Development and structure-activity relationships of tanshinones as selective 11β-hydroxysteroid dehydrogenase 1 inhibitors  

作　　者：Xu Deng Su-Ling Huang Jian Ren Zheng-Hong Pan Yu Shen Hao-Feng Zhou Zhi-Li Zuo Ying Leng Qin-Shi Zhao 

机构地区：[1]State Key Laboratory of Phytochemistry and Plant Resources in West China,Kunming Institute of Botany,Chinese Academy of Sciences,Kunming 650204,China [2]Xiangya School of Pharmaceutical Sciences,Central South University,Changsha 410013,China [3]State Key Laboratory of Drug Research,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai 201203,China [4]Guangxi Key Laboratory of Functional Phytochemicals Research and Utilization,Guangxi Institute of Botany,Chinese Academy of Sciences,Guilin 541006,China

出　　处：《Natural Products and Bioprospecting》2022年第1期573-585,共13页应用天然产物（英文）

基　　金：the National Natural Science Foundation of China (No.U1502223);Hunan Provincial Key Research and Development Project (Grant No.2021WK2005 to X.Deng);Natural Science Foundation of Hunan Province (Grant No.2021JJ30894 to X.Deng);the open fund of State Key Laboratory of Phytochemistry and Plant Resource in West China (Grant No.P2020-KF03).

摘　　要：11β-Hydroxysteroid dehydrogenase 1(11β-HSD1)represents a promising drug target for metabolic syndrome,includ-ing obesity and type 2 diabetes.Our initial screen of a collection of natural products from Danshen led to the identi-fication of tanshinones as the potent and selective 11β-HSD1 inhibitors.To improve the druggability and explore the structure-activity relationships(SARs),more than 40 derivatives have been designed and synthesized using tanshinone IIA and cryptotanshinone as the starting materials.More than 10 derivatives exhibited potent in vitro 11β-HSD1 inhibitory activity and good selectivity over 11β-HSD2 across human and mouse species.Based on the biological results,SARs were further discussed,which was also partially rationalized by a molecular docking model of 1 bound to the 11β-HSD1.Remarkably,compounds 1,17 and 30 significantly inhibited 11β-HSD1 in 3T3-L1 adipocyte and in livers of ob/ob mice,which merits further investigations as anti-diabetic agents.This study not only provides a series of novel selective 11β-HSD1 inhibitors with promising therapeutic potentials in metabolic syndromes,but also expands the boundaries of the chemical and biological spaces of tanshinones.

关 键 词：Metabolic syndrome TANSHINONES Selective 11β-HSD1 inhibitors Structure-activity relationships 

分 类 号：O62[理学—有机化学]