新型螺环反苯环丙胺衍生物作为赖氨酸特异性去甲基化酶1（LSD1）抑制剂
Novel spirocyclic tranylcypromine derivatives as lysine-specific demethylase 1 (LSD1) inhibitors.
作者信息
Shi Ying, Wu Yan-Ran, Su Ming-Bo, Shen Dong-Hao, Gunosewoyo Hendra, Yang Fan, Li Jia, Tang Jie, Zhou Yu-Bo, Yu Li-Fang
机构信息
Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University 3663 North Zhongshan Road Shanghai 200062 China
CAS Key Laboratory of Receptor Research, National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences 189 Guo Shou Jing Road Shanghai 201203 China
出版信息
RSC Adv. 2018 Jan 5;8(3):1666-1676. doi: 10.1039/c7ra13097j. eCollection 2018 Jan 2.
Herein we describe the design, synthesis, and biological evaluation of a novel series of tranylcypromine-based LSD1 inhibitors conformational restriction using spiro ring systems. A simple, direct spirocyclic analog of tranylcypromine (compounds 8a and 8b) was shown to be a 28- to 129-fold more potent inhibitor of LSD1 enzyme compared to tranylcypromine. Further incorporation of various substituted benzyl groups to the amino group resulted in a suite of 2',3'-dihydrospiro[cyclopropane-1,1'-inden]-2-amines that are potent LSD1 inhibitors with excellent selectivity profiles (14a, 15b, 16a, 19a and 20b) against closely related enzymes such as MAO-A, MAO-B, and LSD2.
在此，我们描述了一系列基于反苯环丙胺的新型LSD1抑制剂的设计、合成及生物学评价，这些抑制剂利用螺环系统进行构象限制。与反苯环丙胺相比，一种简单、直接的反苯环丙胺螺环类似物（化合物8a和8b）对LSD1酶的抑制活性高28至129倍。在氨基上进一步引入各种取代苄基，得到了一系列2',3'-二氢螺[环丙烷-1,1'-茚]-2-胺，它们是强效的LSD1抑制剂，对密切相关的酶如MAO-A、MAO-B和LSD2具有优异的选择性（14a、15b、16a、19a和20b）。
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