2. Academic Validation
  3. Design, synthesis and biological evaluation of vincamine derivatives as potential pancreatic β-cells protective agents for the treatment of type 2 diabetes mellitus

Design, synthesis and biological evaluation of vincamine derivatives as potential pancreatic β-cells protective agents for the treatment of type 2 diabetes mellitus

  • Eur J Med Chem. 2020 Feb 15;188:111976. doi: 10.1016/j.ejmech.2019.111976.
Junwei Wang 1,  Xue Lv 2,  Jiawen Xu 1,  Xinpeng Liu 1,  Te Du 3,  Guanglong Sun 3,  Jing Chen 3,  Xu Shen 1,  Jiaying Wang 4,  Lihong Hu 5
Affiliations

Affiliations

  • 1 Jiangsu Key Laboratory for Functional Substance of Chinese Medicine, Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Stake Key Laboratory Cultivation Base for TCM Quality and Efficacy, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, PR China.
  • 2 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, PR China.
  • 3 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, PR China; University of Chinese Academy of Sciences, Beijing, 100049, PR China.
  • 4 Jiangsu Key Laboratory for Functional Substance of Chinese Medicine, Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Stake Key Laboratory Cultivation Base for TCM Quality and Efficacy, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, PR China. Electronic address: wangjy@njucm.edu.cn.
  • 5 Jiangsu Key Laboratory for Functional Substance of Chinese Medicine, Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Stake Key Laboratory Cultivation Base for TCM Quality and Efficacy, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, PR China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, PR China; University of Chinese Academy of Sciences, Beijing, 100049, PR China. Electronic address: lhhu@njucm.edu.cn.
PMID: 31918073 DOI: 10.1016/j.ejmech.2019.111976
Abstract

A series of vincamine derivatives were designed, synthesized and evaluated as pancreatic β-cells protective agents for type 2 diabetes mellitus. Most of the compounds displayed potent pancreatic β-cells protective activities and five derivatives were found to exhibit 20-50-fold higher activities than vincamine. Especially for compounds Vin-C01 and Vin-F03, exhibited a remarkable EC50 value of 0.22 μM and 0.27 μM, respectively. Their pancreatic β-cells protective activities increased approximately 2 times than vincamine. In cell viability assay, compounds Vin-C01 and Vin-F03 could effectively promote β-cell survival and protect β-cells from STZ-induced Apoptosis. Further cellular mechanism of action studies demonstrated that their potent β-cells protective activities were achieved by regulating IRS2/PI3K/Akt signaling pathway. The present study evidently showed that compounds Vin-C01 and Vin-F03 were two more potent pancreatic β-cells protective agents compared to vincamine and might serve as promising lead candidates for the treatment of type 2 diabetes mellitus.

Keywords

Pancreatic β-cells protective agents; Structural modifications; Structure-activity relationships; Type 2 diabetes mellitus; Vincamine derivatives.

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