EZH2甲基转移酶抑制剂的设计、合成及其抑制活性  

Synthesis and methylation inhibitory activity of EZH2 methyltransferase inhibitors

作　　者：张晓攀 姚志艺 ZHANG Xiaopan;YAO Zhiyi(School of Chemical and Environmental Engineering,Shanghai Institute of Technology,Shanghai 201418,Shanghai,China)

机构地区：[1]上海应用技术大学化学与环境工程学院,上海201418

出　　处：《精细化工》2020年第10期2083-2089,共7页Fine Chemicals

基　　金：国家自然科学基金(21472208)。

摘　　要：对2-(3-甲基-6-甲氧基喹唑啉-2-氨基)-6-(1-苯基-1H-四唑-5-硫甲基)-4-嘧啶酮(DCE-254)进行了分子对接,设计、合成了14个DCE-254类似物。以4-氯乙酰乙酸乙酯、1-苯基-5-巯基四氮唑、盐酸胍、取代苯甲酰氯、取代异硫氰酸酯等为原料,合成了这些类似物Ⅴa~Ⅵh。采用MS、1HNMR和13CNMR对这些类似物的结构进行了表征。H3K27me放射性甲基化抑制测试得到了5个具有较强甲基化抑制作用的DCE-254类似物,活性最好的是N-[4-羟基-6-(1-苯基-1H-四氮唑-5-硫甲基)-2-嘧啶]-N′-2-甲氧基-5-甲基苯基硫脲(Ⅵf),其甲基化抑制率达到77%,优于DCE-254的70%。Molecular docking of 2-[(6-methoxyquinazolin-2-yl)amino]-6-{[(1-phenyl-1 H-tetrazol-5-yl)thio]methyl}pyrimidin-4-(3 H)-one(DCE-254)was carried out and 14 analogues were designed and synthesized.AnaloguesⅤa~Ⅵh were synthesized using ethyl 4-chloroacetoacetate and 1-phenyl-5-mercaptotetrazole,guanidine hydrochloride,substituted benzoyl chloride and substituted isothiocyanate and so on as raw materials.These compounds were characterized by MS,1 HNMR and 13 CNMR.Five kinds of DCE-254 analogues with strong methylation inhibition were obtained by the radioactive methylation inhibition assay of H3 K27 me.Among them,1-(2-methoxy-5-methylphenyl)-3-{6-oxo-4-[(1-phenyl-1 H-tetrazol-5-yl)thio]methyl}-1,6-dihydropyrimidin-2-ylthiourea(Ⅵf)showed the most active,and the methylation inhibition rate was 77%,which was better than that of DCE-254(70%).

关 键 词：EZH2甲基转移酶 甲基化抑制剂 抗肿瘤活性 医药原料 

分 类 号：TQ464.8[化学工程—制药化工]