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 decantenate 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.In this study, twenty-one2-phenyl-4-aryl indenopyridines containing hydroxyl group at ortho, meta, or para position of phenyl ring were systematically designed and synthesized. They were evaluated for their topo I and II inhibitory activities, and cytotoxicity against several human cancer cell lines. Compounds 8  , 11  , 14  , and 17   showed significant selective topo II inhibitory activityat both 100 �M and 20 �M. Compounds 17  showed the most significant cytotoxicity against T47D cell line whereas weaker cytotoxicity against HCT15, DU145 and HEK293 cell lines as compared to positive controls. Structure-activity relationship (SAR) study revealed that hydroxyl group at meta or para position of 2-phenyl ring of indenopyridinehas an important role in displaying selective topo IIa inhibitory activity.Keywords: Antitumor agents,Cytotoxicity, Hydroxylated 2-phenyl-4-aryl indenopyridine, Terpyridine, Topoisomerase IIainhibitor

Design, synthesis, biological evaluation, and structure-activity relationship study of hydroxylated 2-phenyl-4-aryl indenopyridines as selective topoisomerase IIa inhibitor

247th National Meeting (2014)

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