A new methodology for the synthesis of fluorinated exo-glycals and their time-dependent inhibition of UDP-galactopyranose mutase
A new methodology for the synthesis of fluorinated exo-glycals and their time-dependent inhibition of UDP-galactopyranose mutase
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DOI：
10.1002/chem.200500991
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发表时间：
2006-04-03
影响因子：
4.3
通讯作者：
Vincent, SP
中科院分区：
文献类型：
--
作者：
Caravano, A;Dohi, H;Vincent, SP
含氟碳水化合物是一类重要的糖基加工酶的机理探针。在这项研究中，我们描述了第一个合成的氟化和膦酰化的exo-glycals和它们相应的核苷酸糖的半乳糖呋喃糖系列。我们已经开发的合成方案是在膦酰化外糖上的Selectfluor介导的消除/消除序列，并且它提供了氟化碳水化合物化学的新入口。具有挑战性的E/Z立体化学分配所产生的四取代的烯烃，其中带有烷氧基，烷基，氟，和膦酰基，已通过NMR实验实现。已经制备了相应的（E）-和（Z）-核苷酸氟糖，并测试了其作为UDP-吡喃半乳糖苷酶（UGM）的抑制剂。UGM是一种黄素酶，催化尿苷二磷酸（UDP）-吡喃半乳糖异构化为UDP-呋喃半乳糖，这是重要的分枝杆菌细胞壁糖缀合物生物合成的关键步骤。发现两种非对映体分子显示UGM的时间依赖性失活，如使用非氟化外糖核苷酸的初步结果所预期的。两个氟化分子的抑制特性使我们认为，尽管存在的黄素辅因子内的UGM催化位点的失活机制通过两个电子过程进行。
Fluorinated carbohydrates constitute a very important class of mechanistic probes for glycosyl-processing enzymes. In this study, we describe the first synthesis of fluorinated and phosphonylated exo-glycals and their corresponding nucleotide sugars in the galactofuranose series. The synthetic protocol that we have developed is a Selectfluor-mediated fluorination/elimination sequence on phosphonylated exo-glycals, and it offers a new entry into fluorinated carbohydrate chemistry. The challenging E/Z stereochemical assignment of the resulting tetra-substituted alkenes, which bear an alkoxy, an alkyl, a fluoro, and a phosphonyl group, has been achieved through NMR experiments. The corresponding (E)- and (Z)-nucleotide fluorosugars have been prepared and tested as inhibitors of UDP-galactopyranose mutase (UGM). UGM is a flavoenzyme that catalyzes the isomerization of uridine diphosphate(UDP)-galactopyranose into UDP-galactofuranose, a key step of the biosynthesis of important mycobacterial cell-wall glycoconjugates. The two diastereomeric molecules were found to display time-dependent inactivation of UGM, as expected from preliminary results using non-fluorinated exo-glycal nucleotides. The inhibitory properties of the two fluorinated molecules led us to suggest that the inactivation mechanism proceeds through two-electron processes, despite the presence of the flavin cofactor within the UGM catalytic site.