Pure Diastereomers of a Tranylcypromine-Based LSD1 Inhibitor: Enzyme Selectivity and In-Cell Studies

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

doi:10.1021/ml500424z

Pure Diastereomers of a Tranylcypromine-Based LSD1 Inhibitor: Enzyme Selectivity and In-Cell Studies

ACS Med Chem Lett. 2014 Dec 8;6(2):173-7. doi: 10.1021/ml500424z. eCollection 2015 Feb 12.

Authors

Sergio Valente¹, Veronica Rodriguez¹, Ciro Mercurio², Paola Vianello³, Bruna Saponara⁴, Roberto Cirilli⁴, Giuseppe Ciossani⁵, Donatella Labella¹, Biagina Marrocco¹, Giovanni Ruoppolo⁶, Oronza A Botrugno³, Paola Dessanti³, Saverio Minucci⁷, Andrea Mattevi⁵, Mario Varasi³, Antonello Mai⁸

Affiliations

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 Department of Therapeutic Research and Medicines Evaluation, Italian National Institute of Health , 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 Dipartimento di Oncologia Sperimentale, IEO-European Institute of Oncology , Via Adamello 16, 20139 Milano, Italy ; Department of Biosciences, University of Milan , 20100 Milan, Italy.
⁸ 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.

Abstract

The pure four diastereomers (11a-d) of trans-benzyl (1-((4-(2-aminocyclopropyl)phenyl)amino)-1-oxo-3-phenylpropan-2-yl)carbamate hydrochloride 11, previously described by us as LSD1 inhibitor, were obtained by enantiospecific synthesis/chiral HPLC separation method. Tested in LSD1 and MAO assays, 11b (S,1S,2R) and 11d (R,1S,2R) were the most potent isomers against LSD1 and were less active against MAO-A and practically inactive against MAO-B. In cells, all the four diastereomers induced Gfi-1b and ITGAM gene expression in NB4 cells, accordingly with their LSD1 inhibition, and 11b and 11d inhibited the colony forming potential in murine promyelocytic blasts.

Keywords: Epigenetics; leukemia; lysine-specific demethylase; stereoisomers; tranylcypromine.