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

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.

journal_name

Eur J Med Chem

authors

Valente S,Rodriguez V,Mercurio C,Vianello P,Saponara B,Cirilli R,Ciossani G,Labella D,Marrocco B,Monaldi D,Ruoppolo G,Tilset M,Botrugno OA,Dessanti P,Minucci S,Mattevi A,Varasi M,Mai A

doi

10.1016/j.ejmech.2015.02.060

subject

Has Abstract

pub_date

2015-04-13 00:00:00

pages

163-74

eissn

0223-5234

issn

1768-3254

pii

S0223-5234(15)00156-7

journal_volume

94

pub_type

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