Amide-1,2,3-triazole bioisosterism: the glycogen phosphorylase case
Amide-1,2,3-triazole bioisosterism: the glycogen phosphorylase case
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DOI：
10.1016/j.tetasy.2009.03.021
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发表时间：
2009-05-07
影响因子：
--
通讯作者：
Laszlo, Somsak
中科院分区：
文献类型：
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作者：
Chrysina, Evangelia D.;Bokor, Eva;Laszlo, Somsak
全-O-乙酰化的β-D-吡喃葡萄糖基叠氮化物通过PMe 3转化为中间体亚氨基膦，然后酰化为N-酰基-β-D-吡喃葡萄糖胺。在Cu（I）催化的叠氮化物-炔环加成反应中，相同的叠氮化物和取代的乙炔得到1-（β-D-吡喃葡萄糖基）-4-取代的-1，2，3-三唑。通过Zemplen方法将这些产物脱保护，得到β-D-Glc（p）-NHCO-R衍生物以及1-（β-D-Glc（p））-4-R-1，2，3-三唑，它们被评价为兔肌糖原磷酸化酶B的抑制剂。对酰胺与三唑具有相同的R基团显示出相似的抑制常数。对酶抑制剂复合物的X射线晶体学研究显示，与R = 2-萘基和羟甲基的结合对具有高度相似性，而对于R = Ph和1-萘基化合物，观察到芳香部分的不同取向和280 s环构象的变化。本研究提供了酰胺-1，2，3-三唑生物电子等排关系的新实例。(C)2009爱思唯尔有限公司保留所有权利。
Per-O-acetylated beta-D-glucopyranosyl azide was transformed into an intermediate iminophosphorane by PMe3 which was then acylated to N-acyl-beta-D-glucopyranosylamines. The same azide and substituted acetylenes gave 1-(beta-D-glucopyranosyl)-4-substituted-1,2,3-triazoles in Cu(I)-catalyzed azide-alkyne cycloadditions. Deprotection of these products by the Zemplen method furnished beta-D-Glc(p)-NHCO-R derivatives as well as 1-(beta-D-Glc(p))-4-R-1,2,3-triazoles which were evaluated as inhibitors of rabbit muscle glycogen phosphorylase b. Pairs of amides versus triazoles with the same R group displayed similar inhibition constants. X-ray crystallographic studies on the enzyme-inhibitor complexes revealed high similarities in the binding of pairs with R = 2-naphthyl and hydroxymethyl, while for the R = Ph and 1-naphthyl compounds a different orientation of the aromatic part and changes in the conformation of the 280s loop were observed. By this study new examples of amide-1,2,3-triazole bioisosteric relationship have been provided. (C) 2009 Elsevier Ltd. All rights reserved.