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Three-component Castagnoli-Cushman reaction with ammonium acetate delivers 2-unsubstituted isoquinol-1-ones as potent inhibitors of poly(ADP-ribose) polymerase (PARP)
Journal of Enzyme inhibition and Medicinal Chemistry ( IF 5.6 ) Pub Date : 2021-08-31 , DOI: 10.1080/14756366.2021.1969386
Alexander Safrygin 1 , Petr Zhmurov 1 , Dmitry Dar'in 1 , Sergey Silonov 2 , Mariia Kasatkina 2 , Yulia Zonis 2 , Maxim Gureev 3 , Mikhail Krasavin 1
Affiliation  

Abstract

An earlier described three-component variant of the Castagnoli-Cushman reaction employing homophthalic anhydrides, carbonyl compound and ammonium acetate was applied towards the preparation of 1-oxo-3,4-dihydroisoquinoline-4-carboxamides with variable substituent in position 3. These compounds displayed inhibitory activity towards poly(ADP-ribose) polymerase (PARP), a clinically validated cancer target. The most potent compound (PARP1/2 IC50 = 22/4.0 nM) displayed the highest selectivity towards PARP2 in the series (selectivity index = 5.5), more advantageous ADME prameters compared to the clinically used PARP inhibitor Olaparib.



中文翻译:


与乙酸铵的三组分 Castagnoli-Cushman 反应产生 2-未取代的异喹啉-1-酮,作为聚 (ADP-核糖) 聚合酶 (PARP) 的有效抑制剂


 抽象的


先前描述的使用高邻苯二甲酸酐、羰基化合物和乙酸铵的 Castagnoli-Cushman 反应的三组分变体被应用于制备 3 位具有可变取代基的 1-氧代-3,4-二氢异喹啉-4-甲酰胺。这些化合物对聚(ADP-核糖)聚合酶(PARP)表现出抑制活性,聚(ADP-核糖)聚合酶是一种经过临床验证的癌症靶标。该系列中最有效的化合物(PARP1/2 IC 50 = 22/4.0 nM)对PARP2表现出最高的选择性(选择性指数= 5.5),与临床使用的PARP抑制剂Olaparib相比,ADME参数更有利。

更新日期:2021-08-31
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