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A Customizable Approach for the Enzymatic Production and Purification of Diterpenoid Natural Products
Published on: October 4, 2019
Triterpenoids with multi-skeletons as 11 β -HSD1 inhibitors from Euphorbia sikkimensis
Chu-Hong Fang1, Yu-Peng Li2, Ying Li2
1Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong, 264117, China; School of Biological Science and Technology, University of Jinan, 336 West Road of Nan Xinzhuang, Jinan, 250022, China.
Abstract:
An exploration for 11β-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-3β,7α-diol (1) and (23E)-3β-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)-3β-hydroxy-25-methoxy-eupha-8,23-diene-7-one (4) and (23E)-3β-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 11β-HSD1 with IC50 values of 6.50 ± 0.22, 1.31 ± 0.34, 9.38 ± 0.64, and 8.27 ± 0.33 μM, 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 11β-HSD1 in the molecular docking experiments.
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