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.
Copyright © 2019 Elsevier Masson SAS. All rights reserved.