Citation: 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. Discovery and development of tricyclic matrinic derivatives as anti-diabetic candidates by AMPKα activation[J]. Chinese Chemical Letters, ;2023, 34(1): 107561. doi: 10.1016/j.cclet.2022.05.075 shu

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

Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China

kongweijia@imb.pumc.edu.cn

songdanqing@imb.pumc.edu.cn

jiang.jdong@163.com

Received Date: 19 January 2022
Revised Date: 9 May 2022
Accepted Date: 23 May 2022
Available Online: 27 May 2022

Figures(7)

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/calmodulin-dependent protein kinase (CaMKK), which synergistically activates AMPKα and 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.
- Tricyclic matrinic derivatives,
- Glucose consumption,
- Diabetes mellitus,
- AMP-activated protein kinase (AMPK)
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