Pure enantiomers of benzoylamino-tranylcypromine: LSD1 inhibition, gene modulation in human leukemia cells and effects on clonogenic potential of murine promyelocytic blasts
Pure enantiomers of benzoylamino-tranylcypromine: LSD1 inhibition, gene modulation in human leukemia cells and effects on clonogenic potential of murine promyelocytic blasts
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DOI：
10.1016/j.ejmech.2015.02.060
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发表时间：
2015-04-13
影响因子：
6.7
通讯作者：
Mai, Antonello
中科院分区：
文献类型：
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作者：
Valente, Sergio;Rodriguez, Veronica;Mai, Antonello
制备了N-(2-，3-和4-(2-氨基环丙基)苯基)苯甲酰胺盐酸盐11a-j的纯对映体，并对LSD1和MAO酶进行了测定。对区域异构体11a-j的评价表明，通过将苯甲酰胺部分从邻位转移到间位，并主要转移到三羟环丙胺苯环的对位，而不依赖于它们的反式或顺式立体化学，抗LSD1的效力净增加。尤其是对位取代的11a，b(反式)和11g，h(顺式)化合物在低纳摩尔水平下表现出对LSD1和MAO-A的抑制作用，而对MAO-B的抑制作用较弱。Meta类似物11c，d(反式)和11i，j(顺式)一般对MAO-A的效力较弱，但比对LSD1更有效。在细胞分析中，所有对映体和偏对映体都能通过诱导GFI-1b和ITGAM基因的表达来抑制LSD1，其中11b、c和11g-I的作用最强。此外，11b和11g，h对小鼠早幼粒细胞的克隆形成能力有强烈的抑制作用。(C)2015年爱思唯尔·马森公司。版权所有。
The pure enantiomers of the N-(2-, 3-, and 4-(2-aminocyclopropyl)phenyl)benzamides hydrochlorides 11a-j were prepared and tested against LSD1 and MAO enzymes. The evaluation of the regioisomers 11a-j highlighted a net increase of the anti-LSD1 potency by shifting the benzamide moiety from ortho to meta and mainly to para position of tranylcypromine phenyl ring, independently from their trans or cis stereochemistry. In particular, the para-substituted 11a,b (trans) and 11g,h (cis) compounds displayed LSD1 and MAO-A inhibition at low nanomolar levels, while were less potent against MAO-B. The meta analogs 11c,d (trans) and 11i,j (cis) were in general less potent, but more efficient against MAO-A than against LSD1. In cellular assays, all the para and meta enantiomers were able to inhibit LSD1 by inducing Gfi-1b and ITGAM gene expression, with 11b,c and 11g-i giving the highest effects. Moreover, 11b and 11g,h strongly inhibited the clonogenic potential of murine promyelocytic blasts. (C) 2015 Elsevier Masson SAS. All rights reserved.