New synthetic methods for the preparation of carbohydrate-based vaccines

描述(由申请人提供)：糖生物学和糖药物发展的一个主要障碍是缺乏纯的和结构明确的碳水化合物和糖偶联物。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，没有通用的方法来制备具有生物学意义的复杂碳水化合物，一个主要的绊脚石是缺乏可靠的方法来立体选择性地形成1，2-顺式糖苷。我们的初步研究表明，用手性助剂取代的糖基供体，如(S)-(苯硫甲基)苄基醚，可用于1，2-顺式糖苷的立体选择性引入，如α-葡萄糖苷和α-半乳糖苷。手性助剂的邻基参与导致了一种准稳定的非正规硫离子，由于空间和电子因素，它形成了一个反式十氢萘环体系。α-硫离子被羟基取代，导致α-糖苷的立体选择性引入。这一应用的目的是进一步发展合成方法，并将其应用于制备有潜力开发为疫苗的低聚糖。将建立助剂与常用的糖基化方案和保护基团操作的兼容性。以辅助剂为基础的方法学将扩展到引入各种各样的1，2-顺式糖苷。新一代手性助剂的性能将得到改善，如更好的酸稳定性，在敏感保护基团存在下选择性可移除，以及与高活性糖基供体相容。最后，新的方法将被应用于从图拉氏方济氏菌和炭疽芽孢杆菌衍生的低聚糖的合成，这两种低聚糖是A类生物恐怖分子。将进行免疫学实验，以确定合成的化合物是否可以用作疫苗候选。与公共健康相关：糖生物学和糖类药物发展的一个主要障碍是缺乏纯的和结构上定义明确的碳水化合物。建议开发新的合成方法来制备定义明确的复杂碳水化合物。新的方法将被应用于从病原体中提取的寡糖的制备，这些低聚糖被归类为A类生物恐怖分子。将进行免疫学实验，以确定合成的化合物是否可以用作疫苗候选。

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.