title: Characterization of activity and binding mode of glycyrrhetinic acid derivatives inhibiting 11β-hydroxysteroid dehydrogenase type 2.
abstract: Modulation of intracellular glucocorticoid availability is considered as a promising strategy to treat glucocorticoid-dependent diseases. 18β-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 11β-hydroxysteroid dehydrogenases (11β-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 11β-HSD1 and fifteen 11β-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 11β-HSD2 inhibitors. The data generated significantly extends our knowledge on structure-activity relationship of GA derivatives as 11β-HSD inhibitors. Using recombinant enzymes we found also potent inhibition of mouse 11β-HSD2, despite significant species-specific differences. The selected GA derivatives potently inhibited 11β-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 11β-HSD1 or 11β-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 11β-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.
authors.affiliation: Swiss Center for Applied Human Toxicology and Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, CH-4056 Basel, Switzerland.
authors.forename: Denise V
authors.initials: DV
authors.lastname: Kratschmar
authors.forename: Anna
authors.initials: A
authors.lastname: Vuorinen
authors.forename: Thierry
authors.initials: T
authors.lastname: Da Cunha
authors.forename: Gerhard
authors.initials: G
authors.lastname: Wolber
authors.forename: Dirk
authors.initials: D
authors.lastname: Classen-Houben
authors.forename: Otto
authors.initials: O
authors.lastname: Doblhoff
authors.forename: Daniela
authors.initials: D
authors.lastname: Schuster
authors.forename: Alex
authors.initials: A
authors.lastname: Odermatt
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D005938:Glucocorticoids / Q000737:chemistry / Q000378:metabolism; D006034:Glycyrrhetinic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D015394:Molecular Structure; D017434:Protein Structure, Tertiary; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism
chemical_list: D005938:Glucocorticoids; D007527:Isoenzymes; D011965:Receptors, Glucocorticoid; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2; D006034:Glycyrrhetinic Acid