Discovery and development of tricyclic matrinic derivatives as anti-diabetic candidates by AMPKαactivation  

作　　者：Yinghong Li Yuanhui Zhang Tianyu Niu Yudong Pang Yulong Shi Qingxuan Zeng Jingpu Zhang Jingyang Zhu Xiuli Zhong Yanxiang Wang Yan Wang Sheng Tang Weijia Kong Danqing Song Jiandong Jiang 

机构地区：[1]Institute of Medicinal Biotechnology,Chinese Academy of Medical Sciences&Peking Union Medical College,Beijing 100050,China

出　　处：《Chinese Chemical Letters》2023年第1期289-294,共6页中国化学快报（英文版）

基　　金：supported by CAMS Innovation Fund for Medical Sciences(No.2021-12M-1-030);the Natural Science Foundation of Beijing Municipality(No.7202131);Chinese Pharmaceutical Association-Yiling Pharmaceutical Innovation Fund for Biomedicine(No.GL-1-B04-20190397)。

摘　　要：We found compound 12N-p-trifluoromethylbenzenesulfonyl matrinane(1)was a potent anti-diabetic agent.Thirty-five tricyclic matrinic derivatives were synthesized and determined for their stimulatory effects on glucose consumption in L6 myotubes,taking 1 as the lead.In high-fat diet(HFD)and STZ induced diabetic mice,9a significantly lowers blood glucose,improves glucose tolerance,and especially alleviates diabetic nephropathy and islet damage.Mechanism study indicates that 9a simultaneously targets mitochondrial complex I to increase AMP/ATP ratio,as well as liver kinase B1(LKB1)and calcium/calmodulindependent protein kinase(Ca MKK),which synergistically activates AMPKαand then stimulates glucose transporter 4(GLUT4)membrane translocation and 2-deoxyglucose(2-DG)uptake to exert anti-diabetic efficacy.Therefore,compound 9a with a novel structure is a promising anti-diabetic candidate with the advantage of multiple-target mechanism,worthy of further investigation.

关 键 词：Tricyclic matrinic derivatives Glucose consumption Diabetes mellitus AMP-activated protein kinase(AMPK) 

分 类 号：R587.1[医药卫生—内分泌]