Design, synthesis and bioevaluation of 1H-indole-4-carboxamide derivatives as potent poly(ADP-ribose) polymerase-1 inhibitors

Abstract

Two new series of 1H-indole-4-carboxamide derivatives were designed and synthesized as potent PARP-1 inhibitors. These compounds were further evaluated for PARP-1 enzyme and cellular inhibitory activity, resulting in the identification of compound LX15 with superior potency against both the PARP-1 (IC₅₀ = 13 nM) and BRCA1 deficient cells (CC₅₀ = 0.98 μM), and it is more potent than AG014699. In addition, LX15 displayed excellent selectivity between the BRCA1 deficient cells and wild type MCF-7 cells (CC₅₀ = 0.98 μM vs. CC₅₀ = 22 μM). The studies of the mechanism indicated that LX15 significantly caused the accumulation of DNA double-strand breaks and impaired the cell-cycle progression in BRCA1 deficient cells. Moreover, LX15 exhibited reasonable PK profiles and significantly potentiated the efficacy of temozolomide (TMZ) in MCF-7 cells in vitro and the B16F10 murine melanoma model in vivo. All results indicated that LX15 could be a promising drug candidate for further study.