2. Academic Validation
  3. Pure Diastereomers of a Tranylcypromine-Based LSD1 Inhibitor: Enzyme Selectivity and In-Cell Studies

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.
Sergio Valente 1,  Veronica Rodriguez 1,  Ciro Mercurio 2,  Paola Vianello 3,  Bruna Saponara 4,  Roberto Cirilli 4,  Giuseppe Ciossani 5,  Donatella Labella 1,  Biagina Marrocco 1,  Giovanni Ruoppolo 6,  Oronza A Botrugno 3,  Paola Dessanti 3,  Saverio Minucci 7,  Andrea Mattevi 5,  Mario Varasi 3,  Antonello Mai 8
Affiliations

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.
PMID: 25699146 DOI: 10.1021/ml500424z
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.

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