Heterocycle-containing tranylcypromine derivatives endowed with high anti-LSD1 activity

As regioisomers/bioisosteres of 1a, a 4-phenylbenzamide tranylcypromine (TCP) derivative previously disclosedby us, we report here the synthesis and biological evaluation of some (hetero)arylbenzoylaminoTCP derivatives 1b-6, in which the 4-phenyl moiety of 1a was shifted at the benzamide C3 position orreplaced by 2- or 3-furyl, 2- or 3-thienyl, or 4-pyridyl group, all at the benzamide C4 or C3 position. Inanti-LSD1-CoREST assay, all the meta derivatives were more effective than the para analogues, with themeta thienyl analogs 4b and 5b being the most potent (IC50 values ¼ 0.015 and 0.005 lM) and the mostselective over MAO-B (selectivity indexes: 24.4 and 164). When tested in U937 AML and prostate cancerLNCaP cells, selected compounds 1a,b, 2b, 3b, 4b, and 5a,b displayed cell growth arrest mainly in LNCaPcells. Western blot analyses showed increased levels of H3K4me2 and/or H3K9me2 confirming the involvementof LSD1 inhibition in these assays.