School of Pharmacy, University of East Anglia, Norwich, NR4 7TJ, UK.
Norwich Medical School, University of East Anglia, Norwich, NR4 7TJ, UK.
ChemMedChem. 2021 Apr 20;16(8):1316-1324. doi: 10.1002/cmdc.202000754. Epub 2021 Feb 3.
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 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.
赖氨酸特异性脱甲基酶 1（LSD1/KDM1A）氧化去除组蛋白上的甲基，其异常活性与包括急性髓细胞性白血病（AML）在内的多种癌症相关。我们报告了一系列新型反苯环丙胺类似物，其芳环的 4 位带有酰胺基。这些化合物，如分别带有苄基和苯乙酰胺取代基的 5a 和 5b，对 LSD1 的抑制作用以及一系列 AML 细胞系的细胞增殖具有强效的亚微摩尔 IC 值。细胞内 H3K4me2、CD86、CD11b 和 CD14 的表达水平呈剂量依赖性增加，支持 LSD1 抑制的作用机制。这些反苯环丙胺的叔丁基和乙基氨基甲酸酯衍生物尽管在 LSD1 抑制方面没有活性，但在基于细胞的测定中具有相似的效力，且作用更快。这表明氨基甲酸酯可以作为代谢不稳定的反苯环丙胺前药，具有更好的药代动力学特性。
