Triterpenoids with multi-skeletons as 11 -HSD1 inhibitors from Euphorbia sikkimensis

An exploration for 11fl-HSD1 inhibitors from the whole plant of Euphorbia sikkimensis led to the identification of 10 undescribed triterpenoids 1-10, as well as 7 known triterpenoids (11-17). Their structures were determined by a combination of spectrum elucidations, conformational analyses and quantum chemical calculations. (23E)25-methoxy-eupha-14,23-diene-3fl,7a-diol (1) and (23E)-3fl-dihydroxy-27-noreupha-7,23-diene-25-one (2) are two rare cases that feature a rearrangement of Me-30 (14 -> 8) and a degradation of Me-27, respectively, in the euphane-type triterpenoid family. It is an interesting phenomenon that (23E)-3fl-hydroxy-25-methoxy-eupha8,23-diene-7-one (4) and (23E)-3fl-hydroxy-25-methoxy-lanost-8,23-diene-7-one (5) coexist in the same plant, sharing the same planar structure but belonging to different structural types of triterpenoids. Compounds 3-5 and 14 show significant inhibitory activity against 11fl-HSD1 with IC50 values of 6.50 +/- 0.22, 1.31 +/- 0.34, 9.38 +/- 0.64, and 8.27 +/- 0.33 mu M, respectively. The structure-activity relationship study shows that the euphane-type triterpenoids exhibit the best inhibitory activity, which is in accord with the fact of the euphane-type triterpenoids having the best ability to bind to the active pocket of 11fl-HSD1 in the molecular docking experiments.