Design, synthesis and pharmacological evaluation of new 3-(1H-benzimidazol-2-yl)quinolin-2(1H)-one derivatives as potential antitumor agents.

A series of new 3-(1H-benzimidazol-2-yl)quinolin-2(1H)-one derivatives (5a-5d) were designed and synthesized as antitumor agents. In vitro antitumor assay results showed that some compounds exhibited moderate to high inhibitory activity against HepG2, SK-OV-3, NCI-H460 and BEL-7404 tumor cell lines, and most compounds exhibited much lower cytotoxicity against the HL-7702 normal cell line compared to 5-FU and cisplatin. In vivo antitumor assay results demonstrated that 5a exhibited effective inhibition on tumor growth in the NCI-H460 xenograft mouse model and that 5d displayed excellent antiproliferative activity in the BEL-7402 xenograft model. These results suggested that both 5a and 5d could be used as anticancer drug candidates. Mechanistic studies suggested that compounds 5a and 5d exerted their antitumor activity by up-regulation of Bax, intracellular Ca release, ROS generation, downregulation of Bcl-2, activation of caspase-9 and caspase-3 and subsequent cleavage of PARP, inhibition of CDK activity and activation of the p53 protein.