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

Veronica Rodriguez; Sergio Valente; Stefano Rovida; Dante Rotili; Giulia Stazi; Alessia Lucidi; Giuseppe Ciossani; Andrea Mattevi; Oronza A. Botrugno; Paola Dessanti; Ciro Mercurio; Paola Vianello; Saverio Minucci; Mario Varasi; Antonello Mai

doi:10.1039/C4MD00507D

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 Varasi^d and Antonello Mai*^af

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* 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.

MedChemComm

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

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