Design, synthesis and biological evaluation of novel molecules as potent PARP-1 inhibitors

被引：10
|
作者：
Shen, Hui [1 ]
Ge, Yiran [2 ]
Wang, Junwei [1 ]
Li, Hui [1 ]
Xu, Yungen [1 ,2 ]
Zhu, Qihua [1 ,2 ]
机构：
[1] China Pharmaceut Univ, Jiangsu Key Lab Drug Design & Optimizat, Nanjing 211198, Peoples R China
[2] China Pharmaceut Univ, Dept Med Chem, Nanjing 211198, Peoples R China
来源：
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2021年 / 47卷
基金：
中国国家自然科学基金;
关键词：
Antitumor drug; DNA repair; PARP-1; inhibitors; Drug design; POLY(ADP-RIBOSE); DISCOVERY;
D O I：
10.1016/j.bmcl.2021.128169
中图分类号：
R914 [药物化学];
学科分类号：
100701 ;
摘要：
Two series of novel compounds with inhibition activity against PARP-1 were designed and synthesized. All target compounds were evaluated for their PARP-1 inhibition activity, and compounds with high PARP-1 inhibition activity were selected to assess for cellular assays in vitro. Among them, compound II-4 displayed impressive results in both PARP-1 enzyme inhibition with IC50 value of 0.51 nM and anti-proliferation activity against HCT116 and HCC1937 cell lines with IC50 values of 6.62 nM and 12.65 nM, respectively. Also, II-4 exhibited good metabolic stability in vitro with t(1/2) of 173.25 min and CLint of 0.04 mL/min/mg. Prediction of molecular properties and protein docking were applied to structure design. Our study provides potential lead compounds and design directions for the development of PARP-1 inhibitors.
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页数：6
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