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

Sergio Valente; Veronica Rodriguez; Ciro Mercurio; Paola Vianello; Bruna Saponara; Roberto Cirilli; Giuseppe Ciossani; Donatella Labella; Biagina Marrocco; Daria Monaldi; Giovanni Ruoppolo; Mats Tilset; Oronza A. Botrugno; Paola Dessanti; Saverio Minucci; Andrea Mattevi; Mario Varasi; Antonello Mai

doi:10.1016/j.ejmech.2015.02.060

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

Sergio Valente, Veronica Rodriguez, Ciro Mercurio, Paola Vianello, Bruna Saponara, Roberto Cirilli, Giuseppe Ciossani, Donatella Labella, Biagina Marrocco, Daria Monaldi, Giovanni Ruoppolo, Mats Tilset, Oronza A. Botrugno, Paola Dessanti, Saverio Minucci, Andrea Mattevi, Mario Varasi, Antonello Mai

Istituto Europeo di Oncologia

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	163-174
Number of pages	12
Journal	European Journal of Medicinal Chemistry
Volume	94
DOIs	https://doi.org/10.1016/j.ejmech.2015.02.060
Publication status	Published - Apr 13 2015

Keywords

Epigenetics
Leukemia
Lysine-specific demethylase 1
Stereoisomers
Tranylcypromine

ASJC Scopus subject areas

Drug Discovery
Organic Chemistry
Pharmacology

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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, O. A., Dessanti, P., Minucci, S., Mattevi, A., Varasi, M., & Mai, A. (2015). 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, 94, 163-174. https://doi.org/10.1016/j.ejmech.2015.02.060

Pure enantiomers of benzoylamino-tranylcypromine : LSD1 inhibition, gene modulation in human leukemia cells and effects on clonogenic potential of murine promyelocytic blasts. / Valente, Sergio; Rodriguez, Veronica; Mercurio, Ciro; Vianello, Paola; Saponara, Bruna; Cirilli, Roberto; Ciossani, Giuseppe; Labella, Donatella; Marrocco, Biagina; Monaldi, Daria; Ruoppolo, Giovanni; Tilset, Mats; Botrugno, Oronza A.; Dessanti, Paola; Minucci, Saverio; Mattevi, Andrea; Varasi, Mario; Mai, Antonello.

In: European Journal of Medicinal Chemistry, Vol. 94, 13.04.2015, p. 163-174.

Research output: Contribution to journal › Article › peer-review

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 2015, '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, vol. 94, pp. 163-174. https://doi.org/10.1016/j.ejmech.2015.02.060

Valente, Sergio ; Rodriguez, Veronica ; Mercurio, Ciro ; Vianello, Paola ; Saponara, Bruna ; Cirilli, Roberto ; Ciossani, Giuseppe ; Labella, Donatella ; Marrocco, Biagina ; Monaldi, Daria ; Ruoppolo, Giovanni ; Tilset, Mats ; Botrugno, Oronza A. ; Dessanti, Paola ; Minucci, Saverio ; Mattevi, Andrea ; Varasi, Mario ; Mai, Antonello. / Pure enantiomers of benzoylamino-tranylcypromine : LSD1 inhibition, gene modulation in human leukemia cells and effects on clonogenic potential of murine promyelocytic blasts. In: European Journal of Medicinal Chemistry. 2015 ; Vol. 94. pp. 163-174.

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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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T2 - LSD1 inhibition, gene modulation in human leukemia cells and effects on clonogenic potential of murine promyelocytic blasts

AU - Valente, Sergio

AU - Rodriguez, Veronica

AU - Mercurio, Ciro

AU - Vianello, Paola

AU - Saponara, Bruna

AU - Cirilli, Roberto

AU - Ciossani, Giuseppe

AU - Labella, Donatella

AU - Marrocco, Biagina

AU - Monaldi, Daria

AU - Ruoppolo, Giovanni

AU - Tilset, Mats

AU - Botrugno, Oronza A.

AU - Dessanti, Paola

AU - Minucci, Saverio

AU - Mattevi, Andrea

AU - Varasi, Mario

AU - Mai, Antonello

PY - 2015/4/13

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N2 - 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.

AB - 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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