Characterization of activity and binding mode of glycyrrhetinic acid derivatives inhibiting 11β-hydroxysteroid dehydrogenase type 2

被引:47
|
作者
Kratschmar, Denise V. [3 ,4 ]
Vuorinen, Anna [1 ,2 ]
Da Cunha, Thierry [3 ,4 ]
Wolber, Gerhard [5 ,6 ]
Classen-Houben, Dirk [7 ]
Doblhoffe, Otto [7 ]
Schuster, Daniela [1 ,2 ]
Odermatt, Alex [3 ,4 ]
机构
[1] Univ Innsbruck, Inst Pharm, Dept Pharmaceut Chem, A-6020 Innsbruck, Austria
[2] Univ Innsbruck, CMBI, A-6020 Innsbruck, Austria
[3] Univ Basel, Swiss Ctr Appl Human Toxicol, CH-4056 Basel, Switzerland
[4] Univ Basel, Div Mol & Syst Toxicol, Dept Pharmaceut Sci, CH-4056 Basel, Switzerland
[5] Free Univ Berlin, Inst Pharm, D-14195 Berlin, Germany
[6] Inte Ligand GmbH, A-1070 Vienna, Austria
[7] Onepharm Res & Dev GmbH, A-1210 Vienna, Austria
来源
基金
瑞士国家科学基金会;
关键词
11 beta-Hydroxysteroid dehydrogenase; Glucocorticoid; Steroid metabolism; Inhibitor; Glycyrrhetinic acid; Pharmacophore; 18-BETA-GLYCYRRHETINIC ACID; CELL-PROLIFERATION; 11-BETA-HSD1; INHIBITORS; SELECTIVE INHIBITORS; GLUCOCORTICOIDS; EXPRESSION; ARTHRITIS; RAT; HYPERTENSION; CLONING;
D O I
10.1016/j.jsbmb.2010.12.019
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Modulation of intracellular glucocorticoid availability is considered as a promising strategy to treat glucocorticoid-dependent diseases. 18 beta-Glycyrrhetinic acid (GA), the biologically active triterpenoid metabolite of glycyrrhizin, which is contained in the roots and rhizomes of licorice (Glycyrrhiza spp.), represents a well-known but non-selective inhibitor of 11 beta-hydroxysteroid dehydrogenases (11 beta-HSDs). However, to assess the physiological functions of the respective enzymes and for potential therapeutic applications selective inhibitors are needed. In the present study, we applied bioassays and 3D-structure modeling to characterize nine 11 beta-HSD1 and fifteen 11 beta-HSD2 inhibiting GA derivatives. Comparison of the GA derivatives in assays using cell lysates revealed that modifications at the 3-hydroxyl and/or the carboxyl led to highly selective and potent 11 beta-HSD2 inhibitors. The data generated significantly extends our knowledge on structure-activity relationship of GA derivatives as 11 beta-HSD inhibitors. Using recombinant enzymes we found also potent inhibition of mouse 11 beta-HSD2, despite significant species-specific differences. The selected GA derivatives potently inhibited 11 beta-HSD2 in intact SW-620 colon cancer cells, although the rank order of inhibitory potential differed from that obtained in cell lysates. The biological activity of compounds was further demonstrated in glucocorticoid receptor (GR) transactivation assays in cells coexpressing GR and 11 beta-HSD1 or 11 beta-HSD2. 3D-structure modeling provides an explanation for the differences in the selectivity and activity of the GA derivatives investigated. The most potent and selective 11 beta-HSD2 inhibitors should prove useful as mechanistic tools for further anti-inflammatory and anti-cancer in vitro and in vivo studies. Article from the Special issue on Targeted Inhibitors. (C) 2011 Elsevier Ltd. All rights reserved.
引用
收藏
页码:129 / 142
页数:14
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