Synthesis of sulfated neoglycopolymers: Selective P-selectin inhibitors
Synthesis of sulfated neoglycopolymers: Selective P-selectin inhibitors
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DOI：
10.1021/ja964046x
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发表时间：
1997-04-02
影响因子：
15
通讯作者：
Kiessling, LL
中科院分区：
文献类型：
--
作者：
Manning, DD;Hu, X;Kiessling, LL
硫酸化糖介导重要的生理过程。例如，促进白细胞运输至炎症部位的 L-和 P-选择素蛋白可识别硫酸化碳水化合物残基。 1, 2 几种密集 O-糖基化蛋白，包括 PSGL-1、CD34 和 GlyCAM-1，已被鉴定为高亲和力、含硫酸盐选择素配体。 3 具有这些天然存在的糖阵列特征的分子可用于调节或促进受天然碳水化合物决定因素影响的生理过程。生成这些配体的结构类似物是一个重大挑战：糖表位不仅充满官能团，而且以多价展示形式展示。 4 我们报告了一种合成配体的策略，该配体呈现多个拷贝的硫酸化碳水化合物决定簇，并应用该策略来创建高亲和力选择性 P-选择素抑制剂。我们对碳水化合物硫酸化在选择素识别中的作用的研究推动了生成显示多个硫酸化糖残基的材料。 5, 6 对于单价糖衍生物，特定位置的硫酸化可以微妙地改变特定配体的选择素结合特性。在凝集素刀豆球蛋白 A 的研究中，当相互作用是多价时，单价糖配体的蛋白质结合特异性的微小变化被放大。 7 如果选择素-碳水化合物相互作用受益于多价结合，则假设可以通过展示特定硫酸化碳水化合物残基的多个拷贝来生成高亲和力、选择性选择素配体。 8 通过开环复分解聚合 (ROMP) 合成了多价糖衍生物，并生成了刀豆球蛋白 A 的有效特异性配体。 7 该方法应用于选择素配体的合成将提供解决多价结合在选择素碳水化合物相互作用中的作用的方法。然而，目标选择素配体具有阴离子硫酸盐取代基，并且具有硫酸盐基团的单体的ROMP是未知的。因此，我们合成了带有硫酸化糖残基的单体，以开发这些底物 ROMP 的有效方案。我们的目标单体基于两种天然存在的含硫酸盐配体，它们结合 P-和 L-选择素、糖脂硫苷脂、9、10 和糖蛋白 GlyCAM-1。 11 硫苷脂和 GlyCAM-1 都可以作为多齿配体。例如，脑硫苷脂可以聚集形成胶束，这是可能的选择素结合物质。 GlyCAM-1 是一种粘蛋白，显示多个拷贝的硫酸化碳水化合物决定簇，包括 6′-磺基唾液酸 Lewis x [6′-磺基 sLex: NeuNAcR2 f 3 (6-O-SO3) Galβ1 f 4 (FucR1 f 3) GlcNAc]。 12 在设计选择素配体时，我们试图通过提供多个拷贝的 3-硫酸化半乳糖（其糖取代基）来模拟硫苷脂。为了模拟决定簇 6'-磺基 sLex、GlyCAM-1 的电荷分布，我们的计划是生成带有 3, 6-二磺基半乳糖残基的多价寡聚物。硫酸化糖通过异头连接体连接至降冰片烯或 7-氧杂降冰片烯支架（方案 1）。此类衍生物的 ROMP 将提供线性聚合物，该聚合物显示糖残基，每个重复单元的密度为 1 个表位。尽管聚合物内糖类的线性展示模仿硫苷脂胶束的一些特征，但这些底物的不同之处在于新糖聚合物的糖类决定簇无法显着重组。这种呈现方式和高...
Sulfated saccharides mediate important physiological processes. For example, the proteins L-and P-selectin, which facilitate leukocyte trafficking to sites of inflammation, recognize sulfated carbohydrate residues. 1, 2 Several densely O-glycosylated proteins, including PSGL-1, CD34, and GlyCAM-1, have been identified as high affinity, sulfate-containing selectin ligands. 3 Molecules that share the features of these naturallyoccurring saccharide arrays could be used to modulate or promote physiological processes effected by the natural carbohydrate determinants. Generating structural analogs of these ligands is a significant challenge: not only are the saccharide epitopes replete with functional groups but they are exhibited in multivalent displays. 4 We report a strategy for the synthesis of ligands that present multiple copies of sulfated carbohydrate determinants and the application of this strategy to the creation of high affinity selective inhibitors of P-selectin. Impetus to generate materials displaying multiple sulfated saccharide residues arose from our investigations of the role of carbohydrate sulfation in selectin recognition. 5, 6 For monovalent saccharide derivatives, sulfation at a specific position can subtly alter the selectin-binding properties of a particular ligand. In studies with the lectin concanavalin A, small changes in the protein binding specificity of monovalent saccharide ligands were amplified when the interactions were multivalent. 7 If selectin-carbohydrate interactions benefit from multivalent binding, it was hypothesized that high-affinity, selective selectin ligands could be generated by displaying multiple copies of particular sulfated carbohydrate residues. 8 Multivalent saccharide derivatives have been synthesized by the ring-opening metathesis polymerization (ROMP), and potent, specific ligands for concanavalin A have been generated. 7 The application of this method to the synthesis of selectin ligands would provide the means to address the role of multivalent binding in selectincarbohydrate interactions. The target selectin ligands, however, possess anionic sulfate substituents, and ROMP of monomers with sulfate groups is unknown. Therefore, we synthesized monomers bearing sulfated saccharide residues to develop an effective protocol for ROMP of these substrates. Our target monomers were based on two naturally-occurring sulfate-containing ligands that bind P-and L-selectin, glycolipid sulfatides, 9, 10 and the glycoprotein GlyCAM-1. 11 Both sulfatides and GlyCAM-1 can function as multidentate ligands. For example, sulfatides can aggregate to form micelles, which are the likely selectin-binding species. GlyCAM-1 is a mucin that displays multiple copies of sulfated carbohydrate determinants, including 6′-sulfo sialyl Lewis x [6′-sulfo sLex: NeuNAcR2 f 3 (6-O-SO3) Galβ1 f 4 (FucR1 f 3) GlcNAc]. 12 In designing selectin ligands, we sought to imitate the sulfatides by presenting multiple copies of 3-sulfated galactose, their saccharide substituent. To mimic the charge distribution of the determinant 6′-sulfo sLex, GlyCAM-1, our plan was to generate multivalent oligomers bearing 3, 6-disulfo galactose residues. The sulfated saccharides were attached through an anomeric linker to either a norbornene or 7-oxanorbornene scaffold (Scheme 1). ROMP of such derivatives will afford linear polymers that display saccharide residues with a density of 1 epitope per repeat unit. Although the linear display of saccharides within the polymers mimics some features of sulfatide micelles, these substrates differ in that saccharide determinants of the neoglycopolymers are unable to reorganize dramatically. This mode of presentation and the high …