New synthetic methods for the preparation of carbohydrate-based vaccines

描述（由申请人提供）：糖生物学和糖医学发展的主要障碍是缺乏纯的和结构明确的碳水化合物和糖缀合物。在许多情况下，定义明确的低聚糖只能通过化学合成获得。不幸的是，目前还没有一种通用的方法来制备具有生物学重要性的复合碳水化合物，其中一个主要的障碍是缺乏一种可靠的方法来形成1,2-顺式糖苷的立体选择性。我们的初步研究表明，用手性助剂取代的糖基供体，如(S)-（苯基硫甲基）苄基醚，可以用于立体选择性引入1,2-顺式糖苷，如a-糖苷和a-半乳糖苷。手性助剂的邻基参与生成了准稳定的球端磺酸离子，由于空间和电子因素，形成了反式十氢化萘环体系。羟基取代-磺酸离子导致a-糖苷的立体选择性引入。本申请的目的是进一步发展合成方法，并将其应用于有可能开发为疫苗的低聚糖的制备。将建立助剂与常用糖基化方案和保护基团操作的相容性。基于辅助的方法将扩展到引入各种1,2-顺式糖苷。新一代的手性助剂将具有更好的酸稳定性，在敏感的保护基团存在下选择性去除，并且与高活性的糖基供体相容。最后，将新方法应用于a类生物恐怖制剂土拉菌和炭疽芽孢杆菌低聚糖的合成。将进行免疫学实验，以确定合成化合物是否可以用作候选疫苗。公共卫生相关性：糖生物学和糖医学进展的主要障碍是缺乏纯的和结构明确的碳水化合物。建议开发新的合成方法来制备具有良好定义的复合碳水化合物。新方法将应用于制备从病原体中提取的低聚糖，这被归类为a类生物恐怖制剂。将进行免疫学实验，以确定合成化合物是否可以用作候选疫苗。

DESCRIPTION (provided by applicant): A major obstacle to advances in glycobiology and glyco-medicine is the lack of pure and structurally well-defined carbohydrates and glycoconjugates. In many cases, well-defined oligosaccharides can only be obtained by chemical synthesis. Unfortunately, no general method is available for the preparation of complex carbohydrates of biological importance and one of the main stumbling blocks is the lack of a reliable methodology for the stereoselective formation of 1,2-cis-glycosides. Our preliminary studies have shown that a glycosyl donor substituted with a chiral auxiliary, such as a (S)-(phenylthiomethyl)benzyl ether, can be employed for the stereoselective introduction of 1,2-cis glycosides such as a-glucosides and a-galactosides. Neighboring group participation by the chiral auxiliary leads to a quasi-stable anomeric sulfonium ion, which due to steric and electronic factors is formed as a trans-decalin ring system. Displacement of the ¿-sulfonium ion by a hydroxyl leads to the stereoselective introduction of a-glycosides. The aim of this application is to further develop the synthetic methodology and apply it to the preparation of oligosaccharides that have the potential to be developed as vaccines. The compatibility of the auxiliaries with commonly used glycosylation protocols and protecting group manipulations will be established. The auxiliary based methodology will be extended to the introduction of a wide variety of 1,2-cis-glycosides. A new generation of chiral auxiliary will be developed with improved properties such better acid stability, selective removable in the presence of sensitive protecting groups, and compatible with highly reactive glycosyl donors. Finally, the new methodology will be applied to the synthesis of oligosaccharides derived from Francisella tularensis and Bacillus anthracis, which are category-A bio-terrorism agents. Immunological experiments will be performed to establish whether the synthetic compounds can be employed as vaccine candidates. PUBLIC HEALTH RELEVANCE: A major obstacle to advances in glycobiology and glyco-medicine is the lack of pure and structurally well-defined carbohydrates. It is proposed to develop new synthetic methodologies for the preparation for well-defined complex carbohydrates. The new methodology will be applied to the preparation of oligosaccharides derived from pathogens, which are classified as category-A bio- terrorism agents. Immunological experiments will be performed to establish whether the synthetic compounds can be employed as vaccine candidates.