SYNTHESIS OF STABLE GALACTO DISACCHARIDE MIMETICS

稳定半乳糖二糖模拟物的合成

• 批准号: 6363290
• 负责人: DAVID R. MOOTOO
• 金额: $ 27.9万
• 依托单位: HUNTER COLLEGE
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-03-01 至 2003-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6363290
• 关键词: carbohydrate analog; chemical synthesis; cyclic compound; cycloalkene; disaccharides; galactose; glycosides; glycosylphosphatidylinositols; ketal; stereochemistry

There is considerable interest in molecules which mimic carbohydrates involved in mechanisms associated with health disorders. Carbohydratees analogs in which the exocyclic or endocyclic acetal oxygen is replaced by a methylene, C-glycoside or carbasugar respectively have attracted interest. These molecules are expected to have similar conformational and steric properties, and therefore similar ligating characteristics as the natural O-saccharide. Importantly, they are not glycosides and therefore will be stable to glycosyl processing enzymes and to chemical hydrolysis. They are potentially useful as therapeutic agents or tools for biochemical research. This project deals with new methodology for the synthesis of three groups of glycomimetics: C-glycosides and carbasugars of Galbeta glycosides, and C-glycosides of glycophospatidyl (GPI) subunits. The specific aims are: (I) C-glycosides which are potential Iselectin ligands and could provide the basis for the design of novel, hydrolytically, stable anti-inflammatory agents. (II) C-Glycosides and carbasugars of Gal-beta-disaccharides, which are substrates for preparation of stable complexes with glycosyl processing enzymes and may have inhibitory properties. (III) C-glycoside analogs of GPI components, which are relevant to the investigation of GPI related processes, such as survival mechanisms in parasitic protozoa and signal transduction related to insulin action. The synthetic strategy centers on novel chemistry of thio- isopropylidinated acetals (TIA's). The method is well suited for making disaccharide mimetics, although it may be just as easily applied to monosaccharide structures. The concept for making disaccharide analogs involves the initial linking of a cyclic sugar derivative to a TIA synthon. Subsequently, the second ring is formed by an oxocarbenium ion-alkene cyclization to give a dihydropyran or cyclohexene derivative, depending on the choice of the TIA fragment used. Stereoselective functionalization of the alkene leads to the targeted glycomimetics. This strategy provides solutions to the problems of coupling efficiency and stereoselectivity which limit the direct connection of two intact cyclic sugar derivatives.

人们对模仿碳水化合物的分子非常感兴趣 参与与健康障碍相关的机制。 碳水化合物 环外或环内缩醛氧被取代的类似物 分别被亚甲基、C-糖苷或卡巴糖吸引 兴趣。 这些分子预计具有相似的构象 和空间特性，因此具有相似的连接特性 作为天然O-糖。 重要的是，它们不是糖苷， 因此对糖基加工酶和化学物质是稳定的 水解。 它们可能用作治疗剂或工具 用于生化研究。 该项目涉及合成三种物质的新方法 糖模拟物组：Galbeta 的 C-糖苷和卡巴糖 糖苷和糖磷脂酰 (GPI) 亚基的 C-糖苷。 这 具体目标是： (I) C-糖苷，是潜在的 Iselectin 配体并可以为设计新颖的、 水解、稳定的抗炎剂。 (II) C-糖苷和 Gal-β-二糖的碳糖，是 与糖基加工酶制备稳定的复合物，并且可以 具有抑制特性。 (III) GPI的C-糖苷类似物 与 GPI 相关调查相关的组件 过程，例如寄生原生动物的生存机制和信号 与胰岛素作用相关的转导。 合成策略以硫代的新型化学为中心 异丙胺缩醛（TIA）。 该方法非常适合制作 二糖模拟物，尽管它可能同样容易应用于 单糖结构。 制造二糖类似物的概念 涉及环糖衍生物与 TIA 的初始连接 合成子。 随后，第二个环由氧碳鎓形成 离子-烯烃环化得到二氢吡喃或环己烯衍生物， 取决于所使用的 TIA 片段的选择。 立体选择性 烯烃的功能化产生了目标糖模拟物。 该策略为耦合效率问题提供了解决方案 和立体选择性限制了两个完整的直接连接 环糖衍生物。