Highly potent non-steroidal FXR agonists protostane-type triterpenoids: Structure-activity relationship and mechanism
Highly potent non-steroidal FXR agonists protostane-type triterpenoids: Structure-activity relationship and mechanism
复制标题
高效非甾体FXR激动剂原甾烷型三萜：构效关系及机制
DOI：
10.1016/j.ejmech.2019.111652
复制
发表时间：
2019-11-15
影响因子：
6.7
通讯作者：
Ma, Xiao-Chi
中科院分区：
文献类型：
--
作者：
Luan, Zhi-Lin;Huo, Xiao-Kui;Ma, Xiao-Chi
Farnesoid X receptor (FXR) is a key regulator in charge of bile acid synthesis, transport, and metabolism. Activation of FXR represses bile acid synthesis and increases its excretion and transport, consequently protecting the liver functions. Thus, FXR is considered as a critical therapeutic target of cholestasis and nonalcoholic steatohepatitis. Herein, we isolated and identified fourteen new protostane-type triterpenoids (1-14) and four known analogues (15-18) from Alisma orientale, and finally constructed a small library of protostane-type triterpenoids (1-70) to investigate their structure-activity relationship with FXR, further leading to obtain compound 15 with potent agonistic activity against FXR (EC50 = 90 nM). Extensive in vitro investigation confirmed high efficacy of compound 15 against FXR in living cell, and revealed its underlying mechanism for FXR activation (amino acid residues Arg331 and Ser332) by molecular docking and site-directed mutagenesis technology. (C) 2019 Elsevier Masson SAS. All rights reserved.
