Identification of new halogen-containing 2,4-diphenyl indenopyridin-5-one derivative as a boosting agent for the anticancer responses of clinically available topoisomerase inhibitors

Based on previous reports on the significance of halogen moieties and the indenopyridin-5-one skeleton, we designed and synthesized a novel series of halogen (F-, Cl-, Br-, CF₃- and OCF₃-)-containing 2,4-diphenyl indenopyridin-5-ones and their corresponding -5-ols. Unlike indenopyridin-5-ols, most of the prepared indenopyridin-5-ones with Cl-, Br-, and CF₃- groups at the 2-phenyl ring conferred a strong dual Topoisomerase I/IIα inhibitory effect. Among the series, para-bromophenyl substituted compound 9 exhibited the most potent Topoisomerase inhibition and antiproliferative effects, which showed dependency upon the Topoisomerase gene expression level of diverse Cancer cells. In particular, as a DNA minor groove-binding non-intercalative Topoisomerase I/IIα catalytic inhibitor, compound 9 synergistically promoted the Anticancer efficacy of clinically applied Topoisomerase I/IIα poisons both in vitro and in vivo, having the great advantage of alleviating poison-related toxicities.