论文部分内容阅读
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。
Objective To design and synthesize a new type of poly (ADP-ribose) polymerase (PARP-1) inhibitor and evaluate its inhibitory activity against PARP-1. Methods A series of 3-aminobenzamides were designed based on the existing structure-activity relationship and pharmacophore characteristics. 3-Aminobenzamides or 2-fluoro-5-aminobenzamides were used as starting materials in combination with N- Boc-protected nitrogen-containing alicyclic carboxylic acid, condensing, removing the Boc protecting group, and reductive amination to synthesize the target compound. The inhibitory activity of the target compound on PARP-1 was evaluated by NAD ~ + chemical quantitative method. Results Thirty new derivatives of 3-aminobenzamides were synthesized. The structures of the target compounds were confirmed by ~ 1H-NMR and LC-MS. Among them, 20 showed inhibitory activity against PARP-1 IC 50 value is 0.19 ~ 7.58μmol·L -1). Conclusion The structure-activity relationship of these compounds was discussed preliminarily. The mode of action of the target compound and PARP-1 was explored by molecular docking, in order to provide a reference for further structural transformation.