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.

 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。