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Noha S.M.,University of Innsbruck | Jazzar B.,University of Tubingen | Kuehnl S.,University of Innsbruck | Rollinger J.M.,University of Innsbruck | And 5 more authors.
Bioorganic and Medicinal Chemistry Letters

The release of arachidonic acid, a precursor in the production of prostaglandins and leukotrienes, is achieved by activity of the cytosolic phospholipase A 2α (cPLA 2α). Signaling mediated by this class of bioactive lipids, which are collectively referred to as eicosanoids, has numerous effects in physiological and pathological processes. Herein, we report the development of a ligand-based pharmacophore model and pharmacophore-based virtual screening of the National Cancer Institute (NCI) database, leading to the identification of 4-(hexadecyloxy)-3-(2-(hydroxyimino)- 3-oxobutanamido)benzoic acid (NSC 119957) as cPLA 2α inhibitor in cell-free and cell-based in vitro assays. © 2011 Elsevier Ltd. All rights reserved. Source

Kutil Z.,Academy of Sciences of the Czech Republic | Kutil Z.,Czech University of Life Sciences | Kvasnicova M.,Academy of Sciences of the Czech Republic | Temml V.,Institute of Pharmacy Pharmaceutical Chemistry | And 6 more authors.
International Journal of Food Properties

Stilbenes contained in various foods are associated with health beneficial effects. In this study six natural and one synthetic stilbene were tested for their potential to regulate the activity of lipoxygenase and cyclooxygenase in vitro. The most potent inhibitor of 5-lipoxygenase was pterostilbene (IC50 = 9.32 M), whereas the strongest inhibitor of cyclooxygenase-1 and cyclooxygenase-2 was pinostilbene (IC50s = 1.90 and 0.35 M, respectively). Pterostilbene (IC50s = 11.70 and 27.04 M for cyclooxygenase-1 and cyclooxygenase-2, respectively) and oxyresveratrol (IC50s = 18.49; 2.79 and 14.71 M for 5-lipoxygenase, cyclooxygenase-1, and cyclooxygenase-2, respectively) were capable to inhibit catalytic activity of all three tested enzymes. Isorhapontigenin (IC50s = 8.81 and 24.00 M for cyclooxygenase-1 and cyclooxygenase-2, respectively) and rhapontigenin (IC50s = 24.55 and 36.12 M for cyclooxygenase-1 and cyclooxygenase-2, respectively) were only moderate or weak inhibitors of both cyclooxygenase forms. In summary, these results indicated that besides the known cyclooxygenase inhibitor resveratrol also other natural stilbenes could be potent inhibitors of the arachidonic acid pathway and deserve further attention as compounds with promising health benefits. © Copyright 2015 Taylor & Francis Group, LLC. Source

Kutil Z.,Academy of Sciences of the Czech Republic | Kutil Z.,Czech University of Life Sciences | Temml V.,Institute of Pharmacy Pharmaceutical Chemistry | Maghradze D.,Agricultural University of Georgia | And 5 more authors.
Mediators of Inflammation

Cyclooxygenases and lipoxygenases are proinflammatory enzymes; the former affects platelet aggregation, vasoconstriction, vasodilatation and later the development of atherosclerosis. Red wines from Georgia and central and western Europe inhibited cyclooxygenase-1 (COX-1) activity in the range of 63-94%, cyclooxygenase-2 (COX-2) activity in the range of 20-44% (tested at a concentration of 5 mL/L), and 5-lipoxygenase (5-LOX) activity in the range of 72-84% (at a concentration of 18.87 mL/L). White wines inhibited 5-LOX in the range of 41-68% at a concentration of 18.87 mL/L and did not inhibit COX-1 and COX-2. Piceatannol (IC50 = 0.76 M) was identified as a strong inhibitor of 5-LOX followed by luteolin (IC50 = 2.25 M), quercetin (IC50 = 3.29 M), and myricetin (IC50 = 4.02 M). trans-Resveratrol was identified as an inhibitor of COX-1 (IC50 = 2.27 M) and COX-2 (IC50 = 3.40 M). Red wine as a complex mixture is a powerful inhibitor of COX-1, COX-2, and 5-LOX, the enzymes involved in eicosanoid biosynthetic pathway. © 2014 Zsofia Kutil et al. Source

Duwensee K.,Innsbruck Medical University | Schwaiger S.,University of Innsbruck | Tancevski I.,Innsbruck Medical University | Eller K.,Medical University of Graz | And 10 more authors.

Objective: Cholesteryl ester transfer protein (CETP) plays a central role in the metabolism of high-density lipoprotein particles. Therefore, we searched for new drugs that bind to CETP and modulate its activity. Methods: A preliminary pharmacophore-based parallel screening approach indicated that leoligin, a major lignan of Edelweiss (Leontopodium alpinum Cass.), might bind to CETP. Therefore we incubated leoligin ex vivo at different concentrations with human (n= 20) and rabbit plasma (n= 3), and quantified the CETP activity by fluorimeter. Probucol served as positive control. Furthermore, we dosed CETP transgenic mice with leoligin and vehicle control by oral gavage for 7 days and measured subsequently the in vivo modulation of CETP activity (n= 5 for each treatment group). Results: In vitro, leoligin significantly activated CETP in human plasma at 100. pM (p= 0.023) and 1. nM (p= 0.042), respectively, whereas leoligin concentrations of 1. mM inhibited CETP activity (p= 0.012). The observed CETP activation was not species specific, as it was similar in magnitude for rabbit CETP. In vivo, there was also a higher CETP activity after oral dosage of CETP transgenic mice with leoligin (p= 0.015). There was no short-term toxicity apparent in mice treated with leoligin. Conclusion: CETP agonism by leoligin appears to be safe and effective, and may prove to be a useful modality to alter high-density lipoprotein metabolism. © 2011 Elsevier Ireland Ltd. Source

Schuster D.,Institute of Pharmacy Pharmaceutical Chemistry | Kowalik D.,Helmholtz Center for Environmental Research | Kirchmair J.,Institute of Pharmacy Pharmaceutical Chemistry | Laggner C.,Institute of Pharmacy Pharmaceutical Chemistry | And 10 more authors.
Journal of Steroid Biochemistry and Molecular Biology

17β-Hydroxysteroid dehydrogenase type 3 and 5 (17β-HSD3 and 17β-HSD5) catalyze testosterone biosynthesis and thereby constitute therapeutic targets for androgen-related diseases or endocrine-disrupting chemicals. As a fast and efficient tool to identify potential ligands for 17βHSD3/5, ligand- and structure-based pharmacophore models for both enzymes were developed. The models were evaluated first by in silico screening of commercial compound databases and further experimentally validated by enzymatic efficacy tests of selected virtual hits. Among the 35 tested compounds, 11 novel inhibitors with distinct chemical scaffolds, e.g. sulfonamides and triazoles, and with different selectivity properties were discovered. Thereby, we provide several potential starting points for further 17β-HSD3 and 17β-HSD5 inhibitor development. Article from the Special issue on Targeted Inhibitors. © 2011 Elsevier Ltd. All rights reserved. Source

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