Design, synthesis, and anticancer activities of 8,9-substituted Luotonin A analogs as novel topoisomerase I inhibitors

A series of 8,9-substituted Luotonin A analogs were designed, synthesized, and evaluated for antiproliferative activity against four cancer cell lines. The structure–activity relationship study revealed that the in vitro anticancer activity of Luotonin A was significantly improved by the introduction of 8-piperazine group and the 5-deaza modification. Two promising compounds 6a and 7a displayed potent topoisomerase I inhibitory activity. And a rational binding mode of 7a with topoisomerase I–DNA complex was proposed based on the molecular docking study.