Solution-Phase Automated Synthesis of Oligosaccharides

低聚糖的溶液相自动化合成

• 批准号: 7801456
• 负责人: NICOLA L. B. POHL
• 金额: $ 19.03万
• 依托单位: LUCELLA BIOSCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-01 至 2012-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7801456
• 关键词: Acetic Acids; Address; Amines; Automation; Basic Science; Candidiasis; Carbohydrates; Carbonates; Cell physiology; Chloride Ion; Chlorides; Communicable Diseases; Complex; Custom; Deacetylation; Development; Diagnostic; Disaccharides; Electrons; Exercise; Gel Chromatography; Goals; Hand; High Pressure Liquid Chromatography; Influenza; Libraries; Medical; Metabolic Diseases; Methanol; Methods; Methylene Chloride; Molecular; Mucopolysaccharidoses; Oils; Oligosaccharides; Phase; Polysaccharides; Potassium; Preparation; Procedures; Process; Protons; Reaction; Reagent; Reflux; Relative (related person); Research Design; Robotics; Running; Sampling; Science; Signal Transduction; Sodium; Solutions; Solvents; Source; Staging; Staphylococcus aureus; Tea; Testing; Thin Layer Chromatography; Time; Toluene; Vaccines; Vacuum; Variant; Vial device; Viral; arm; base; carbohydrate structure; evaporation; glycosylation; innovation; operation; planetary Atmosphere; public health relevance; research study; response; silochrome; success; sugar; trichloroacetamide; triethylamine; tumor progression

DESCRIPTION (provided by applicant): The synthesis of carbohydrates remains a complex exercise that involves tremendous labor and large amounts of expensive building blocks and reagents. Even once a process for making a carbohydrate has been developed, manufacture of that molecule in all the variants that biologists demand for their studies to drive glycomics remains labor and material intensive. The lack of ready access to a range of carbohydrate structures, given the extreme difficulty in isolating sufficient and pure quantities from natural sources, has been a severe limitation to advancing not only the science but also the resulting carbohydrate based vaccines and diagnostics built on this basic understanding. The long-term goal of the proposed project is to develop the commercial custom synthesis of oligosaccharides using stable and, if possible, crystalline building blocks in association with an innovative new automated solution-phase process for building block assembly. This phase I proposal addresses roadblocks that stand in the way of the development of this process at this stage. The specific aims are 1) the preparation of a range of N-phenyl substituted trifluoroacetimidoyl halides as glycosyl activating reagents; 2) the preparation of different trifluoroacetimidoyl based glycosyl donors with tests of their stability and reactivity; and 3) the reaction of these donors with a range of glycosyl acceptors to form disaccharide libraries in a solution-phase-based automation strategy amenable to iterative oligosaccharide synthesis. At the conclusion of these studies, stable glycosyl donors reactive with a wide range of glycosyl acceptors in a solution phase automation platform will have been discovered to pave the way for a standardized set of carbohydrate building blocks for on-demand custom-order oligosaccharide synthesis. PUBLIC HEALTH RELEVANCE: Carbohydrates are increasingly recognized as fundamental molecular constituents in a wide range of cellular processes of medical importance, including infectious disease responses (fungal, e.g candidiasis; viral, e.g. influenza; and bacterial, e.g. Staphylococcus aureus), cancer progression, and congenital metabolic disorders (e.g. mucopolysaccharidosis). This proposal will develop methods for the first rapid automated assembly of oligosaccharides in solution for use in medical diagnostics and basic science studies.

描述（由申请人提供）：碳水化合物的合成仍然是一项复杂的工作，涉及巨大的劳动力和大量昂贵的构件和试剂。即使开发出了制造碳水化合物的方法，生物学家为了研究糖组学而需要的所有变体的分子制造仍然是劳动和材料密集型的。由于从天然来源中分离足够和纯量的碳水化合物结构极其困难，因此缺乏现成的途径，这不仅严重限制了科学的发展，而且也严重限制了基于这种基本理解的基于碳水化合物的疫苗和诊断方法的发展。拟议项目的长期目标是开发商业定制合成低聚糖，使用稳定的，如果可能的话，与创新的自动化溶液相过程的积木组装相关联的结晶积木。第一阶段的建议处理了现阶段阻碍这一进程发展的障碍。具体目的是1）制备一系列N-苯基取代的三氟乙酰亚氨酰卤化物作为糖基活化试剂; 2）制备不同的基于三氟乙酰亚氨酰的糖基供体，并测试其稳定性和反应性;和3）这些供体与一系列糖基受体反应，以在基于溶液相的自动化策略中形成二糖文库，该策略适合于迭代寡糖合成。在这些研究的结论中，将发现在溶液相自动化平台中与广泛的糖基受体反应的稳定的糖基供体，从而为用于按需定制顺序寡糖合成的标准化碳水化合物结构单元组铺平道路。 公共卫生相关性：碳水化合物越来越多地被认为是广泛的具有医学重要性的细胞过程中的基本分子成分，包括感染性疾病反应（真菌，例如念珠菌病;病毒，例如流感;和细菌，例如金黄色葡萄球菌）、癌症进展和先天性代谢紊乱（例如粘多糖病）。该提案将开发用于医疗诊断和基础科学研究的溶液中寡糖的首次快速自动组装方法。