新型2-芳基苯并咪唑作为选择性突变异柠檬酸脱氢酶2 R140Q抑制剂的设计与合成
Design and synthesis of novel 2-arylbenzimidazoles as selective mutant isocitrate dehydrogenase 2 R140Q inhibitors.
作者信息
Li Zhenyu, Wu Xingkang, Jia Lejiao, Li Jun, Zhang Rui, Tang Hui, Li Zhiying, Bu Huagang, Shen Chengwu
机构信息
Department of Pharmacy, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, PR China.
Modern Research Center for Traditional Chinese Medicine, Shanxi University, Taiyuan, Shanxi 030006, PR China.
出版信息
Bioorg Med Chem Lett. 2020 May 1;30(9):127070. doi: 10.1016/j.bmcl.2020.127070. Epub 2020 Feb 28.
A series of novel 2-arylbenzimidazoles have been designed, synthesized and evaluated for their inhibitory activity against IDH2 R140Q mutant. The preliminary results indicated that four compounds 7b, 7c, 7m and 7r displayed the potent inhibitory activity against IDH2 R140Q mutant. Among them, compound 7c showed the highest inhibitory activity, with the IC value of 0.26 μM, which was more active than positive control enasidenib. The exquisite selectivity of 7c for IDH2 R140Q mutant isoform was demonstrated by the poor activity against the IDH1 R132C mutant, IDH1 R132H mutant, wild-type IDH1, IDH2 R172K mutant and the wild-type IDH2.
设计、合成了一系列新型2-芳基苯并咪唑，并对其针对异柠檬酸脱氢酶2（IDH2）R140Q突变体的抑制活性进行了评估。初步结果表明，四种化合物7b、7c、7m和7r对IDH2 R140Q突变体表现出强效抑制活性。其中，化合物7c表现出最高的抑制活性，IC值为0.26 μM，比阳性对照恩杂鲁胺更具活性。7c对IDH2 R140Q突变体亚型具有出色的选择性，这通过其对IDH1 R132C突变体、IDH1 R132H突变体、野生型IDH1、IDH2 R172K突变体和野生型IDH2的低活性得以证明。
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