of cancer cells. In this work, benzofuran[3,2-d]pyrimidine-4(3H)-one was used as a framework to design and synthesize a series of novel PARP-1 inhibitors by introducing thiosemicarbazone or its derivatives into the scafford. Among all the target compounds, 19b and 19c were found to exhibit more potent inhibitory activity and higher selectivity against PARP-1 than Olaparib, especially the latter had
聚
ADP核糖聚合酶-1(PARP-1)是PARP蛋白家族最重要的成员之一,在DNA损伤修复、
基因转录和癌细胞凋亡中发挥着至关重要的作用。本工作以
苯并呋喃[3,2- d ]
嘧啶-4(3H ) -酮为骨架,通过将缩
氨基
硫脲或其衍
生物引入支架中,设计合成了一系列新型PARP-1
抑制剂。在所有目标化合物中,19b和19c比OlaPARib对PARP-1表现出更强的抑制活性和更高的选择性,特别是后者对PARP-1酶和PARP-2/PARP的IC 50 值为0.026 μM -1 选择性是
奥拉帕尼的 85.19 倍。除了对测试的癌
细胞系具有很强的细胞毒性外,19c对 SK-OV-3 细胞最敏感,IC 50值为 4.98 μM,优于
奥拉帕尼。抗癌机制研究表明,19c可通过抑制PARP-1活性来抑制DNA单链断裂修复并加剧DNA双链断裂,并通过线粒体凋亡途径促进癌细胞凋亡。