Discovery of [1,2,4]triazolo[1,5-a]pyrimidines derivatives as potential anticancer agents

In this work, we reported the discovery of compound 6i with potent antiproliferative activity against MGC-803. Among these compounds, the most potent compound 6i could effectively inhibit MGC-803 (IC50 = 0.96 mM), being around 38-fold selectivity over GES-1. Further underlying mechanism studies indicated that 6i inhibited the colony formation, migration of MGC-803, and exerted anti-proliferative effect by inducing G0/G1 phase arrest in MGC-803 cells. Cell apoptosis was induced by 6i through activating mitochondria-mediated intrinsic pathway and the death receptor-mediated extrinsic pathway. 6i induced cell apoptosis by elevating the level of ROS. Also, 6i up-regulated pro-apoptotic Bax and p53 level, while down-regulating anti-apoptotic Bcl-2 protein expression. Furthermore, acute toxicity experiment indicated 6i exhibited good safety in vivo. Therefore, 6i may be a template for future development of [1,2,4] triazolo [1,5-a]pyrimidine-based anti-cancer agents. (C) 2020 Elsevier Masson SAS. All rights reserved.

Automated summary

Compound 6i showed potent anti-proliferative activity against MGC-803 with good safety in vivo. Mechanistic studies revealed that 6i induced apoptosis in MGC-803 cells through multiple pathways, suggesting its potential as a template for anti-cancer agents.