CIHIDECAR-CONICET, Departamento de Química Orgánica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina.
J Org Chem. 2011 May 6;76(9):3064-77. doi: 10.1021/jo102421e. Epub 2011 Apr 8.
The synthesis of multivalent glycoclusters, designed to be compatible with biological systems, is reported. A variety of 1-thio-β-D-galactosides linked to a terminal triple bond through oligoethyleneglycol chains of variable lengths has been synthesized. Also, azide-containing oligosaccharide scaffolds were prepared from trehalose, maltose, and maltotriose by direct azidation with NaN(3)/PPh(3)/CBr(4). Click reaction between the thiogalactoside residues and the azide scaffolds under microwave irradiation afforded a family of glycoclusters containing 1 to 4 residues of 1-thio-β-D-galactose. The yields went from moderate to excellent, depending on the valency of the desired product. Deacetylation with Et(3)N/MeOH/H(2)O led to the final products. Complete characterization of the products was performed by NMR spectroscopy and HR-MS techniques. Their activities as inhibitors of β-galactosidase from E. coli were determined by using the Lineweaver-Burk method. The use of hydrophilic carbohydrate scaffolds for the synthesis of multivalent galactosides represents an interesting approach to improve their pharmacokinetics and bioavailability. In addition, the presence of the thioglycosidic bond will improve their stability in biological fluids.
报道了一种设计成与生物系统兼容的多价糖簇的合成方法。通过寡乙二醇链将各种 1-硫代-β-D-半乳糖苷连接到末端三键上，寡乙二醇链的长度可变。此外，还通过 NaN(3)/PPh(3)/CBr(4)直接氮化作用，从海藻糖、麦芽糖和麦芽三糖制备了含有叠氮化物的寡糖支架。在微波辐射下，硫代半乳糖苷残基与叠氮化物支架之间的点击反应得到了一系列含有 1 至 4 个 1-硫代-β-D-半乳糖残基的糖簇。根据所需产物的价数，产率从中等到优异不等。用 Et(3)N/MeOH/H(2)O 脱乙酰化得到最终产物。通过 NMR 光谱和高分辨率质谱技术对产物进行了完全表征。通过 Lineweaver-Burk 法测定了它们作为大肠杆菌β-半乳糖苷酶抑制剂的活性。使用亲水糖支架合成多价半乳糖苷代表了一种提高其药代动力学和生物利用度的有趣方法。此外，硫糖苷键的存在将提高它们在生物流体中的稳定性。
