摘要/Abstract

合成了一系列新型的3-(吲哚-3-基)-4-(吡唑并[3,4-c]哒嗪-3-基)马来酰亚胺, 并评价了其对异柠檬酸脱氢酶1突变体(R132H)的抑制活性. 大多数化合物对IDH1-R132H表现出较强的活性. 其中化合物3-(1-(3-(1-(1H-咪唑-1-基)丙基)-6-溴-1H-吲哚-3-基)-4-(1-甲基-1H-吡唑并[3,4-c]哒嗪-3-基)-1H-吡咯-2,5-二酮(9b)是最有前途的IDH1-R132H抑制剂, IC₅₀值为31 nmol/L, 并能显著抑制异柠檬酸脱氢酶1突变(R132H)型人脑星形胶质母细胞瘤细胞中2-HG的产生. 根据实验数据进行了初步的构效关系讨论和分子模拟研究.
关键词: 3-(吲哚-3-基)-4-(吡唑并[3,4-c]哒嗪-3-基)马来酰亚胺, 异柠檬酸脱氢酶1突变体(R132H)抑制剂, 合成, 生物活性
A series of novel 3-(indol-3-yl)-4-(pyrazolo[3,4-c]pyridazin-3-yl)maleimides were synthesized and evaluated for their inhibitory activity against mutant isocitrate dehydrogenase-1 (R132H). Most compounds exhibited potent potency to IDH1-R132H. Among them, compound9bwas the most promising IDH1-R132H inhibitor with IC₅₀ values of 31 nmol/L and could significantly inhibit the production of 2-HG in human brain astroblastoma cells with mutant isocitrate dehydrogenase-1 （R132H). Preliminary structure-activity relationship and molecular modeling studies were discussed based on the experimental data obtained.
Key words: 3-(indol-3-yl)-4-(pyrazolo[3,4-c]pyridazin-3-yl)maleimide, mutant isocitrate dehydrogenase-1 (R132H) inhibitor, synthesis, biological activity


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