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

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

Sergio Valente et al. ACS Med Chem Lett.

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.

Figures

Figure 1
Figure 1
Structures of known irreversible (16) and reversible (710) LSD1 inhibitors.
Figure 2
Figure 2
Chemical structures of the four stereoisomers of the prototype 11, compounds 11ad.
Scheme 1
Scheme 1
Figure 3
Figure 3
Gfi-1b and ITGAM gene expression modulation by 11ad in NB4 cells. Compounds were tested at their anti-LSD1 IC50 values. Data are expressed as average fold induction versus the vehicle (DMSO).

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