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首页> 外文期刊>European Journal of Medicinal Chemistry: Chimie Therapeutique >Synthesis of aryl phosphates based on pyrimidine and triazine scaffolds.
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Synthesis of aryl phosphates based on pyrimidine and triazine scaffolds.

机译：基于嘧啶和三嗪支架的芳基磷酸酯的合成。

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摘要

The syntheses of the triazinyl-based bis-aryl phosphates 2 and 3, and of the aminopyrimidyl-based aryl phosphate 4 are described. Each compound contains a diaryl ether-phosphate structural motif. The synthetic route to bis-aryl phosphates 2 and 3 consisted in two nucleophilic substitution reactions with amines from cyanuric chloride, followed by a Suzuki coupling with the resulting 2,4-diamino-6-chloro-1,3,5-triazine derivative 12 to introduce the diaryl ether functionality. Aryl phosphate 4 was obtained via condensation of aryl guanidine 34 with aryloxyphenyl butenone 31. These de novo-designed aryl phosphates were evaluated as potential inhibitors of the Grb2-SH2 domain using an ELISA assay. The water-soluble sodium salt 26 of 3 gave an IC(50) value in the high micromolar range. Molecular modeling studies were subsequently performed upon modifying the 1,3,5-trisubstituted triazine scaffold of 3. Non-phosphate derivatives encompassing cyclopropane, pyrrole, keto-acid, and IZD fragments were thus step-wise designed and their Grb2-SH2 complexes were modeled by molecular dynamics. Some derivatives gave rise to an enriched pattern of H-bonds and cation-pi interactions with Grb2-SH2.
机译：描述了三嗪基双芳基磷酸酯2和3的合成以及氨基嘧啶基磷酸芳基磷酸芳基4.每种化合物含有二芳基醚 - 磷酸酯结构基序。双 - 芳基磷酸酯2和3的合成途径由来自氰尿嘧啶的胺的两种亲核取代反应组成，然后用由所得2,4-氨基-6-氯-1,3,5-三嗪衍生物12的铃木偶联。介绍二芳基醚功能。通过芳基胍34与芳基氧基苯基丁酮31的缩合获得芳基磷酸芳基4.这些DE Novo-设计的芳基磷酸酯使用ELISA测定评价为GRB2-SH2结构域的潜在抑制剂。水溶性钠盐26的3含量为高微摩尔范围内的IC（50）值。随后进行分子建模研究，在改变3.包含环丙烷，吡咯，酮酸和IZD片段的非磷酸衍生物的1,3,5-三取代的三嗪支架上进行。因此，设计了逐步设计，并且它们的GRB2-SH2络合物是由分子动力学建模。一些衍生物产生与GRB2-SH2的H键和阳离子-PI相互作用的富集模式。

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