2′,6′-Dihalostyrylanilines, Pyridines, and Pyrimidines for the Inhibition of the Catalytic Subunit of Methionine S-Adenosyltransferase-2
作者:Vitaliy M. Sviripa、Wen Zhang、Andrii G. Balia、Oleg V. Tsodikov、Justin R. Nickell、Florence Gizard、Tianxin Yu、Eun Y. Lee、Linda P. Dwoskin、Chunming Liu、David S. Watt
DOI:10.1021/jm5004864
日期:2014.7.24
group attached in a para orientation relative to the 2,6-dihalostyryl subunit, and (3) either an N-methylaniline or a 2-(N,N-dimethylamino)pyridine ring. These modifications led to FIDAS agents that were active in the low nanomolar range, that formed water-soluble hydrochloride salts, and that possessed the desired property of not inhibiting the human hERG potassium ion channel at concentrations at which
用氟化N,N-二烷基氨基芪(FIDAS 试剂)抑制异二聚体甲硫氨酸 S-腺苷转移酶-2 (MAT2A) 的催化亚基为治疗肝癌和结直肠癌提供了潜在的途径,其中发生了这种酶的上调。对结构-活性关系的研究导致鉴定出活性最强的化合物为 (1) 2,6-二氟苯乙烯基或 2-氯-6-氟苯乙烯基亚基,(2) N-甲氨基或N,N-二甲氨基以相对于 2,6-二卤代苯乙烯亚基的对位方向连接,和 (3) N-甲基苯胺或 2-( N ,N-二甲氨基)吡啶环。这些修饰导致 FIDAS 试剂在低纳摩尔范围内具有活性,形成水溶性盐酸盐,并且在 FIDAS 试剂抑制 MAT2A 的浓度下具有不抑制人 hERG 钾离子通道的所需特性。活性 FIDAS 试剂可以通过改变对癌细胞存活和生长必不可少的甲基化反应来抑制癌细胞。