N-1 位含取代苄基的喹唑啉-2, 4 (1H, 3H)-二酮类 PARP-1 抑制剂的设计、合成及活性评价

Design,synthesis and biological evaluation of novel para-substituted 1-benzyl-quinazoline-2,4(1H,3H)-diones as human PARP-1 inhibitors

聚腺苷二磷酸核糖聚合酶-1[poly(ADP-ribose)polymerase-1,PARP-1]是一种蛋白修饰酶,通过使底物蛋白发生聚ADP核糖化,参与损伤DNA的修复过程,是研制新型抗肿瘤药物的潜在靶点。本文设计合成了一系列新结构的N-1位苄基取代的喹唑啉-2,4(1H,3H)-二酮类衍生物,评价了化合物7a^7e、8a^8f、9a^9c和10a^10c对PARP-1酶的抑制活性,发现了9个化合物对PARP-1酶抑制活性IC50值在4.6~39.2μmol·L-1水平。为了阐述构效关系,并为进一步结构改造提供依据,采用分子对接方法探索了上述化合物与PARP-1的结合方式。

Poly（ADP-ribose） polymerase-1 （PARP-1） has emerged as a promising anticancer drug target due to its key role in the DNA repair process. It can polymerize ADP-ribose units on its substrate proteins which are involved in the regulation of DNA repair. In this work, a novel series of para-substituted 1-benzyl-quinazoline-2, 4 （1H, 3H）-diones was designed and synthesized, and the inhibitory activities against PARP-1 of compounds 7a-7e, 8a-8f, 9a-9e and 10a-10c were evaluated. Of all the tested compounds, nine compounds displayed inhibitory activities with IC50 values ranging from 4.6 to 39.2 μmol·L^-1. In order to predict the binding modes of the potent molecules, molecular docking was performed using CDOCKER algorithm, and that will facilitate to further develop more potent PARP-1 inhibitors with a quinazolinedione scaffold.