Topoisomerase (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 decatenate the replicated chromosomes by transiently breaking of double strands of DNA. Therefore, many researches are attracted to develop selective topo II inhibitors as antitumor agents. Our previous studies showed that conformationally constrained rigid analogs of 2,4,6-trisubstituted pyridine containing 5,6-dihydrobenzo[h]quinoline moiety is important for topo inhibitory activities, and cytotoxicity against several human cancer cell lines. Various compounds possessing indenopyridine moiety were reported to have anticancer activity. For the development of potential anticancer agents, we designed and synthesized 30 new 2,4-diaryl indenopyridine derivatives containing aryl moiety such as 2- or 3- furyl, 2- or 3-thienyl, 2- or 3-pyridyl, and phenyl at 2- or 4- position of central pyridine. They were evaluated for topoisomerase I and II inhibitory activity, and cytotoxicity against several human cancer cell lines. Among prepared 30 compounds, 7, 8, 9, 10, 12, 14, 16, 19, 20, 22, and 23 with 2- or 3-furyl and/or 2- or 3-thienyl either at 2- or 4-position of central pyridine showed the significant or moderate topoisomerase II inhibitory activity. Compounds 7, 8, 11, 12, 13, and 22 with 2-furyl, 2- thienyl or 3-thienyl at 2-position of central pyridine showed the significant or moderate topoisomerase I inhibitory activity. Especially, compound 12 with strong topoisomerase II inhibitory activity at 100 µM and 20 µM, and moderate topoisomerase I inhibitory activity displayed strong cytotoxicity against several human cancer cell lines. Keywords: 2,4-Diaryl indenopyridine; Topoisomerase I and II inhibition; Cytotoxicity; Anticancer agents

2,4-Diaryl-indenopyridine derivatives: Design, synthesis, topoisomerase I and II inhibition, cytotoxicity, and structure-activity relationship study

249th National Meeting (2015)

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