Synthesis of Carboxamide-Containing Tranylcypromine Analogues as LSD1 (KDM1A) Inhibitors Targeting Acute Myeloid Leukemia.

Autor: Teresa Borrello M; School of Pharmacy, University of East Anglia, Norwich, NR4 7TJ, UK., Benelkebir H; School of Pharmacy, University of East Anglia, Norwich, NR4 7TJ, UK., Lee A; School of Pharmacy, University of East Anglia, Norwich, NR4 7TJ, UK., Hin Tam C; School of Pharmacy, University of East Anglia, Norwich, NR4 7TJ, UK., Shafat M; Norwich Medical School, University of East Anglia, Norwich, NR4 7TJ, UK., Rushworth SA; Norwich Medical School, University of East Anglia, Norwich, NR4 7TJ, UK., Bowles KM; Norwich Medical School, University of East Anglia, Norwich, NR4 7TJ, UK., Douglas L; Protein Core Facility and Cancer Sciences, Cancer Research UK Centre and Experimental Cancer Medicines Centre University of Southampton Southampton General Hospital, Southampton, SO16 6YD, UK., Duriez PJ; Protein Core Facility and Cancer Sciences, Cancer Research UK Centre and Experimental Cancer Medicines Centre University of Southampton Southampton General Hospital, Southampton, SO16 6YD, UK., Bailey S; Protein Core Facility and Cancer Sciences, Cancer Research UK Centre and Experimental Cancer Medicines Centre University of Southampton Southampton General Hospital, Southampton, SO16 6YD, UK., Crabb SJ; Protein Core Facility and Cancer Sciences, Cancer Research UK Centre and Experimental Cancer Medicines Centre University of Southampton Southampton General Hospital, Southampton, SO16 6YD, UK., Packham G; Protein Core Facility and Cancer Sciences, Cancer Research UK Centre and Experimental Cancer Medicines Centre University of Southampton Southampton General Hospital, Southampton, SO16 6YD, UK., Ganesan A; School of Pharmacy, University of East Anglia, Norwich, NR4 7TJ, UK.
Jazyk: angličtina
Zdroj: ChemMedChem [ChemMedChem] 2021 Apr 20; Vol. 16 (8), pp. 1316-1324. Date of Electronic Publication: 2021 Feb 03.
DOI: 10.1002/cmdc.202000754
Abstrakt: Lysine-specific demethylase 1 (LSD1/KDM1A) oxidatively removes methyl groups from histone proteins, and its aberrant activity has been correlated with cancers including acute myeloid leukemia (AML). We report a novel series of tranylcypromine analogues with a carboxamide at the 4-position of the aryl ring. These compounds, such as 5 a and 5 b with benzyl and phenethylamide substituents, respectively, had potent sub-micromolar IC 50 values for the inhibition of LSD1 as well as cell proliferation in a panel of AML cell lines. The dose-dependent increase in cellular expression levels of H3K4me2, CD86, CD11b and CD14 supported a mechanism involving LSD1 inhibition. The tert-butyl and ethyl carbamate derivatives of these tranylcypromines, although inactive in LSD1 inhibition, were of similar potency in cell-based assays with a more rapid onset of action. This suggests that carbamates can act as metabolically labile tranylcypromine prodrugs with superior pharmacokinetics.
(© 2021 Wiley-VCH GmbH.)
Databáze: MEDLINE
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