The Multivalent Effect in Glycosidase Inhibition: Probing the Influence of Architectural Parameters with Cyclodextrin-based Iminosugar Click Clusters
The Multivalent Effect in Glycosidase Inhibition: Probing the Influence of Architectural Parameters with Cyclodextrin-based Iminosugar Click Clusters
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DOI：
10.1002/chem.201102266
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发表时间：
2011-12-01
影响因子：
4.3
通讯作者：
Compain, Philippe
中科院分区：
文献类型：
--
作者：
Decroocq, Camille;Rodriguez-Lucena, David;Compain, Philippe
与大多数凝集素相反，葡糖苷酶可能似乎是多价结合的无希望的靶点，因为它们仅显示单个活性位点。为了探索多价对糖苷酶抑制的潜力，已经设计和制备了前所未有的基于环糊精的亚氨基糖缀合物。在微波活化下，炔丙基化多价β-环糊精与叠氮臂N-烷基1-脱氧野尻霉素衍生物之间通过CuI催化的叠氮炔环加成反应进行合成。用一组糖苷酶对这类新的拟糖簇进行的评估揭示了迄今为止观察到的多价糖苷酶抑制剂的最强亲和力增强，结合增强超过α-甘露糖苷酶的相应单价配体高达四个数量级。这些结果表明，多价概念延伸到碳水化合物识别过程以外的糖模拟酶抑制。
In contrast to most lectins, glycosidases may appear to be unpromising targets for multivalent binding because they display only a single active site. To explore the potential of multivalency on glycosidase inhibition, unprecedented cyclodextrin-based iminosugar conjugates have been designed and prepared. The synthesis was performed by way of CuI-catalyzed azidealkyne cycloaddition reaction under microwave activation between propargylated multivalent beta-cyclodextrins and an azide-armed N-alkyl 1-deoxynojirimycin derivative. Evaluation with a panel of glycosidases of this new class of glycomimetic clusters revealed the strongest affinity enhancement observed to date for a multivalent glycosidase inhibitor, with binding enhancement up to four orders of magnitude over the corresponding monovalent ligand for a-mannosidase. These results demonstrate that the multivalency concept extends beyond carbohydratelectin recognition processes to glycomimeticenzyme inhibition.