Design, synthesis and biological evaluation of mogrol derivatives as a novel class of AMPKα2β1γ1 activators

Junwei Wang; Junhua Liu; Zhifu Xie; Jia Li; Jingya Li; Lihong Hu

doi:10.1016/j.bmcl.2019.126790

Design, synthesis and biological evaluation of mogrol derivatives as a novel class of AMPKα2β1γ1 activators

Bioorg Med Chem Lett. 2020 Jan 15;30(2):126790. doi: 10.1016/j.bmcl.2019.126790. Epub 2019 Nov 9.

Authors

Junwei Wang¹, Junhua Liu¹, Zhifu Xie², Jia Li², Jingya Li³, Lihong Hu⁴

Affiliations

¹ Jiangsu Key Laboratory for Functional Substance of Chinese Medicine, Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, State Key Laboratory Cultivation Base for TCM Quality and Efficacy, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China.
² Shanghai Institute of Materia Medica, University of Chinese Academy of Sciences, Shanghai 201203, China.
³ Shanghai Institute of Materia Medica, University of Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: [email protected].
⁴ Jiangsu Key Laboratory for Functional Substance of Chinese Medicine, Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, State Key Laboratory Cultivation Base for TCM Quality and Efficacy, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China; Shanghai Institute of Materia Medica, University of Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: [email protected].

PMID: 31744674
DOI: 10.1016/j.bmcl.2019.126790

Abstract

Adenosine monophosphate-activated protein kinase (AMPK) has been considered as a promising drug target for its regulation in both glucose and lipid metabolism. Mogrol was originally identified from high throughput screening as a small molecule activator of AMPK subtype α2β1γ1. In order to enhance its potency on AMPK and summarize the structure-activity relationships, a series of mogrol derivatives were designed, synthesized and evaluated in pharmacological AMPK activation assays. The results showed that the amine derivatives at the 24-position can improve the potency. Among them, compounds 3 and 4 exhibited the best potency (EC₅₀: 0.15 and 0.14 μM) which was 20 times more potent than mogrol (EC₅₀: 3.0 μM).

Keywords: AMPK; AMPKα2β1γ1 activators; Mogrol derivatives; Structure-activity relationships.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

AMP-Activated Protein Kinases / chemistry
AMP-Activated Protein Kinases / metabolism*
Allosteric Regulation / drug effects
Cucurbitaceae / chemistry
Cucurbitaceae / metabolism
Drug Design*
Enzyme Activators / chemical synthesis*
Enzyme Activators / metabolism
Enzyme Activators / pharmacology
Humans
Structure-Activity Relationship
Triterpenes / metabolism*
Triterpenes / pharmacology

Substances

Enzyme Activators
Triterpenes
AMP-Activated Protein Kinases