Pure enantiomers of benzoylamino-tranylcypromine: LSD1 inhibition, gene modulation in human leukemia cells and effects on clonogenic potential of murine promyelocytic blasts

European Journal of Medicinal Chemistry
Sergio ValenteAntonello Mai

Abstract

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.

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Citations

Dec 29, 2015·Journal of Medicinal Chemistry·Tom E McAllisterChristopher J Schofield
Dec 10, 2015·Epigenomics·Xueshun WangPeng Zhan
Jan 5, 2017·Cold Spring Harbor Perspectives in Medicine·Ashwini JambhekarYang Shi
Mar 10, 2017·Epigenetics : Official Journal of the DNA Methylation Society·Hideaki Niwa, Takashi Umehara
Jun 21, 2019·Medicinal Research Reviews·Daniela TomaselliAntonello Mai
Dec 15, 2020·Journal of Enzyme Inhibition and Medicinal Chemistry·Yang LiGuojun Zhang
Oct 21, 2020·European Journal of Medicinal Chemistry·Amr K A BassGamal El-Din A Abuo-Rahma
Dec 8, 2020·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Shujing ZhangHongmin Liu

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