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

Modulation of intracellular glucocorticoid availability is considered as a promising strategy to treat glucocorticoid-dependent diseases. 18?-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?-hydroxysteroid dehydrogenases (11?-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?-HSD1 and fifteen 11?-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?-HSD2 inhibitors. The data generated significantly extends our knowledge on structure-activity relationship of GA derivatives as 11?-HSD inhibitors. Using recombinant enzymes we found also potent inhibition of mouse 11?-HSD2, despite significant species-specific differences. The selected GA derivatives potently inhibited 11?-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?-HSD1 or 11?-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?-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.