吲哚类LSD1抑制剂的设计合成及酶抑制活性评价  

Design, synthesis and enzyme inhibitory evaluation of indole-based LSD1 inhibitors

作　　者：王林[1] 王靖凯 张子恒 张翔宇 孙印 赵冬梅[1] WANG Lin;WANG Jing-kai;ZHANG Zi-heng;ZHANG Xiang-yu;SUN Yin;ZHAO Dong-mei(Key Laboratory of Structure-Based Drug Design and Discovery(Shenyang Pharmaceutical University),Ministry of Education,Shenyang 110016,China)

机构地区：[1]沈阳药科大学基于靶点的药物设计与研究教育部重点实验室,辽宁沈阳110016

出　　处：《中国药物化学杂志》2022年第8期600-607,共8页Chinese Journal of Medicinal Chemistry

摘　　要：目的 设计合成一系列吲哚类衍生物,以期得到对组蛋白赖氨酸特异性去甲基化酶1(LSD1)具有较好抑制活性的新化合物。方法 以4-溴-3-氯苯胺为起始原料,经过重氮化、还原、亲核加成、还原消除、Fischer吲哚环合、取代、Suzuki-Miyaura偶联、水解反应得到相应的羧酸,再与不同的胺发生缩合反应、脱除保护基得到目标化合物,并测试目标化合物对LSD1的体外抑制活性。结果与结论合成15个未见文献报道的新化合物,其结构均经核磁共振氢谱与质谱确证,其中化合物10b对LSD1表现出强效的抑制活性(IC_(50)=0.053μmol·L^(-1))。Based on a rational drug design strategy, we designed and synthesized a series of indole derivatives as potent lysine specific demethylase 1(LSD1) inhibitors and tested their enzyme inhibitory activities.Starting from 4-bromo-3-chloroaniline, fifteen novel LSD1 inhibitors were obtained via diazotization, reduction, nucleophilic addition, reduction elimination, Fischer indole cyclization, substitution, Suzuki-Miyaura coupling, hydrolysis, condensation and deprotecting reaction.All the structures of target compounds were confirmed by ESI-MS and ~1H-NMR.The enzyme inhibitory activities in vitro of target compounds were tested using horseradish peroxidase assay.The results showed that compound 10 b displayed potent enzyme inhibition against LSD1 with an IC_(50)value of 0.053 μmol·L^(-1).

关 键 词：表观遗传学 组蛋白赖氨酸特异性去甲基化酶1 吲哚类化合物 抗肿瘤 合成 

分 类 号：R914[医药卫生—药物化学]