Malcomson Thomas, Yelekci Kemal, Borrello Maria Teresa, Ganesan A, Semina Elena, De Kimpe Norbert, Mangelinckx Sven, Ramsay Rona R
Biomedical Sciences Research Complex, University of St Andrews, UK.
Department of Bioinformatics and Genetics, Kadir Has University, Istanbul, Turkey.
FEBS J. 2015 Aug;282(16):3190-8. doi: 10.1111/febs.13260. Epub 2015 Mar 27.
Cyclopropylamines, inhibitors of monoamine oxidases (MAO) and lysine-specific demethylase (LSD1), provide a useful structural scaffold for the design of mechanism-based inhibitors for treatment of depression and cancer. For new compounds with the less common cis relationship and with an alkoxy substituent at the 2-position of the cyclopropyl ring, the apparent affinity determined from docking experiments revealed little difference between the enantiomers. Using the racemate, kinetic parameters for the reversible and irreversible inhibition of MAO were determined. No inhibition of LSD1 was observed. For reversible inhibition, most compounds gave high IC50 values with MAO A, but sub-micromolar values with MAO B. After pre-incubation of the cyclopropylamine with the enzyme, the inhibition was irreversible for both MAO A and MAO B, and the activity was not restored by dilution. Spectral changes during inactivation of MAO A included bleaching at 456 nm and an increased absorbance at 400 nm, consistent with flavin modification. These derivatives are MAO B-selective irreversible inhibitors that do not show inhibition of LSD1. The best inhibitor was cis-N-benzyl-2-methoxycyclopropylamine, with an IC50 of 5 nm for MAO B and 170 nm for MAO A after 30 min pre-incubation. This cis-cyclopropylamine is over 20-fold more effective than tranylcypromine, so may be studied as a lead for selective inhibitors of MAO B that do not inhibit LSD1.
环丙胺是单胺氧化酶（MAO）和赖氨酸特异性去甲基化酶（LSD1）的抑制剂，为设计用于治疗抑郁症和癌症的基于机制的抑制剂提供了有用的结构支架。对于具有较少见的顺式关系且在环丙基环的2位带有烷氧基取代基的新化合物，对接实验测定的表观亲和力显示对映体之间差异不大。使用外消旋体，测定了MAO可逆和不可逆抑制的动力学参数。未观察到对LSD1的抑制作用。对于可逆抑制，大多数化合物对MAO A的IC50值较高，但对MAO B的IC50值为亚微摩尔。环丙胺与酶预孵育后，对MAO A和MAO B的抑制均为不可逆，且稀释后活性未恢复。MAO A失活过程中的光谱变化包括456 nm处的漂白和400 nm处吸光度增加，与黄素修饰一致。这些衍生物是MAO B选择性不可逆抑制剂，不显示对LSD1的抑制作用。最佳抑制剂是顺式-N-苄基-2-甲氧基环丙胺，预孵育30分钟后对MAO B的IC50为5 nm，对MAO A的IC50为170 nm。这种顺式环丙胺比反苯环丙胺有效20倍以上，因此可作为不抑制LSD1的MAO B选择性抑制剂的先导化合物进行研究。
