EZH2甲基转移酶抑制剂的设计、合成及甲基化抑制活性

Design, synthesis and methylation inhibitory activity of EZH2 methyltransferase inhibitors

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种DCE-254类似物。以4-氯乙酰乙酸乙酯和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种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% 结果优于DCE-254。

Abstract:

Abstract: Molecular docking of 2-[(6-methoxyquinazolin-2-yl)amino]-6-{[(1-phenyl-1H-tetrazol-5-yl)thio]methyl}pyrimidin-4-(3H)-one (DCE-254) was carried out and 14 analogues were designed and synthesized. Analogues Ⅴa~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 and 1HNMR. Five kinds of DCE-254 analogues with strong methylation inhibition were obtained by the radioactive methylation inhibition assay of H3K27me. Among them, 1-(2-methoxy-5-methylphenyl)-3-(6-oxo-4-{[(1-phenyl-1H-tetrazol-5-yl)thio]methyl}-1,6-dihydropyrimidin-2-ylthiourea (Ⅵf) showed the most active, and the inhibition rate was 77%, which was better than that of DCE-254. Key words: EZH2 methyltransferase; methylation inhibitor; antitumor activities; drug and cosmetic materials