设计、合成和生物评价一系列含有硫腙类似物的苯并呋喃[3,2-d]嘧啶-4(3H)-酮衍生物，作为新型PARP-1抑制剂。
Design, synthesis, and biological evaluation of a series of benzofuran[3,2-d]pyrimidine-4(3H)-one derivatives containing thiosemicarbazone analogs as novel PARP-1 inhibitors.
发表日期：2023 Aug 01
作者：
Yuanjiang Wang, Kun Li, Wenqing Xu, Shaohua Gou
来源：
BIOORGANIC CHEMISTRY
摘要：
聚腺苷二磷酸核糖聚合酶-1（PARP-1）是PARP蛋白家族中最重要的成员之一，在DNA损伤修复、基因转录和癌细胞凋亡中起着关键作用。在这项工作中，苯并呋喃[3,2-d]嘧啶-4(3H)-酮被用作设计和合成一系列新型的PARP-1抑制剂的框架，通过将硫脲肼及其衍生物引入到骨架中。在所有目标化合物中，19b和19c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酶的IC50值为0.026μM，对Olaparib的PARP-2/PARP-1选择性为85.19倍。除了对所测试的癌细胞系具有强大的细胞毒性外，19c对SK-OV-3细胞最敏感，其IC50值为4.98μM，优于Olaparib。抗癌机制研究表明，19c能通过抑制PARP-1活性来抑制DNA单链断裂修复，加剧DNA双链断裂，并通过线粒体凋亡途径促进癌细胞凋亡。
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Poly ADP ribose polymerase-1 (PARP-1), one of the most important members of the PARP protein family, plays a crucial role in DNA damage repair, gene transcription, and apoptosis 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 an IC50 value of 0.026 μM against PARP-1 enzyme and a PARP-2/PARP-1 selectivity of 85.19-fold over Olapanib. Apart from strong cytotoxicity against the tested cancer cell lines, 19c was most sensitive to SK-OV-3 cells, with an IC50 value of 4.98 μM superior to Olaparib. Anti-cancer mechanism studies revealed that 19c could inhibit DNA single-strand breakage repair and aggravate DNA double-strand breakage by inhibiting PARP-1 activity, and promote the apoptosis of cancer cells through the mitochondrial apoptosis pathway.Copyright © 2023 Elsevier Inc. All rights reserved.