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

A series of vincamine derivatives were designed, synthesized and evaluated as pancreatic beta-cells protective agents for type 2 diabetes mellitus. Most of the compounds displayed potent pancreatic beta-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 mu NI and 0.27 mu M, respectively. Their pancreatic beta-cells protective activities increased approximately 2 times than vincamine. In cell viability assay, compounds Vin-001 and Vin-F03 could effectively promote beta-cell survival and protect beta-cells from STZ-induced apoptosis. Further cellular mechanism of action studies demonstrated that their potent protective activities were achieved by regulating IRS2/Pl3K/Akt signaling pathway. The present study evidently showed that compounds Vin-C01 and Vin-F03 were two more potent pancreatic beta-cells protective agents compared to vincamine and might serve as promising lead candidates for the treatment of type 2 diabetes mellitus. (C) 2019 Elsevier Masson SAS. All rights reserved.