Inhibition of FAD-dependent lysine-specific demethylases by chiral polyamine analogues

Lysine-specific demethylases 1 and 2 (LSD1 and LSD2) are flavoenzyme demethylases, and their inhibitors are considered as potential chemical tools and anticancer agents. Here we report polyamine-based inhibitors of LSD1 and LSD2. In the initial screening, partially constrained polyamine 2 which contains three trans-cyclopentane units with a total of six stereogenic centers, showed the most potent LSD1-inhibitory activity. We then prepared a set of optical isomers of 2 and evaluated their inhibitory activities toward LSD1, LSD2, monoamine oxidases A and B (MAO-A and MAO-B). Optical isomers of 2 showed LSD1-inhibitory activity with K _i values of 2.2 to 6.4 μM, and LSD2-inhibitory activity with K _i values of 4.4 to 39 μM; there was a general preference for LSD1 to LSD2. All of them showed weak to negligible inhibition of MAO-A and MAO-B. This selectivity seemed to reflect the differences in the size and shape of the catalytic cavity of target enzymes, and our strategy of employing a set of optical isomers appears to be an effective approach for exploring the structural features of this family of enzymes. Polyamine 9 showed most potent LSD1-inhibitory activity (K _i = 2.2 μM in vitro), and it also inhibited the proliferation of HL-60 cells (IC₅₀ = 49 μM). On the other hand, 12 was the most potent inhibitors of LSD2 with in vitro K _i values of 4.4 μM.