Design, synthesis, and biological activity of N-alkylated analogue of NCL1, a selective inhibitor of lysine-specific demethylase 1Electronic supplementary information (ESI) available: Syntheses and analytical data of the test compounds; procedures for biological evaluation. See DOI: 10.1039/c4md00330f

Lysine-specific demethylase 1 (LSD1), the first histone demethylase to be identified, catalyzes specifically the demethylation of the mono- and dimethyl groups of histone H3 lysine 4, and its dysregulation is thought to contribute to the development of cancer. We have recently reported that NCL1 ( 4 ) is the first cell-active LSD1-selective inhibitor. To find LSD1 inhibitors that show higher potency than NCL1 ( 4 ), we designed and synthesized an N -alkylated analogue of NCL1 ( 5 ), and evaluated its biological activity. In enzyme assays, compound 5 was six times more potent than 4 , and compound 5 exhibited cell growth inhibition in cervical cancer HeLa cell line and neuroblastoma SH-SY5Y cell line. Compound 5 should be useful as a lead structure for anticancer drugs. A hybridization of NCL1 and compound 5 led to the identification of a potent lysine-specific demethylase 1 inhibitor 5 .