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

Abstract

A series of new 3-(1H-benzimidazol-2-yl)quinolin-2(1H)-one derivatives (5a₁-5d₆) 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 5a₃ exhibited effective inhibition on tumor growth in the NCI-H460 xenograft mouse model and that 5d₃ displayed excellent antiproliferative activity in the BEL-7402 xenograft model. These results suggested that both 5a₃ and 5d₃ could be used as anticancer drug candidates. Mechanistic studies suggested that compounds 5a₃ and 5d₃ exerted their antitumor activity by up-regulation of Bax, intracellular Ca²⁺ 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.

Keywords: 3-(1H-benzimidazol-2-yl)quinolin-2(1H)-one derivatives; Action mechanism; Antitumor activity; Synthesis; p53.