期刊
RSC ADVANCES
卷 6, 期 84, 页码 80784-80796出版社
ROYAL SOC CHEMISTRY
DOI: 10.1039/c6ra12591c
关键词
-
资金
- Chinese National Science Foundation, China Pharmaceutical University [81273375, 21372260]
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 mu M), 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 mu M vs. CC50 = 22 mu M). 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.
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