Identification of novel PARP-1 inhibitors: Drug design, synthesis and biological evaluation
Identification of novel PARP-1 inhibitors: Drug design, synthesis and biological evaluation
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新型 PARP-1 抑制剂的鉴定：药物设计、合成和生物学评价
DOI：
10.1016/j.bmcl.2015.08.060
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发表时间：
2015
影响因子：
2.7
通讯作者：
Zhiyu Li
中科院分区：
文献类型：
--
作者：
Zhouling Xie;Youli Zhou;Wei Zhao;He Jiao;Yu Chen;Yong Yang;Zhiyu Li
合成了一系列含有2，3-二氢-1H-[1，2]二氮杂卓[4，5，6-cd]吲哚-1，4（6 H）-二酮的新型骨架的AG 014699衍生物，并评价了其对PARP-1酶和两种细胞系MCF-7细胞和BRCA 1缺陷型MDA-MB-436细胞的抑制活性。我们的结果表明，在这项工作中合成的所有AG 014699衍生物中，化合物6和7显示出强烈的PARP-1抑制活性（IC 50分别为3.5 nM和2.4 nM），仅比AG 014699的效力低4倍和3倍。化合物6还对MCF-7细胞（CC 50 = 25.8 μM）和BRCA 1缺陷型MDA-MB-436细胞（CC 50 = 5.4 μM）具有显着的细胞抑制活性，几乎与AG 014699一样好，表明它可以成为一个有前途的化合物进行进一步评估。
A series of AG014699 derivatives containing a novel scaffold of 2,3-dihydro-1H-[1,2]diazepino[4,5,6-cd]indole-1,4(6H)-dione were synthesized and evaluated for their inhibitory activities toward PARP-1 enzyme and two cell lines, MCF-7 cells and the BRCA1-deficient MDA-MB-436 cells. Our results demonstrated that of all AG014699 derivatives synthesized in this work, compounds6and7showed strong PARP-1 inhibitory activity (IC50= 3.5 nM and 2.4 nM, respectively), only four and three times less potent than AG014699. Compound6also had significantly cell inhibitory activity against both MCF-7 cells (CC50= 25.8 μM) and theBRCA1-deficient MDA-MB-436 cells (CC50= 5.4 μM), nearly as good as AG014699, indicating that it can be a promising compound for further evaluation.