3-(Benzo[d]thiazol-2-yl)-4-aminoquinoline derivatives as novel scaffold topoisomerase I inhibitor via DNA intercalation: design, synthesis, and antitumor activities

Twenty-seven 3-(benzo[d]thiazol-2-yl)-4-aminoquinoline derivatives have been designed and synthesized as topoisomerase I inhibitors. Thein vitroanti-proliferation evaluation against four human cancer cell lines (MGC-803, HepG-2, T24, and NCI-H460) and one normal cell line (HL-7702) indicated that most of them exhibited potent cytotoxicity. Among them,5awas identified as the most promising candidate with a low IC(50)value of about 2.20 +/- 0.14 and was selected for further exploration. Spectroscopic analyses and agarose-gel electrophoresis assays indicated that5acould interact with DNA and strongly inhibit topoisomerase I (Topo I). Further screening of the Topo I activity of compounds5b,5c,5e,5f,5h,5i,5j,5l, and5nsuggested that some of the compounds might exert quite a different cytotoxicity profile to that of5a. Molecular modeling studies confirmed that5aadopts a unique mode to interact with DNA and Topo I. Other molecular mechanistic studies suggested that the treatment of MGC-803 cells with5ainduces S phase arrest, up-regulates the pro-apoptotic protein, down-regulates the anti-apoptotic protein, activates caspase-3, and subsequently induces mitochondrial dysfunction so as to induce cell apoptosis. Thein vivoefficiency of5awas also evaluated on MGC-803 xenograft nude mice and the relative tumor growth inhibition was 42.4% at 12 mg kg(-1)without an obvious loss in the body weight.