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Eur J Med Chem. 2015 Apr 13;94:163-74. doi: 10.1016/j.ejmech.2015.02.060. Epub 2015 Mar 3.

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

Author information

1
Department of Drug Chemistry and Technologies, Sapienza University of Roma, P.le A. Moro 5, 00185 Roma, Italy.
2
Genextra Group, DAC s.r.l. Via Adamello 16, 20139 Milano, Italy.
3
Dipartimento di Oncologia Sperimentale, IEO - European Institute of Oncology, Via Adamello 16, 20139 Milano, Italy.
4
Italian National Institute of Health, Department of Therapeutic Research and Medicines Evaluation, Via Regina Elena 299, 00161 Roma, Italy.
5
Department of Biology and Biotechnology, University of Pavia, Via Ferrata 1, 27100 Pavia, Italy.
6
Department of Sense Organs, Sapienza University of Roma, P.le A. Moro 5, 00185 Roma, Italy.
7
Centre of Theoretical and Computational Chemistry (CTCC), Department of Chemistry, P.O. Box 1033, Blindern, N-0315 Oslo, Norway.
8
Dipartimento di Oncologia Sperimentale, IEO - European Institute of Oncology, Via Adamello 16, 20139 Milano, Italy; Department of Biosciences, University of Milan, 20100 Milan, Italy.
9
Department of Drug Chemistry and Technologies, Sapienza University of Roma, P.le A. Moro 5, 00185 Roma, Italy; Pasteur Institute - Cenci Bolognetti Foundation, Sapienza University of Roma, P.le A. Moro 5, 00185 Roma, Italy. Electronic address: antonello.mai@uniroma1.it.

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.

KEYWORDS:

Epigenetics; Leukemia; Lysine-specific demethylase 1; Stereoisomers; Tranylcypromine

PMID:
25768700
DOI:
10.1016/j.ejmech.2015.02.060
[Indexed for MEDLINE]

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