Design, synthesis and biological evaluation of 4-amidobenzimidazole acridine derivatives as dual PARP and Topo inhibitors for cancer therapy

PARP-1 could repair the DNA damages induced by Topo inhibitors, therefore inhibiting Topo and PARP-1 simultaneously might be able to overcome resistance and improve outcomes. In this study a series of 4-amidobenzimidazole acridines were designed and synthesized as dual Topo and PARP-1 inhibitors. Compound 111 displayed good inhibitory activities against Topo and PARP-1, as well as significantly inhibited cancer cells proliferation. Further mechanistic evaluations indicated that 111 treatment in MCF-7 cells induced accumulated DNA double-strand breaks, prompted remarkable apoptosis, and caused prominent GO/G1 cell cycle arrest. Moreover, 111 greatly suppressed tumor growth in mice, and displayed favorable metabolic properties in liver microsomes. Our study suggested that single agents inhibiting Topo and PARP concurrently might be an alternative for cancer therapy and 111 represented a potential lead compound for development of antitumor agents. (C) 2017 Elsevier Masson SAS. All rights reserved.