Discovery of novel 1,2,4-triazine-chalcone hybrids as anti-gastric cancer agents via an axis of ROS-ERK-DR5 in vitro and in vivo.

In this work, a series of novel 1,2,4-triazine-chalcone hybrids were designed through the molecular hybridization strategy, synthesized by two step chlorinations and further aldol condensation and evaluated their antiproliferative activity against MGC-803, HCT-116, PC-3, EC-109 and A549 cells. Compound 9l displayed significant antiproliferative activity against MGC-803, HCT-116, PC-3, EC-109 and A549 cell lines with IC 50 values of 0.41, 0.43, 0.61, 0.78 and 0.52 μM, respectively. Subsequent mechanistic investigations suggested that compound 9l induced the generation of ROS and inhibited the activation of the ERK pathway. Compound 9l induced extrinsic cell apoptosis by up-regulating DR5 dependent on the generation of ROS, while up-regulation of DR5 caused by compound 9l relied on the inhibition of ERK. Thus, compound 9l inhibited the gastric cancer cells via an axis of ROS-ERK-DR5 in vitro. Compound 9l also showed potent activity on cell proliferation inhibition, and was effective in suppressing the growth of MGC-803 xenograft tumor in nude mice without obvious toxicity. Therefore, compound 9l is to be reported as anti-gastric cancer agent in vitro and in vivo via an axis of ROS-ERK-DR5. [ABSTRACT FROM AUTHOR]