SYNTHESIS OF STABLE GALACTO DISACCHARIDE MIMETICS

稳定半乳糖二糖模拟物的合成

• 批准号: 6519902
• 负责人: DAVID R. MOOTOO
• 金额: $ 28.49万
• 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 2003-06-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6519902
• 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.

人们对模拟碳水化合物的分子很感兴趣 与健康失调有关的机制。 糖类 环外或环内缩醛氧被取代的类似物 通过亚甲基、C-糖苷或卡巴糖分别吸引 兴趣 预期这些分子具有类似的构象 和空间位阻性质，因此类似的连接特性 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试剂稳定， 水解 它们作为治疗剂或工具是潜在有用的 用于生化研究。 本项目涉及三个综合的新方法 糖模拟物组：Galbeta的C-糖苷和卡巴糖 糖苷和糖磷酰（GPI）亚基的C-糖苷。 的 具体目标是：（I）作为潜在I选择素的C-糖苷 配体，为设计新型， 水解稳定的抗炎剂。(II)C-糖苷和 Gal-β-二糖的碳糖，其是 制备具有糖基加工酶的稳定复合物， 具有抑制特性。(III)GPI的C-糖苷类似物 组成部分，这是有关调查的GPI有关 过程，如寄生原生动物的生存机制和信号 与胰岛素作用有关的转导。 合成策略集中在硫代- 异丙基缩二醇（TIA）。 该方法非常适合于制造 二糖模拟物，尽管它可以同样容易地应用于 单糖结构。 制备二糖类似物的概念 涉及环状糖衍生物与TIA的初始连接 合成子 随后，第二环由氧碳正离子形成， 离子-烯烃环化得到二氢吡喃或环己烯衍生物， 这取决于所使用的TIA片段的选择。 立体选择 烯烃的官能化导致目标糖模拟物。 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 环状糖衍生物。