Inhibition of FAD-dependent lysine-specific demethylases by chiral polyamine analoguesElectronic supplementary information (ESI) available: NMR spectra and HPLC chromatogram of novel polyamines, molecular docking simulation of 2 against LSD1 crystal structure, kinetic analysis of LSD1, LSD2, MAO-A, and MAO-B activities by polyamines. See DOI: 10.1039/c8ra07879c

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 (IC 50 = 49 μM). On the other hand, 12 was the most potent inhibitors of LSD2 with in vitro K i values of 4.4 μM. Polyamine-based inhibitors of lysine-specific demethylases 1 and 2 (LSD1 and LSD2) have been developed using solid-phase synthesis.