Heterocycle-containing tranylcypromine derivatives endowed with high anti-LSD1 activity. (31st December 2022)

• Record Type: Journal Article
• Authors: Fioravanti, Rossella; Rodriguez, Veronica; Caroli, Jonatan; Chianese, Ugo; Benedetti, Rosaria; Di Bello, Elisabetta; Noce, Beatrice; Zwergel, Clemens; Corinti, Davide; Viña, Dolores; Altucci, Lucia; Mattevi, Andrea; Valente, Sergio; Mai, Antonello
• Is Part Of: Journal of enzyme inhibition and medicinal chemistry. Volume 37:Number 1(2022)
• Page Start: 973
• Page End: 985
• Publication Date: 2022-12-31
• Subjects: Epigenetics -- histone demethylase -- anticancer activity; Enzyme inhibitors -- Periodicals; Enzyme Inhibitors -- periodicals; Biochemistry -- periodicals; 572.7
• DOI: 10.1080/14756366.2022.2052869
• Languages: English
• ISSNs: 1475-6366

Abstract

Abstract: As regioisomers/bioisosteres of 1a, a 4-phenylbenzamide tranylcypromine (TCP) derivative previously disclosed by us, we report here the synthesis and biological evaluation of some (hetero)arylbenzoylamino TCP derivatives 1b -6, in which the 4-phenyl moiety of 1a was shifted at the benzamide C3 position or replaced by 2- or 3-furyl, 2- or 3-thienyl, or 4-pyridyl group, all at the benzamide C4 or C3 position. In anti-LSD1-CoREST assay, all the meta derivatives were more effective than the para analogues, with the meta thienyl analogs 4b and 5b being the most potent (IC50 values = 0.015 and 0.005 μM) and the most selective over MAO-B (selectivity indexes: 24.4 and 164). When tested in U937 AML and prostate cancer LNCaP cells, selected compounds 1a, b, 2b, 3b, 4b, and 5a, b displayed cell growth arrest mainly in LNCaP cells. Western blot analyses showed increased levels of H3K4me2 and/or H3K9me2 confirming the involvement of LSD1 inhibition in these assays. Graphical Abstract: UF0001