Synthesis Of Mucin Type O-Glycans Via Ionic Catch And Release Methodology. Towards The Automated Synthesis Of Oligosaccharides.

碳水化合物已成为生物和医学中重要的分子识别因子，但其合成仍存在一定的困难。制备不同寡糖文库的组合方法非常缺乏，糖生物学研究的进展受到阻碍，因为不得不依赖孤立的材料或复杂低聚物的冗长靶向合成。低聚糖的自动化合成将提供对以多样性为导向的寡糖库的访问，从而不仅加强糖生物学研究，而且还促进基于碳水化合物的药物发现。在这项提案中，我们概述了一个雄心勃勃和范围广泛的计划，旨在合成粘蛋白家族的寡糖成分，其功能和性质尚待研究。近年来，已有报道鉴定了在整个肠道中发现的一些关键候选粘蛋白寡糖结构，但没有一种结构可以商业化使用，而且据我们所知，还没有通过化学方法合成。这类多糖的特定片段的合成将有助于我们了解它们的生物学和疾病意义，并将为生物探索提供纯粹的材料，这将对糖阵列筛选、诊断测试、疫苗合成和基于多糖的治疗产生重大影响。同时，我们的目标是开发低聚糖的通用合成和快速纯化的新方法。建议的技术是基于固定化介质(离子液体)和适当标记的碳水化合物之间的离子对相互作用，从而能够捕获和释放所需的产品，从而大大简化了纯化。另一方面，我们将探索离子液体(ILS)作为可循环使用的糖基化反应的双重溶剂/催化剂的范围。我们的长期目标是将这一方法应用于复杂低聚糖结构的自动化合成，这是缺乏有效的自动化技术的。

Carbohydrates have emerged as important factors of molecular recognition in biology and medicine, however they are still difficult to synthesize. Combinatorial approaches to prepare diverse libraries of oligosaccharides are greatly lacking and progress in glycobiology research has been hindered by having to rely on either isolated materials or lengthy target-oriented syntheses of complex oligomers. An automated synthesis of oligosaccharides would provide access to diversity-orientated oligosaccharide libraries to enhance not only glycobiology research, but also carbohydrate-based drug discovery. In this proposal we have outlined an ambitious and wide ranging programme aimed at synthesizing oligosaccharide components of the mucin family of proteins, for which the function and properties have yet to be investigated. In recent years, reports have emerged identifying some key candidate mucin oligosaccharide structures found throughout the intestinal track, however none are commercially available and, as far as we are aware, have not been chemically synthesized. The synthesis of defined fragments of this class of glycans will be critical to help us understand their biological and disease implications and will provide pure materials for biological exploration, which will subsequently have significant impact on glycoarray screening, diagnostic tests, vaccine synthesis and glycan-based therapeutics. Concurrently, we aim to develop new methodology for the general synthesis and rapid purification of oligosaccharides. The proposed technique is based on ionic pair interactions between an immobilization media (ionic liquid) and a suitably tagged carbohydrate that would enable catch and release of the required product, simplifying greatly purification. In another aspect, we will explore the scope of ionic liquids (ILs) as dual solvent/catalysts for glycosylation reactions that can be recycled. It is our long term objective to apply this methodology to the automated synthesis of complex oligosaccharide structures, for which effective automated techniques are lacking.