Many researchers are attracted to develop selective Topoisomerase (topo) II inhibitors as anticancer agents. Topo II plays crucial role in many nuclear processes that generate topological problems. In addition, topo II is the only enzyme available to disentangle the topological problems in chromosomes, which must occur during the completion of replication, and to decantenate the replicated chromosomes by transiently breaking of double strands of DNA. For the development of novel anticancer agents, we designed and synthesized hydroxylated 2,4-diphenyl indenopyridines, and evaluated their topoisomerase inhibitory activity as well as their cytotoxicity against several human cancer cell lines. The structure-activity relationship study showed that indenopyridines with hydroxyl group at meta or para positions of 2- or 4-phenyl ring displayed selective and significant topoisomerase IIα (topo IIα) inhibitory activity and potent cytotoxicity. Positive correlation between topo IIα inhibition and cytotoxicity was observed for compounds 15, 16, 18-20, 22, 23, 25 and 26. The mode of action of compound 16 was further evaluated to be a non-intercalative topo IIα catalytic inhibitor. Keywords: Hydroxylated 2, 4-diphenyl indenopyridine, Anticancer agents, Terpyridine, Topoisomerase IIα non-intercalative catalytic inhibitor, Cytotoxicity

Development of a novel class of hydroxylated 2, 4-diphenyl indenopyridines as a selective non-intercalative topoisomerase IIα catalytic inhibitor

249th National Meeting (2015)

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