2. Academic Validation
  3. Design and synthesis of epigallocatechin (EGC) analogs selective to inhibit α-amylase over α-glucosidases via the incorporation of caffeine acid and its derivatives

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

  • Bioorg Chem. 2022 Feb;119:105515. doi: 10.1016/j.bioorg.2021.105515.
Wenming Chen 1,  Cui Zhou 2,  Jiansheng Chen 3,  Meizhu Wang 4,  Fang Zhou 1,  Chunmei Wang 5,  Xu Zhang 6,  Wen Zhou 7
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Production Center ＆ TCM and Ethnomedicine Development International Laboratory, The First Hospital of Hunan University of Chinese Medicine, 95, Shaoshan Rd, Changsha, Hunan 410007, China.
  • 2 Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, 200241 Shanghai, China; School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, University Town, Waihuan Rd., Panyu, Guangzhou 510006, China.
  • 3 College of Forestry and Landscape Architecture, South China Agricultural University, 510642, China.
  • 4 School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, University Town, Waihuan Rd., Panyu, Guangzhou 510006, China.
  • 5 Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, 200241 Shanghai, China; Key Laboratory of Veterinary Chemical Drugs and Pharmaceutics, Ministry of Agriculture and Rural, Affairs, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai 200241, China. Electronic address: wangchunmei@shvri.ac.cn.
  • 6 College of Forestry and Landscape Architecture, South China Agricultural University, 510642, China. Electronic address: zhangxu@126.com.
  • 7 Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, 200241 Shanghai, China; Key Laboratory of Veterinary Chemical Drugs and Pharmaceutics, Ministry of Agriculture and Rural, Affairs, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai 200241, China. Electronic address: zhouwen60@126.com.
PMID: 34896919 DOI: 10.1016/j.bioorg.2021.105515
Abstract

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 α-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 α-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 π-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.

Keywords

Antidiabetic drug; Caffeic acid; EGC; HPA inhibitors; Selectivity.

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