Design and Synthesis of Hydrolytically Stable Multivalent Ligands Bearing Thiodigalactoside Analogues for Peanut Lectin and Human Galectin-3 Binding
Design and Synthesis of Hydrolytically Stable Multivalent Ligands Bearing Thiodigalactoside Analogues for Peanut Lectin and Human Galectin-3 Binding
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DOI：
10.1021/jo500883v
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发表时间：
2014-07-18
影响因子：
3.6
通讯作者：
Uhrig, Maria Laura
中科院分区：
文献类型：
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作者：
Cagnoni, Alejandro J.;Kovensky, Jose;Uhrig, Maria Laura
在这里，我们描述了一个新的家庭的水解稳定的糖簇轴承硫代二半乳糖苷（TDG）类似物的β-半乳糖苷结合凝集素的识别元素的设计和合成。TDG类似物通过6-S-乙酰基-α-D-葡萄糖基溴与2，3，4，6-四-O-乙酰基-β-D-半乳糖的异硫脲鎓盐的巯基糖基化合成。TDG类似物的进一步炔丙基化允许在微波活化下通过铜（I）催化的叠氮化物-炔环加成（CuAAC）偶联到叠氮基官能化的寡糖支架。最终的单价、二价和四价配体对大肠杆菌β-半乳糖苷酶的酶水解具有抗性。花生凝集素和人半乳糖凝集素-3的结合亲和力进行了测定，等温滴定量热法，其中示出的K-a常数在微摩尔范围内，以及多价效应。单价配体表现出比硫代二半乳糖苷更高的结合亲和力。用模型配体对两种β-半乳糖苷结合凝集素进行的对接研究表明，三唑环和凝集素氨基酸残基之间存在额外的相互作用，表明该芳香族残基对生物活性具有积极作用。
Herein, we describe the design and synthesis of a novel family of hydrolytically stable glycoclusters bearing thiodigalactoside (TDG) analogues as recognition elements of beta-galactoside binding lectins. The TDG analogue was synthesized by thioglycosylation of a 6-S-acetyl-alpha-D-glucosyl bromide with the isothiouronium salt of 2,3,4,6-tetra-O-acetyl-beta-D-galactose. Further propargylation of the TDG analogue allowed the coupling to azido-functionalized oligosaccharide scaffolds through copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) under microwave activation. The final mono-, di-, and tetravalent ligands were resistant to enzymatic hydrolisis by Escherichia coli beta-galactosidase. Binding affinities to peanut agglutinin and human galectin-3 were measured by isothermal titration calorimetry which showed K-a constants in the micromolar range as well as a multivalent effect. Monovalent ligand exhibited a binding affinity higher than that of thiodigalactoside. Docking studies performed with a model ligand on both beta-galactoside binding lectins showed additional interactions between the triazole ring and lectin amino acid residues, suggesting a positive effect of this aromatic residue on the biological activity.