Design, synthesis and pharmacological evaluation of novel 2-chloro-3-(1 H -benzo[ d ]imidazol-2-yl)quinoline derivatives as antitumor agents: in vitro and in vivo antitumor activity, cell cycle arrest and apoptotic response.

A series of novel 2-chloro-3-(1 H -benzo[ d ]imidazol-2-yl)quinoline derivatives (3a 1 -3d 6 ) were designed and synthesized as antitumor agents. In vitro antitumor assay results showed that some compounds exhibited moderate to high inhibitory activities against HepG2, SK-OV-3, NCI-H460 and BEL-7404 tumor cell lines, and most compounds exhibited much lower cytotoxicities against HL-7702 normal cell line compared to 5-FU and cisplatin. In vivo antitumor assay results showed that the representative compound 3a 1 exhibited effective inhibition on tumor growth in the HepG2 xenograft mouse model. Mechanistic studies suggested that 3a 1 may exert antitumor activity by the up-regulation of Bax, intracellular Ca 2+ release, ROS generation, p21, p27 and p53, downregulation of Bcl-2, activation of caspase-9 and caspase-3 and subsequent cleavage of PARP, and inhibition of CDK activity.