TY - JOUR
T1 - Pure enantiomers of benzoylamino-tranylcypromine
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
Y1 - 2015/4/13
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.
KW - Epigenetics
KW - Leukemia
KW - Lysine-specific demethylase 1
KW - Stereoisomers
KW - Tranylcypromine
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U2 - 10.1016/j.ejmech.2015.02.060
DO - 10.1016/j.ejmech.2015.02.060
M3 - Article
C2 - 25768700
AN - SCOPUS:84924406877
VL - 94
SP - 163
EP - 174
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
SN - 0223-5234
ER -