苯环丙胺类LSD1抑制剂设计、合成及活性研究  

Design,Synthesis and Biological Evaluation of Tranylcypromine Derivatives as Novel LSD1 Inhibitors

作　　者：黄利华 郭佳稳 黄明杰 宋文淇 符运栋 游亚珍 刘宏民 HUANG Lihua;GUO Jiawen;HUANG Mingjie;SONG Wenqi;FU Yundong;YOU Yazhen;LIU Hongmin(College of Chemistry, Zhengzhou University, Zhengzhou 450001, China;School of Collaborative Innovation Center of New Drug Research and Safety Evaluation of Henan Province, Zhengzhou 450001, China)

机构地区：[1]郑州大学化学学院,河南郑州450001 [2]新药创制与药物安全性评价河南省协同创新中心,河南郑州450001

出　　处：《郑州大学学报（理学版）》2021年第1期9-15,共7页Journal of Zhengzhou University:Natural Science Edition

基　　金：国家自然科学基金项目(81430085);河南省重点科技项目(182102310121)。

摘　　要：以(1R,2S)-苯基环丙胺(tranylcypromine,TCP)为原料,合成了一系列分别含有靛红、环烷基和嘌呤骨架的N-取代(1R,2S)-苯基环丙胺衍生物,其结构经HRMS、1H-NMR和13C-NMR证明。生物活性实验表明,靛红-TCP、环烷基-TCP衍生物均对赖氨酸特异性去甲基化酶1(lysine-specific demethylase 1,LSD1)有抑制活性。环己基-TCP衍生物14b抑制LSD1能力最佳(IC50=0.42μmol/L)。初步构效关系(structure activity relationship,SAR)研究表明,在靛红苯环上引入供电子基,增强LSD1抑制活性,引入吸电子基,则削弱LSD1抑制活性。在TCP上引入环烷基,可提高化合物对LSD1和单胺氧化酶(monoamine oxidases,MAOs)的选择性,并增强LSD1抑制活性。A series of N-substituted tranylcypromine(TCP)derivatives containing isatin/cycloalkyl/purine moiety have been synthesized and the structures were confirmed by HRMS,1H-NMR and 13C-NMR.The synthesized compounds showed moderate to good LSD1 inhibitory activities except compound 16.Compound 14b was the most potent inhibitors against LSD1 with IC50=0.42μmol/L.Preliminary structure activity relationship study revealed that the introduction of a cycloalkyl function led the compounds to the enhanced inhibitory activity of LSD1 and the more selectivity over MAOs.

关 键 词：LSD1 N-取代(1R 2S)-苯基环丙胺 还原胺化 

分 类 号：R916[医药卫生—药学]