy R; Mulvey, George; Armstrong, Glen D; Vederas, John C

2014-02-13

354

Development of novel EDG3 antagonists using a 3D database search and their structure-activity relationships.  

PubMed

Sphingosine-1-phosphate (S1P) is an intracellular second messenger and an extracellular mediator through endothelial differentiation gene (EDG) receptors, which are a novel class of G-protein-coupled receptors. Although EDG has attracted much attention because of its various roles, no selective agonists or antagonists have yet been developed. This could account for the delay in clarifying the physiological roles of members of the EDG family. Because precise structural information on EDG receptors is not yet available, pharmacophore models were generated based on structural information for S1P using the rational drug design software Catalyst. Novel antagonists, 2-alkylthiazolidine-4-carboxylic acids, were retrieved from a three-dimensional database search using the pharmacophore models, and these showed activity for EDG3. On the basis of their nonphosphoric acid structure, more potent antagonists, 2-(m- or p-heptylphenyl)thiazolidine-4-carboxylic acid, were developed. PMID:12361389

Koide, Yuuki; Hasegawa, Takeshi; Takahashi, Atsuo; Endo, Akira; Mochizuki, Naoki; Nakagawa, Masako; Nishida, Atsushi

2002-10-10

355

Biological implications of the structural, antithrombin affinity and anticoagulant activity relationships among vertebrate heparins and heparan sulphates.  

PubMed Central

We analysed the distribution, structural characteristics, antithrombin-III-binding properties and anticoagulant activities of heparins and heparan sulphates isolated from the tissues of a wide range of vertebrates. Heparin has a curiously limited distribution, since it was absent from lower aquatic vertebrate species, present in only certain organs such as intestine in many higher vertebrates, and completely absent from the rabbit among mammals examined. The heparins were structurally diverse, and they exhibited a broad range of anticoagulant activities, from approx. 50% to 150% of average commercial heparins. Although there was a rough correlation between the anticoagulant potency of the starting isolate and the proportional content of material exhibiting high-affinity binding to the proteinase inhibitor antithrombin III, activities of high-affinity fractions from heparins low in activity overlapped those of low-affinity fractions from highly active heparins. Heparan sulphates, which in contrast were isolated from nearly all vertebrate organs, contained high-affinity subfractions constituting up to 5% of the starting material and possessing anticoagulant potencies of 2-30 units/mg. In consideration of the heparin data, we infer that its biological function is either species-specific or may be served by other molecular elements, and that there exists considerable diversity in the antithrombin-III-binding sequence of heparin. The more-generally distributed glycosaminoglycan heparan sulphate possesses within its variable structure a small high-affinity subfraction with low anticoagulant potency, whether isolated from aorta or other tissues. Although heparan sulphate appears to have an essential function at the cellular level, we suggest that this is probably not that of providing heparin-like antithrombotic effects on vascular surfaces. PMID:2948492

Hovingh, P; Piepkorn, M; Linker, A

1986-01-01

356

Phenyl-imidazolo-cytidine analogues: structure-photophysical activity relationship and ability to detect single DNA mismatch.  

PubMed

To expand the arsenal of fluorescent cytidine analogues for the detection of genetic material, we synthesized para-substituted phenyl-imidazolo-cytidine ((Ph)ImC) analogues 5a-g and established a relationship between their structure and fluorescence properties. These analogues were more emissive than cytidine (?em 398-420 nm, ? 0.009-0.687), and excellent correlation was found between ? of 5a-g and ?p(-) of the substituent on the phenyl-imidazolo moiety (R(2) = 0.94). Calculations suggested that the dominant tautomer of (Ph)ImC in methanol solution is identical to that of cytidine. DFT calculations of the stable tautomer of selected (Ph)ImC analogues suggested a relationship between the HOMO-LUMO gap and ? and explained the loss of fluorescence in the nitro analogue. Incorporation of the CF3-(Ph)ImdC analogue into a DNA probe resulted in 6-fold fluorescence quenching of the former. A 17-fold reduction of fluorescence was observed for the G-matched duplex vs ODN(CF3-(Ph)ImdC), while for A-mismatched duplex, only a 2-fold decrease was observed. Furthermore, since the quantum yield of ODN(CF3-(Ph)ImdC):ODN(G) was reduced 17-fold vs that of a single strand, whereas that of ODN(CF3-(Ph)ImdC):ORN(G) was reduced only 3.8-fold, ODN(CF3-(Ph)ImdC) appears to be a DNA-selective probe. We conclude that the ODN(CF3-(Ph)ImdC) probe, exhibiting emission sensitivity upon single nucleotide replacement, may be potentially useful for DNA single nucleotide polymorphism (SNP) typing. PMID:24992467

Kovaliov, Marina; Weitman, Michal; Major, Dan Thomas; Fischer, Bilha

2014-08-01

357

Structure and activity relationship for CO and O2 adsorption over gold nanoparticles using density functional theory and artificial neural networks  

NASA Astrophysics Data System (ADS)

In this work, the structure and activity relationship for CO and O2 adsorption over Au2 to Au10 clusters was investigated using density functional theory (DFT) and artificial neural networks as a part of ongoing studies in the literature to understand CO oxidation over gold nanoparticles. The optimum structures for the anionic, neutral, and cationic clusters were determined first using DFT. The structural properties such as binding energy, highest occupied molecular orbital-lowest unoccupied molecular orbital gap, ionization potential, and electron affinity as well as the adsorption energies of CO and O2 were calculated using the same method at various values of user defined descriptors such as the size and charge of the cluster, the presence or absence of unpaired electron, and the coordination number of the adsorption site. Then, artificial neural network models were constructed to establish the relationship between these descriptors and the structural properties, as well as between the structural properties and the adsorption energies. It was concluded that the neural network models can successfully predict the adsorption energies calculated using DFT. The statistically determined relative significances of user defined descriptors and the structural properties on the adsorption energies were also found to be in good agreement with the literature indicating that this approach may be used for the other catalytic systems as well.

Davran-Candan, Tu?ba; Günay, M. Erdem; Y?ld?r?m, Ramazan

2010-05-01

358

Structure-Function Relationships in Prolactin  

Microsoft Academic Search

\\u000a In this chapter, it is the authors’ intent to provide an update on structure-function relationships for PRL. We have only\\u000a covered those PRL varieties for which additional information has been gained since the excellent and comprehensive review\\u000a by Sinha in 1995 (1). Focus is on forms for which a different biological activity is becoming evident, although attention is also drawn

Mary Y. Lorenson; Ameae M. Walker

359

Pyrearinus termitilluminans larval click beetle luciferase: active site properties, structure and function relationships and comparison with other beetle luciferases.  

PubMed

Several beetle luciferases have been cloned and sequenced. However, most studies on structure and function relationships and bioanalytical applications were done with firefly luciferases, which are pH sensitive. Several years ago we cloned Pyrearinus termitilluminans larval click beetle luciferase, which displays the most blue-shifted bioluminescence among beetle luciferases and is pH insensitive. This enzyme was expressed in E. coli, purified, and its properties investigated. This luciferase shows slower luminescence kinetics, K(M) values comparable to other beetle luciferases and high catalytic constant. Fluorescence studies with 8-anilino-1-naphtalene-sulfonic acid (1,8-ANS) and modeling studies suggest that the luciferin binding site of this luciferase is very hydrophobic, supporting the solvent and orientation polarizability effects as determining mechanisms for bioluminescence colors. Although pH insensitive in the range between pH 6-8, at pH 10 this luciferase displays a remarkable red-shift and broadening of the bioluminescence spectrum. Modeling studies suggest that the residue C312 may play an important role in bioluminescence color modulation. Compared to other beetle luciferases, Pyrearinus termitilluminans luciferase also displays higher thermostability and sustained luminescence in a bacterial cell environment, which makes this luciferase particularly suitable for in vivo cell analysis and bioimaging. PMID:20024173

Silva Neto, A J; Scorsato, V; Arnoldi, F G C; Viviani, V R

2009-12-01

360

The fucoidans from brown algae of Far-Eastern seas: anti-tumor activity and structure-function relationship.  

PubMed

The sulfated polysaccharides from brown algae - the fucoidans - are known to be a topic of numerous studies, due to their beneficial biological activities including anti-tumour activity. In this study the effect of fucoidans isolated from brown algae Saccharina cichorioides, Fucus evanescens, and Undaria pinnatifida on the proliferation, neoplastic transformation, and colony formation of mouse epidermal cells JB6 Cl41, human colon cancer DLD-1, breast cancer T-47D, and melanoma RPMI-7951 cell lines was investigated. The algal fucoidans specifically and markedly suppressed the proliferation of human cancer cells with less cytotoxic effects against normal mouse epidermal cells. The highly sulfated (1?3)-?-l-fucan from S. cichorioides was found to be vitally important in the inhibition of EGF-induced neoplastic transformation of JB6 Cl41 cells. In colony formation assay the fucoidans from different species of brown algae showed selective anti-tumour activity against different types of cancer, which depended on unique structures of the investigated polysaccharides. These results provide evidence for further exploring the use of the fucoidans from S. cichorioides, F. evanescens, and U. pinnatifida as novel chemotherapeutics against different types of cancer. PMID:23790906

Vishchuk, Olesya S; Ermakova, Svetlana P; Zvyagintseva, Tatyana N

2013-11-15

361

Design, synthesis, and structure-activity relationships of novel benzothiazole derivatives bearing the ortho-hydroxy N-carbamoylhydrazone moiety as potent antitumor agents.  

PubMed

A series of novel benzothiazole derivatives bearing the ortho-hydroxy N-carbamoylhydrazone moiety were designed and synthesized and their cytotoxic activities against five cancer cell lines (NCI-H226, SK-N-SH, HT29, MKN45, and MDA-MB-231) were screened in vitro. Most of them showed moderate to excellent activity against all the tested cell lines. Among them, compounds 15g (procaspase-3 EC50 = 1.42 ?M) and 16b (procaspase-3 EC50 = 0.25 ?M) exhibited excellent antitumor activity with IC50 values ranging from 0.14 ?M to 0.98 ?M against all cancer cell lines, which were 1.8-8.7 times more active than the first procaspase activating compound (PAC-1) (procaspase-3 EC50 = 4.08 ?M). The structure-activity relationship (SAR) analyses indicated that the introduction of a lipophilic group (a benzyloxy or heteroaryloxy group) at the 4-position of the 2-hydroxy phenyl ring was beneficial to antitumor activity, and the presence of substituents containing nitrogen that are positively charged at physiological pH could also improve antitumor activity. It was also confirmed that the steric effect of the 4-position substituent of the benzyloxy group had a significant influence on cytotoxic activity. PMID:25171780

Ma, Junjie; Chen, Dong; Lu, Kuan; Wang, Lihui; Han, Xiaoqi; Zhao, Yanfang; Gong, Ping

2014-10-30

362

Honaucins A-C, potent inhibitors of inflammation and bacterial quorum sensing: synthetic derivatives and structure-activity relationships.  

PubMed

Honaucins A-C were isolated from the cyanobacterium Leptolyngbya crossbyana which was found overgrowing corals on the Hawaiian coast. Honaucin A consists of (S)-3-hydroxy-?-butyrolactone and 4-chlorocrotonic acid, which are connected via an ester linkage. Honaucin A and its two natural analogs exhibit potent inhibition of both bioluminescence, a quorum-sensing-dependent phenotype, in Vibrio harveyi BB120 and lipopolysaccharide-stimulated nitric oxide production in the murine macrophage cell line RAW264.7. The decrease in nitric oxide production was accompanied by a decrease in the transcripts of several proinflammatory cytokines, most dramatically interleukin-1?. Synthesis of honaucin A, as well as a number of analogs, and subsequent evaluation in anti-inflammation and quorum-sensing inhibition bioassays revealed the essential structural features for activity in this chemical class and provided analogs with greater potency in both assays. PMID:22633410

Choi, Hyukjae; Mascuch, Samantha J; Villa, Francisco A; Byrum, Tara; Teasdale, Margaret E; Smith, Jennifer E; Preskitt, Linda B; Rowley, David C; Gerwick, Lena; Gerwick, William H

2012-05-25

363

Preliminary structure-activity relationship on theonellasterol, a new chemotype of FXR antagonist, from the marine sponge Theonella swinhoei.  

PubMed

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 ? interactions, are present. PMID:23203270

Sepe, Valentina; Ummarino, Raffaella; D'Auria, Maria Valeria; Taglialatela-Scafati, Orazio; Marino, Simona De; D'Amore, Claudio; Renga, Barbara; Chini, Maria Giovanna; Bifulco, Giuseppe; Nakao, Yoichi; Fusetani, Nobuhiro; Fiorucci, Stefano; Zampella, Angela

2012-11-01

364

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

PubMed Central

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 ? interactions, are present. PMID:23203270

Sepe, Valentina; Ummarino, Raffaella; D'Auria, Maria Valeria; Taglialatela-Scafati, Orazio; Marino, Simona De; D'Amore, Claudio; Renga, Barbara; Chini, Maria Giovanna; Bifulco, Giuseppe; Nakao, Yoichi; Fusetani, Nobuhiro; Fiorucci, Stefano; Zampella, Angela

2012-01-01

365

Mechanism of action and relationship between structure and biological activity of Ctx-Ha: a new ceratotoxin-like peptide from Hypsiboas albopunctatus.  

PubMed

The increase in bacterial resistance to current antibiotics has led to the development of new active molecules. We have isolated the antimicrobial peptide Ctx-Ha from the skin secretion of the frog Hypsiboas albopunctatus. The aim of the present work was to elucidate the mechanism of action of this new antimicrobial peptide. The sequence similarity with Ceratotoxin, the pore size, and the pore-like release of carboxyfluorescein from vesicles indicated that Ctx(Ile21)-Ha has a mechanism of action based on the barrel- stave model. In a second part of this work, we synthesized three analogues to provide information about the relationship between the peptide's structure and its biological activity. Ctx(Ile21)-Ha-VD 16, Ctx(Ile21)- Ha-VD 5,16 and Ctx(Ile21)-Ha-I9K were designed to disrupt the peptide's helical structure and change the hydrophobicity/ hydrophilicity and amphipathicity of the apolar face in order to uncouple the antimicrobial activity of Ctx(Ile21)-Ha from its hemolytic activity. To evaluate the effects of the amino acid substitutions on peptide conformation, secondary structure was accessed using CD measurements. The peptides presented a high amount of ?-helical structure in the presence of TFE and LPC. The CD data showed that destruction of the amphipathic ?-helix by the replacing isoleucine by lysine is less harmful to the structure than D-amino acid substitutions. Biological tests demonstrated that all peptides have activity. Nevertheless, the peptide Ctx(Ile21)-Ha-I9K showed the highest value of therapeutic index. Our findings suggest that these peptides are potential templates for the development of new antimicrobial drugs. These studies highlight the importance of single amino acid modification as a tool to modulate the biological activity of antimicrobial peptides. PMID:22519531

Cespedes, Graziely Ferreira; Lorenzón, Esteban Nicolás; Vicente, Eduardo Festozo; Mendes-Giannini, Maria José Soares; Fontes, Wagner; Castro, Mariana Souza; Cilli, Eduardo Maffud

2012-06-01

366

Synthesis and Biological Evaluation of 14-(Aminoalkyl-aminomethyl)aromathecins as Topoisomerase I Inhibitors: Investigating the Hypothesis of Shared Structure-Activity Relationships  

PubMed Central

The aromathecin topoisomerase I (top1) inhibitors offer promising scaffolds for the development of novel cancer chemotherapeutics. They are “composites” of the camptothecin and indenoisoquinoline top1 inhibitors. Interestingly, some structure-activity-relationship (SAR) overlap between the aromathecins and the indenoisoquinolines has been observed. For both classes, placement of certain polar groups in similar regions of the heteroaromatic system improves top1 inhibitory and antiproliferative activities. A series of water-soluble aromathecins substituted at position 14 with diaminoalkanes of various lengths has been prepared. These compounds all possess similar antiproliferative potency, but a general trend is observed: aromathecins with longer diaminoalkane substituents (> 6 carbons) possess lower anti-top1 activity than their smaller counterparts (2–4 carbons), presumably as a result of unfavorable hydrophobic interactions. This trend is also noted with the indenoisoquinolines, revealing additional SAR overlap that supports the hypothesis that there is a “universal” top1 inhibitor SAR. PMID:19783447

Cinelli, Maris A.; Cordero, Brenda; Dexheimer, Thomas S.; Pommier, Yves; Cushman, Mark

2009-01-01

367

Jatrophane diterpenes as modulators of multidrug resistance. Advances of structure-activity relationships and discovery of the potent lead pepluanin A.  

PubMed

From the whole plant of Euphorbia peplus L., five new diterpenes based on a jatrophane skeleton (pepluanins A-E, 1-5) were isolated, together with two known analogues (6 and 7), which served to divulge in detail the structure-activity relationships within this class of P-glycoprotein inhibitors. The results revealed the importance of substitutions on the medium-sized ring (carbons 8, 9, 14, and 15). In particular, the activity is collapsed by the presence of a free hydroxyl at C-8, while it increases with a carbonyl at C-14, an acetoxyl at C-9, and a free hydroxyl at C-15. The most potent compound of the series, pepluanin A, showed a very high activity for a jatrophane diterpene, outperforming cyclosporin A by a factor of at least 2 in the inhibition of Pgp-mediated daunomycin transport. PMID:14761200

Corea, Gabriella; Fattorusso, Ernesto; Lanzotti, Virginia; Motti, Riccardo; Simon, Pierre-Noël; Dumontet, Charles; Di Pietro, Attilio

2004-02-12

368

Structure-Activity Relationship of Adenosine 5?-diphosphoribose at the Transient Receptor Potential Melastatin 2 (TRPM2) Channel: Rational Design of Antagonists  

PubMed Central

Adenosine 5?-diphosphoribose (ADPR) activates TRPM2, a Ca2+, Na+, and K+ permeable cation channel. Activation is induced by ADPR binding to the cytosolic C-terminal NudT9-homology domain. To generate the first structure–activity relationship, systematically modified ADPR analogues were designed, synthesized, and evaluated as antagonists using patch-clamp experiments in HEK293 cells overexpressing human TRPM2. Compounds with a purine C8 substituent show antagonist activity, and an 8-phenyl substitution (8-Ph-ADPR, 5) is very effective. Modification of the terminal ribose results in a weak antagonist, whereas its removal abolishes activity. An antagonist based upon a hybrid structure, 8-phenyl-2?-deoxy-ADPR (86, IC50 = 3 ?M), is more potent than 8-Ph-ADPR (5). Initial bioisosteric replacement of the pyrophosphate linkage abolishes activity, but replacement of the pyrophosphate and the terminal ribose by a sulfamate-based group leads to a weak antagonist, a lead to more drug-like analogues. 8-Ph-ADPR (5) inhibits Ca2+ signalling and chemotaxis in human neutrophils, illustrating the potential for pharmacological intervention at TRPM2. PMID:24304219

2013-01-01

369

Sharing chemical relationships does not reveal structures.  

PubMed

In this study, we propose a new, secure method of sharing useful chemical information from small-molecule libraries, without revealing the structures of the libraries' molecules. Our method shares the relationship between molecules rather than structural descriptors. This is an important advance because, over the past few years, several groups have developed and published new methods of analyzing small-molecule screening data. These methods include advanced hit-picking protocols, promiscuous active filters, economic optimization algorithms, and screening visualizations, which can identify patterns in the data that might otherwise be overlooked. Application of these methods to private data requires finding strategies for sharing useful chemical data without revealing chemical structures. This problem has been examined in the context of ADME prediction models, with results from information theory suggesting it is impossible to share useful chemical information without revealing structures. In contrast, we present a new strategy for encoding the relationships between molecules instead of their structures, based on anonymized scaffold networks and trees, that safely shares enough chemical information to be useful in analyzing chemical data, while also sufficiently blinding structures from discovery. We present the details of this encoding, an analysis of the usefulness of the information it conveys, and the security of the structures it encodes. This approach makes it possible to share data across institutions, and may securely enable collaborative analysis that can yield insight into both specific projects and screening technology as a whole. PMID:24289228

Matlock, Matthew; Swamidass, S Joshua

2014-01-27

370

Structure-Activity Relationship of Au/ZrO2 Catalyst on Formation of Hydroxyl Groups and Its Influence on CO Oxidation  

SciTech Connect

The effect of changes in morphology and surface hydroxyl species upon thermal treatment of zirconia on the oxidation activity of Au/ZrO2 catalyst was studied. We observed using transmission fourier transform infrared (FTIR) spectroscopy progressive changes in the presence of monodentate (type I), bidentate (type II) and hydrogen bridged species (type III) for each of the thermally treated (85 to 500 C) supports consisting of bare zirconia and Au/ZrO2 catalysts. Furthermore, structural changes in zirconia were accompanied by an increase in crystal size (7 to 58 nm) and contraction of the supports porosity (SSA 532 to 7 m2/g) with increasing thermal treatment. Deposition of gold nanoparticles under similar preparation conditions on different thermally treated zirconia resulted in changes in the mean gold cluster size, ranging from 3.7 to 5.6 nm. Changes in the surface hydroxyl species, support structure and size of the gold centers are important parameters responsible for the observed decrease (> 90 %) in CO conversion activity for the Au/ZrO2 catalysts. Density functional theory calculations provide evidence of increased CO binding to Au nanoclusters in the presence of surface hydroxyls on zirconia, which increases charge transfer at the perimeter of the gold nanocluster on zirconia support. This further helps in reducing a model CO-oxidation reaction barrier in the presence of surface hydroxyls. This work demonstrates the need to understand the structure-activity relationship of both the support and active particles for the design of catalytic materials.

Karwacki, Christopher J [US Army Aberdeen Proving Ground; Ganesh, Panchapakesan [ORNL; Gordon, Wesley O [ORNL; Peterson, Gregory W [US Army Aberdeen Proving Ground; Niu, Jun Jie [Drexel University; Gogotsi, Yury G. [Drexel University

2013-01-01

371

Structure-activity relationship of Au-ZrO2 catalyst on formation of hydroxyl groups and its influence on CO oxidation  

SciTech Connect

The effect of changes in morphology and surface hydroxyl species upon thermal treatment of zirconia on the oxidation activity of Au/ZrO2 catalyst was studied. We observed using transmission Fourier transform infrared (FTIR) spectroscopy progressive changes in the presence of monodentate (type I), bidentate (type II) and hydrogen bridged species (type III) for each of the thermally treated (85 to 500 C) supports consisting of bare zirconia and Au/ZrO2 catalysts. Furthermore, structural changes in zirconia were accompanied by an increase in crystal size (7 to 58 nm) and contraction of the supports porosity (SSA 532 to 7 m2 g 1) with increasing thermal treatment. Deposition of gold nanoparticles under similar preparation conditions on different thermally treated zirconia resulted in changes in the mean gold cluster size, ranging from 3.7 to 5.6 nm. Changes in the surface hydroxyl species, support structure and size of the gold centers are important parameters responsible for the observed decrease (>90%) in CO conversion activity for the Au/ZrO2 catalysts. Density functional theory calculations provide evidence of increased CO binding to Au nanoclusters in the presence of surface hydroxyls on zirconia, which increases charge transfer at the perimeter of the gold nanocluster on zirconia support. This further helps in reducing a model CO-oxidation reaction barrier in the presence of surface hydroxyls. This work demonstrates the need to understand the structure activity relationship of both the support and active particles for the design of catalytic materials.

Karwacki, Christopher J [US Army Aberdeen Proving Ground; Ganesh, Panchapakesan [ORNL; Kent, P. R. C. [University of Tennessee, Knoxville (UTK); Gordon, Wesley O [ORNL; Peterson, Gregory W [US Army Aberdeen Proving Ground; Niu, Jun Jie [Drexel University; Gogotsi, Yury G. [Drexel University

2013-01-01

372

Aureobasidins: structure-activity relationships for the inhibition of the human MDR1 P-glycoprotein ABC-transporter.  

PubMed

Cyclic depsipeptide cyclo-[D-Hmp(1)-L-MeVal(2)-L-Phe(3)-L-MePhe(4)-L-Pro(5)-L-aIle+ ++(6)-L-MeVal(7)-L-Leu(8)-L-betaHOMeVal(9)], the antifungal antibiotic aureobasidin A (AbA), was reported to interfere with ATP-binding cassette (ABC) transporters in yeast and mammalian cells, particularly the MDR1 P-glycoprotein (Pgp), a transmembrane phospholipid flippase or "hydrophobic vacuum cleaner" that mediates multidrug resistance (MDR) of cancer cells. In a standardized assay that measures Pgp function by the Pgp-mediated efflux of the calcein-AM Pgp substrate and uses human lymphoblastoid MDR-CEM (VBL(100)) cells as highly resistant Pgp-expressing cells and the cyclic undecapeptide cyclosporin A (CsA) as a reference MDR-reversing agent (IC(50) of 3.4 microM), AbA was found to be a more active Pgp inhibitor (IC(50) of 2.3 microM). Out of seven natural analogues and 18 chemical derivatives of AbA, several were shown to display even more potent Pgp-inhibitory activity. The Pgp-inhibitory activity was increased about 2-fold by some minor modifications such as those found in the naturally occurring aureobasidins AbB ([D-Hiv(1)]-AbA), AbC ([Val(6)]-AbA), and AbD [gammaHOMeVal(9)]-AbA). The replacement of the [Phe(3)-MePhe(4)-Pro(5)] tripeptide by an 8-aminocaprylic acid or the N(7)()-desmethylation of MeVal(7) led to only a 3.3-fold decreased capacity to inhibit Pgp function, suggesting that the Pgp inhibitory potential of aureobasidins, though favored by the establishment of an antiparallel beta-sheet between the [D-Hmp(1)-L-MeVal(2)-L-Phe(3)] and [L-aIle(6)-L-MeVal(7)-L-Leu(8)-] tripeptides, does not critically depend on the occurrence of the [L-Phe(3)-L-MePhe(4)-L-Pro(5)-L-aIle(6)] type II' beta-turn secondary structure. In contrast, the most potent Pgp inhibitors were found among AbA analogues with [betaHO-MeVal(9)] residue alterations, with some data suggesting a negative impact of the [L-Leu(8)-L-betaHOMeVal(9)-D-Hmp(1)] gamma-turn secondary structure on Pgp inhibitory potential. The [2,3-dehydro-MeVal(9)]-AbA was the most potent Pgp inhibitory aureobasidin, being 13-fold more potent than AbA and 19-fold more potent (on a molar basis) than CsA. Finally, there was no correlation between the SAR for the human MDR1 Pgp inhibition and the SAR for Saccharomyces cerevisiae antifungal activity, which is mediated by an inositol phosphoceramide synthase activity. PMID:10891114

Tiberghien, F; Kurome, T; Takesako, K; Didier, A; Wenandy, T; Loor, F

2000-06-29

373

Determinants of Activity at Human Toll-like Receptors 7 and 8: Quantitative Structure-Activity Relationship (QSAR) of Diverse Heterocyclic Scaffolds.  

PubMed

Toll-like receptor (TLR) 7 and 8 agonists are potential vaccine adjuvants, since they directly activate APCs and enhance Th1-driven immune responses. Previous SAR investigations in several scaffolds of small molecule TLR7/8 activators pointed to the strict dependence of the selectivity for TLR7 vis-à-vis TLR8 on the electronic configurations of the heterocyclic systems, which we sought to examine quantitatively with the goal of developing "heuristics" to define structural requisites governing activity at TLR7 and/or TLR8. We undertook a scaffold-hopping approach, entailing the syntheses and biological evaluations of 13 different chemotypes. Crystal structures of TLR8 in complex with the two most active compounds confirmed important binding interactions playing a key role in ligand occupancy and biological activity. Density functional theory based quantum chemical calculations on these compounds followed by linear discriminant analyses permitted the classification of inactive, TLR8-active, and TLR7/8 dual-active compounds, confirming the critical role of partial charges in determining biological activity. PMID:25192394

Yoo, Euna; Salunke, Deepak B; Sil, Diptesh; Guo, Xiaoqiang; Salyer, Alex C D; Hermanson, Alec R; Kumar, Manoj; Malladi, Subbalakshmi S; Balakrishna, Rajalakshmi; Thompson, Ward H; Tanji, Hiromi; Ohto, Umeharu; Shimizu, Toshiyuki; David, Sunil A

2014-10-01

374

Abscisic Acid Structure-Activity Relationships in Barley Aleurone Layers and Protoplasts (Biological Activity of Optically Active, Oxygenated Abscisic Acid Analogs).  

PubMed Central

Optically active forms of abscisic acid (ABA) and their oxygenated metabolites were tested for their biological activity by examining the effects of the compounds on the reversal of gibberellic acid-induced [alpha]-amylase activity in barley (Hordeum vulgare cv Himalaya) aleurone layers and the induction of gene expression in barley aleurone protoplasts transformed with a chimeric construct containing the promoter region of an albumin storage protein gene. Promotion of the albumin storage protein gene response had a more strict stereochemical requirement for elicitation of an ABA response than inhibition of [alpha]-amylase gene expression. The naturally occurring stereoisomer of ABA and its metabolites were more effective at eliciting an ABA-like response. ABA showed the highest activity, followed by 7[prime]-hydroxyABA, with phaseic acid being the least active. Racemic 8[prime]-hydroxy-2[prime],3[prime]-dihydroABA, an analog of 8[prime]-hydroxyABA, was inactive, whereas racemic 2[prime],3[prime]-dihydroABA was as effective as ABA. The differences in response of the same tissue to the ABA enantiomers lead us to conclude that there exists more than one type of ABA receptor and/or multiple signal transduction pathways in barley aleurone tissue. PMID:12228494

Hill, R. D.; Liu, J. H.; Durnin, D.; Lamb, N.; Shaw, A.; Abrams, S. R.

1995-01-01

375

Vibrio cholerae fur mutations associated with loss of repressor activity: implications for the structural-functional relationships of fur.  

PubMed Central

We used the Vibrio cholerae Fur protein as a model of iron-sensitive repressor proteins in gram-negative bacteria. Utilizing manganese mutagenesis, we isolated twelve independent mutations in V. cholerae fur that resulted in partial or complete loss of Fur repressor function. The mutant fur genes were recovered by PCR and sequenced; 11 of the 12 contained point mutations (two of which were identical), and one contained a 7-bp insertion that resulted in premature truncation of Fur. All of the mutants, except that containing the prematurely truncated Fur, produced protein by Western blot (immunoblot) analysis, although several had substantially smaller amounts of Fur and two made an immunoreactive protein that migrated more rapidly on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Nine of the 11 point mutations altered amino acids that are identical in all of the fur genes sequenced so far, suggesting that these amino acids may play important structural or functional roles in Fur activity. Eight of the point mutations occurred in the amino-terminal half of Fur, which is thought to mediate DNA binding; most of these mutations occurred in conserved amino acids that have been previously suggested to play a role in the interaction between adjacent alpha-helices of the protein. Three of the point mutations occurred in the carboxy-terminal half of Fur, which is thought to bind iron. One mutation at histidine-90 was associated with complete loss of Fur function; this amino acid is within a motif previously suggested as being involved in iron binding by Fur. The fur allele mutant at histidine-90 interfered with iron regulation by wild-type fur in the same cell when the mutant allele was present at higher copy number; wild-type fur was dominant over all other fur mutant alleles studied. These results are analyzed with respect to previous models of the structure and function of Fur as an iron-sensitive repressor. Images PMID:8051024

Lam, M S; Litwin, C M; Carroll, P A; Calderwood, S B

1994-01-01

376

Quantitative Nanostructure-Activity Relationship (QNAR) Modeling  

PubMed Central

Evaluation of biological effects, both desired and undesired, caused by Manufactured NanoParticles (MNPs) is of critical importance for nanotechnology. Experimental studies, especially toxicological, are time-consuming, costly, and often impractical, calling for the development of efficient computational approaches capable of predicting biological effects of MNPs. To this end, we have investigated the potential of cheminformatics methods such as Quantitative StructureActivity Relationship (QSAR) modeling to establish statistically significant relationships between measured biological activity profiles of MNPs and their physical, chemical, and geometrical properties, either measured experimentally or computed from the structure of MNPs. To reflect the context of the study, we termed our approach Quantitative Nanostructure-Activity Relationship (QNAR) modeling. We have employed two representative sets of MNPs studied recently using in vitro cell-based assays: (i) 51 various MNPs with diverse metal cores (PNAS, 2008, 105, pp 7387–7392) and (ii) 109 MNPs with similar core but diverse surface modifiers (Nat. Biotechnol., 2005, 23, pp 1418–1423). We have generated QNAR models using machine learning approaches such as Support Vector Machine (SVM)-based classification and k Nearest Neighbors (kNN)-based regression; their external prediction power was shown to be as high as 73% for classification modeling and R2 of 0.72 for regression modeling. Our results suggest that QNAR models can be employed for: (i) predicting biological activity profiles of novel nanomaterials, and (ii) prioritizing the design and manufacturing of nanomaterials towards better and safer products. PMID:20857979

Fourches, Denis; Pu, Dongqiuye; Tassa, Carlos; Weissleder, Ralph; Shaw, Stanley Y.; Mumper, Russell J.; Tropsha, Alexander

2010-01-01

377

Structure-activity relationships of several anisidine and dibenzanthracene isomers in the w/w+ somatic assay of Drosophila melanogaster.  

PubMed

Several structurally related anisidine and dibenzanthracene isomers were evaluated for genotoxic effects in the somatic w/w+ assay of Drosophila melanogaster employing insecticide-susceptible (IS) and insecticide-resistant (IR) tester strains. In addition, and in order to find whether or not at the genetic level a regulatory effect is found, crosses between ISxIR strains and IRxIS strains were done. Chemicals tested were the aromatic amines (AAs) ortho-anisidine (o-AN), meta-anisidine (m-AN), and para-anisidine (p-AN) and the polycyclic aromatic hydrocarbons (PAHs) 1,2;3,4-dibenzanthracene (1,2;3,4-DBA) and 1,2;5,6-dibenzanthracene (1,2;5,6-DBA). As positive control N-nitrosodimethylamine (DMN) was used. Our results show that the genotoxic activity of DMN was higher in the IR than in the IS strain. There seems to be a tendency for slightly lower values as measured by clone induction in crosses between ISxIR and IRxIS. o-AN was positive in the IS strain and in crosses between ISxIR and IRxIS but negative in the IR strain. m-AN, p-AN and 1,2;3,4-DBA proved to be not recombinogenic in all strains and crosses while 1,2;5,6-DBA was positive at the highest concentration tested in all the crosses assayed. These findings show that the recombinogenic activity of the anisidine isomers depends on the position of the chemical group relative to one another and that the position of the benzene ring seems to be structurally relevant for genotoxicity of DBA isomers. With respect to IR and IS strains it remains to be determined to what extent the spectrum of metabolizing capacity really differs between the strains of the test assay. Thus more information is needed about the regulation and expression of the cytochrome-P450 genes and action at the molecular level taking place in the eye imaginal disc as well as between insecticide susceptible and resistant strains after exposure to genotoxic chemicals. PMID:11815257

Rodriguez-Arnaiz, Rosario; Téllez, Guadalupe Ordaz

2002-02-15

378

Application of quantitative structure-activity relationship models of 5-HT1A receptor binding to virtual screening identifies novel and potent 5-HT1A ligands.  

PubMed

The 5-hydroxytryptamine 1A (5-HT1A) serotonin receptor has been an attractive target for treating mood and anxiety disorders such as schizophrenia. We have developed binary classification quantitative structure-activity relationship (QSAR) models of 5-HT1A receptor binding activity using data retrieved from the PDSP Ki database. The prediction accuracy of these models was estimated by external 5-fold cross-validation as well as using an additional validation set comprising 66 structurally distinct compounds from the World of Molecular Bioactivity database. These validated models were then used to mine three major types of chemical screening libraries, i.e., drug-like libraries, GPCR targeted libraries, and diversity libraries, to identify novel computational hits. The five best hits from each class of libraries were chosen for further experimental testing in radioligand binding assays, and nine of the 15 hits were confirmed to be active experimentally with binding affinity better than 10 ?M. The most active compound, Lysergol, from the diversity library showed very high binding affinity (Ki) of 2.3 nM against 5-HT1A receptor. The novel 5-HT1A actives identified with the QSAR-based virtual screening approach could be potentially developed as novel anxiolytics or potential antischizophrenic drugs. PMID:24410373

Luo, Man; Wang, Xiang Simon; Roth, Bryan L; Golbraikh, Alexander; Tropsha, Alexander

2014-02-24

379

Synthesis of 2-(thienyl-2-yl or -3-yl)-4-furyl-6-aryl pyridine derivatives and evaluation of their topoisomerase I and II inhibitory activity, cytotoxicity, and structure-activity relationship.  

PubMed

A series of 2-(thienyl-2-yl or -3-yl)-4-furyl-6-aryl pyridine derivatives were designed, synthesized, and evaluated for their topoisomerase I and II inhibition and cytotoxic activity against several human cancer cell lines. Compounds 10-19 showed moderate topoisomerase I and II inhibitory activity and 20-29 showed significant topoisomerase II inhibitory activity. Structure-activity relationship study revealed that 4-(5-chlorofuran-2-yl)-2-(thiophen-3-yl) moiety has an important