设计、合成新型分子并评估其作为强效 PARP-1 抑制剂的生物活性。
Design, synthesis and biological evaluation of novel molecules as potent PARP-1 inhibitors.
机构信息
Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 211198, China.
Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, China.
出版信息
Bioorg Med Chem Lett. 2021 Sep 1;47:128169. doi: 10.1016/j.bmcl.2021.128169. Epub 2021 Jun 6.
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 IC value of 0.51 nM and anti-proliferation activity against HCT116 and HCC1937 cell lines with IC values of 6.62 nM and 12.65 nM, respectively. Also, II-4 exhibited good metabolic stability in vitro with t of 173.25 min and CL 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.
设计并合成了两系列具有 PARP-1 抑制活性的新型化合物。所有目标化合物均进行了 PARP-1 抑制活性评估，并选择具有高 PARP-1 抑制活性的化合物进行体外细胞检测。其中，化合物 II-4 在 PARP-1 酶抑制方面表现出优异的效果，IC 值为 0.51 nM，对 HCT116 和 HCC1937 细胞系的增殖活性抑制作用的 IC 值分别为 6.62 nM 和 12.65 nM。此外，II-4 在体外具有良好的代谢稳定性，t 值为 173.25 分钟，CL 值为 0.04 mL/min/mg。还应用了分子性质预测和蛋白对接来进行结构设计。本研究为 PARP-1 抑制剂的开发提供了潜在的先导化合物和设计方向。
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