3-氨基苯甲酰胺衍生物PARP-1抑制剂的设计合成及活性评价

Synthesis and biological evaluation of PARP-1 inhibitors with 3-aminobenzamide skeleton

目的设计合成新型结构的聚腺苷二磷酸核糖聚合酶(PARP-1)抑制剂并评价其对PARP-1的抑制活性。方法基于已有构效关系和药效团特征设计了一系列3-氨基苯甲酰胺类化合物;以3-氨基苯甲酰胺或2-氟-5-氨基苯甲酰胺为起始原料与N-Boc保护的含氮脂环羧酸反应,经缩合、脱除Boc保护基、还原胺化反应合成目标化合物。利用NAD^+化学定量法评价目标化合物对PARP-1的抑制活性。结果合成了30个未见文献报道的3-氨基苯甲酰胺类衍生物,目标化合物的结构经~1H-NMR、LC-MS谱确证,其中20个化合物对PARP-1具有一定的抑制活性(IC_(50)值为0.19~7.58μmol·L^(-1))。结论初步探讨了该类化合物的构效关系,利用分子对接方法探索了目标化合物与PARP-1的作用模式,以期为进一步结构改造提供参考。

PARP-1[poly（ADP-ribose） polymerase-1]is involved in a DNA repair process by catalyzing the transfer of ADP-ribose units from NAD to a number of its substrate proteins.It is a promising anticancer drug target and many PARP-1 inhibitors have been developed and used in the clinical trial.In this work,a series of novel 3-aminobenzamide derivatives was designed and synthesized and their inhibitory activities against PARP-1 were evaluated.Of all the tested compounds,twenty compounds displayed inhibitory activities with IC_（50） values ranging from 0.19 to 7.58 μmol·L^-1.The binding pose of compound 4c（R= F,R^1= H,R^2= isobutyl） was predicted using molecular docking to facilitate further structural modification.