LAUSR

With the aim of developing new effective topoisomerase IIα-targeted anticancer agents, we synthesized a series of hydroxy- and halogenated 2,4-diphenyl indeno[1,2-b]pyridinols using a microwave-assisted single step synthetic method, and investigated structure-activity relationships. The majority of compounds with chlorophenyl group at 2-position and phenol group at 4-position of indeno[1,2-b]pyridinols exhibited potent anti-proliferative activity and topoisomerase IIα-selective inhibition. Of the one hundred seventy-two compounds tested, 89 showed highly potent and selective topoisomerase IIα inhibition and anti-proliferative activity in the nanomolar range against human T47D breast (2.6 nM) cancer cell lines. In addition, mechanistic studies revealed compound 89 is a non-intercalative topoisomerase II poison, and in vitro studies showed it had promising cytotoxic effects in diverse breast cancer cell lines and was particularly effective at inducing apoptosis in T47D cells. Furthermore, in vivo administration of compound 89 had significant antitumor effects in orthotopic mouse model of breast cancer.