Design, synthesis and bioevaluation of 1H-indole-4-carboxamide derivatives as potent poly(ADP-ribose) polymerase-1 inhibitors
Design, synthesis and bioevaluation of 1H-indole-4-carboxamide derivatives as potent poly(ADP-ribose) polymerase-1 inhibitors
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DOI：
10.1039/c6ra12591c
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发表时间：
2016-08
期刊：
影响因子：
3.9
通讯作者：
Zhouling Xie;Yu Chen;Pengfei Xu;Youli Zhou;Qian Zhao;He Jiao;Zhiyu Li
中科院分区：
文献类型：
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作者：
Zhouling Xie;Yu Chen;Pengfei Xu;Youli Zhou;Qian Zhao;He Jiao;Zhiyu Li
设计并合成了两个新的1H-吲哚-4-甲酰胺类化合物作为PARP-1抑制剂。进一步评价了这些化合物的PARP-1酶和细胞抑制活性，结果鉴定出化合物LX 15对PARP-1（IC 50 = 13 nM）和BRCA 1缺陷细胞（CC 50 = 0.98 μM）具有上级的效力，并且其效力高于AG 014699。此外，LX 15在BRCA 1缺陷型细胞和野生型MCF-7细胞之间显示出优异的选择性（CC 50 = 0.98 μM vs. CC 50 = 22 μM）。其作用机制研究表明，LX 15可显著引起BRCA 1缺陷细胞DNA双链断裂的积累，并影响细胞周期进程。此外，LX 15表现出合理的PK特征，并显著增强替莫唑胺（TMZ）在体外MCF-7细胞和体内B16 F10鼠黑色素瘤模型中的疗效。这些结果表明，LX 15可能是一个有前途的候选药物进行进一步的研究。
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.