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 (IC 50 = 0.96 μM), 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. Image 1 • The antiproliferative efficacy of [1,2,4]triazolo [1,5-a]pyrimidine derivatives were discovered and further optimized. • 6i effectively inhibited growth of MGC-803 (IC 50 = 0.96 μM), being around 38-fold selectivity over GES-1. • 6i induced cell apoptosis and G0/G1 phase arrest of MGC-803 cells. • 6i exhibited good safety in vivo. [ABSTRACT FROM AUTHOR]