Design, synthesis and bioevaluation of 1H-indole-4-carboxamide derivatives as potent poly(ADP-ribose) polymerase-1 inhibitors. Issue 84 (26th August 2016)

• Record Type: Journal Article
• Authors: Xie, Zhouling; Chen, Yu; Xu, Pengfei; Zhou, Youli; Zhao, Qian; Jiao, He; Li, Zhiyu
• Is Part Of: RSC advances. Volume 6:Issue 84(2016)
• Page Start: 80784
• Page End: 80796
• Publication Date: 2016-08-26
• Subjects: Chemistry -- Periodicals; 540.5
• DOI: 10.1039/c6ra12591c
• Languages: English
• ISSNs: 2046-2069

Abstract

Abstract : LX15 is more potent thanAG014699 in PARP-1 inhibitory activity and BRCA-1 deficient cell inhibitory activity. It is more effective thanAG014699 in potentiating the antitumor activity ofTMZ in vitro and in vivo . Abstract : Two new series of 1 H -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 compoundLX15 with superior potency against both the PARP-1 (IC50 = 13 nM) and BRCA1 deficient cells (CC50 = 0.98 μM), and it is more potent thanAG014699 . 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 thatLX15 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 thatLX15 could be a promising drug candidate for further study.