Design and synthesis of epigallocatechin (EGC) analogs selective to inhibit alpha-amylase over alpha-glucosidases via the incorporation of caffeine acid and its derivatives

文献类型： 外文期刊

第一作者： Chen, Wenming

作者： Chen, Wenming;Zhou, Fang;Chen, Wenming;Zhou, Fang;Zhou, Cui;Wang, Chunmei;Zhou, Wen;Zhou, Cui;Wang, Meizhu;Chen, Jiansheng;Zhang, Xu;Wang, Chunmei;Zhou, Wen

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关键词： HPA inhibitors; EGC; Selectivity; Caffeic acid; Antidiabetic drug

期刊名称：BIOORGANIC CHEMISTRY （ 影响因子：5.307； 五年影响因子：5.321 ）

ISSN： 0045-2068

年卷期： 2022 年 119 卷

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收录情况： SCI

摘要： Natural products are a promising and underappreciated reservoir for the preferred chemical scaffolds in the search of antidiabetic drugs. In this study twenty-one EGC-based derivatives selective to inhibit human pancreatic alpha-amylase (HPA), the enzyme at the top of the starch digestion pyramid, have been designed and synthesized in terms of the lead myricetin-caffeic acid conjugate 1 reported ever. We focus on methylation of caffeic acid, length of a liker, a double bond contained in the linker on the inhibition activity and selectivity of EGC-based conjugates. As a result, methylation of caffeic acid and the length of a linker affect significantly the activity and selectivity of EGC-based conjugates, but the effect of a double in caffeic acid is limited. Conjugate 2a-1 having a six-carbon-atom linker fused to EGC and caffeic acid demonstrates the most ponent inhibitory activity to HPA and its selectivity towards HPA over alpha-glucosidase by far superior to that construct 1. Molecular docking studies reveal that conjugate 2a-1 accommodates well to the active site of HPA with four hydrogen bonds in the form of the preorganization of two moieties EGC and caffeic acid via pi-stacking interaction. Collectively, conjugating caffeic acid and EGC with an appropriate linker possibly provides a new strategy for finding the specific HPA inhibitors in the discovery of anti-diabetes mellitus drugs.

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