Department of Chemical Biology and Drug Discovery, Utrecht Institute for Pharmaceutical Sciences, and Bijvoet Center for Biomolecular Research, Utrecht University, Universiteitsweg 99, 3584 CG Utrecht, The Netherlands.
Complex Carbohydrate Research Center, University of Georgia, Athens, Georgia 30602, United States.
J Org Chem. 2020 Dec 18;85(24):16082-16098. doi: 10.1021/acs.joc.0c01881. Epub 2020 Oct 14.
Heparan sulfates are structurally diverse sulfated polysaccharides that reside at the surface of all animal cells where they can interact with a multitude of proteins, thereby modulating a wide range of physiological and disease processes. We describe here a modular synthetic methodology that can provide libraries of heparan sulfate oligosaccharides that have glucosamine residues modified by different patterns of -acetyl and -sulfate moieties. It is based on the use of glycosyl donors that are modified at C2 by an azido- or trifluoromethylphenyl-methanimine moiety, which allowed the selective installation of α-glycosides. The amino protecting groups can be selectively unmasked by a reduction or acid treatment, allowing the installation of -acetyl and -sulfate moieties, respectively. In combination with the orthogonal hydroxyl protecting groups levulinic (Lev) ester, thexyldimethylsilyl (TDS) ether, allyloxycarbonate (Alloc), and 9-fluorenylmethyl carbonate (Fmoc), different patterns of -sulfation can be installed. The methodology was applied to prepare four hexasaccharides that differ in the pattern of - and -sulfation. These compounds, together with a number of previously prepared HS oligosaccharides, were printed as a glycan microarray to examine the binding selectivities of several HS-binding proteins.
硫酸乙酰肝素是结构多样的硫酸化多糖，位于所有动物细胞的表面，可与多种蛋白质相互作用，从而调节多种生理和疾病过程。我们在此描述了一种模块化的合成方法，可提供具有不同乙酰基和硫酸基修饰模式的硫酸乙酰肝素寡糖文库。它基于使用在 C2 位被叠氮基或三氟甲基苯甲亚胺部分修饰的糖基供体，这允许选择性地安装α-糖苷。氨基保护基团可以通过还原或酸处理选择性地去保护，分别允许安装乙酰基和硫酸基。与正交羟基保护基乙酰基（Lev）酯、四氢呋喃基二甲基硅基（TDS）醚、烯丙氧基羰基（Alloc）和 9-芴基甲氧基羰基（Fmoc）结合使用，可以安装不同模式的硫酸化。该方法已应用于制备在和硫酸化模式上不同的四个六糖。这些化合物与许多先前制备的 HS 寡糖一起被打印成糖芯片，以检查几种 HS 结合蛋白的结合选择性。
