含杂环的曲马普汀衍生物具有高 LSD1 抑制活性。
Heterocycle-containing tranylcypromine derivatives endowed with high anti-LSD1 activity.
机构信息
Department of Drug Chemistry and Technologies, Sapienza University of Rome, Rome, Italy. Laboratory affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti.
Department of Biology and Biotechnology, University of Pavia, Pavia, Italy.
出版信息
J Enzyme Inhib Med Chem. 2022 Dec;37(1):973-985. doi: 10.1080/14756366.2022.2052869.
As regioisomers/bioisosteres of , a 4-phenylbenzamide tranylcypromine (TCP) derivative previously disclosed by us, we report here the synthesis and biological evaluation of some (hetero)arylbenzoylamino TCP derivatives -, in which the 4-phenyl moiety of 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 derivatives were more effective than the analogues, with the thienyl analogs and being the most potent (IC 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 , , , , and 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.
作为我们之前披露的 4-苯基苯甲酰胺反苯环丙胺（TCP）衍生物的区域异构体/生物等排体，我们在此报告一些（杂）芳基苯甲酰氨基 TCP 衍生物 - 的合成和生物学评价，其中 4-苯基部分被转移到苯甲酰胺 C3 位置或被 2-或 3-呋喃基、2-或 3-噻吩基或 4-吡啶基取代，均位于苯甲酰胺 C4 或 C3 位置。在 LSD1-CoREST 测定中，所有的 衍生物均比 类似物更有效，其中噻吩类似物 和 最为有效（IC 值 = 0.015 和 0.005 μM），对 MAO-B 的选择性也最高（选择性指数：24.4 和 164）。在 U937 AML 和前列腺癌 LNCaP 细胞中进行测试时，选定的化合物 、 、 、 和 主要在 LNCaP 细胞中显示出细胞生长停滞。Western blot 分析显示 H3K4me2 和/或 H3K9me2 水平升高，证实 LSD1 抑制参与了这些测定。
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