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Issue 4, 2015
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Pyrrole- and indole-containing tranylcypromine derivatives as novel lysine-specific demethylase 1 inhibitors active on cancer cells†

Veronica Rodriguez,a   Sergio Valente,*a   Stefano Rovida,b   Dante Rotili,a   Giulia Stazi,a   Alessia Lucidi,a   Giuseppe Ciossani,b   Andrea Mattevi,b   Oronza A. Botrugno,d   Paola Dessanti,d   Ciro Mercurio,c   Paola Vianello,d   Saverio Minucci,de   Mario Varasid  and  Antonello Mai*af  
Author affiliations

* Corresponding authors

a Department of Drug Chemistry and Technologies, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy
E-mail: antonello.mai@uniroma1.it

b Department of Biology and Biotechnology, University of Pavia, Via Ferrata 1, 27100 Pavia, Italy

c Genextra Group, DAC s.r.l. Via Adamello 16, 20139 Milano, Italy

d Department of Experimental Oncology, European Institute of Oncology IEO, Via Adamello 16, 20139 Milan, Italy

e Department of Biosciences, University of Milan, 20100 Milan, Italy

f Pasteur Institute - Cenci Bolognetti Foundation, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy

Abstract

On the basis of previous research showing the capability of N-carbobenzyloxy-(Z-)amino acid-tranylcypromine (-TCPA) derivatives to inhibit LSD1, we inserted at the 4-amino-TCPA moiety first a Z-Pro (9) and a Z-Gly (10) residue and then, after the encouraging data obtained for 9, a pyrrole and an indole ring in which the relative N1 position carried a acetophenone, a N-phenyl/benzylacetamide, or a Z chain (11a–f and 12a–f, respectively). In both series, the Z-pyrrole and indole derivatives 11e, f and 12e, f displayed high LSD1 inhibitory activity. The compounds are able to inhibit LSD1 in NB4 cells, increasing the expression of two related genes, GFI-1b and ITGAM, and to induce cell growth arrest in the AML MB4-11 and APL NB4 cell lines.

Graphical abstract: Pyrrole- and indole-containing tranylcypromine derivatives as novel lysine-specific demethylase 1 inhibitors active on cancer cells

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Article information

https://doi.org/10.1039/C4MD00507D
Submitted
08 Nov 2014
Accepted
19 Dec 2014
First published
23 Dec 2014
Med. Chem. Commun., 2015,6, 665-670
Article type
Concise Article
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Pyrrole- and indole-containing tranylcypromine derivatives as novel lysine-specific demethylase 1 inhibitors active on cancer cells

V. Rodriguez, S. Valente, S. Rovida, D. Rotili, G. Stazi, A. Lucidi, G. Ciossani, A. Mattevi, O. A. Botrugno, P. Dessanti, C. Mercurio, P. Vianello, S. Minucci, M. Varasi and A. Mai, Med. Chem. Commun., 2015, 6, 665
DOI: 10.1039/C4MD00507D

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