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练习，涉及巨大的劳动和大量昂贵的构建基块和试剂。即使已经开发了制造碳水化合物的过程，生物学家要求其研究以驱动糖果的所有变体中生产该分子。鉴于将足够和纯净数量与天然来源隔离的极端困难，不仅是对科学的限制，而且不仅可以推进科学，而且还基于这种基本理解，因此缺乏现成的碳水化合物结构的途径。拟议项目的长期目标是使用稳定的寡糖定制寡糖的商业自定义合成，并在可能的情况下与具有创新的新自动化解决方案相结合的构建块组件合作。 I阶段的提议解决了在此阶段妨碍此过程发展的障碍。具体目的是1）制备一系列N-苯基取代的三氟乙酰二酰胺酰卤化物作为糖基激活试剂； 2）制备基于不同的三氟乙酰二酰基糖基供体的稳定性和反应性测试； 3）这些供体与一系列糖基受体的反应在基于溶液 - 相的自动化策略中形成二糖库，可迭代寡糖合成。在这些研究的结论结束时，将发现稳定的糖基供体在溶液相自动化平台中与广泛的糖基受体反应性，为一组标准化的碳水化合物构建块铺平了道路，用于按需定制的寡糖合成。 公共卫生相关性：碳水化合物越来越被公认为是基本的分子组成，在多种医学重要性的细胞过程中，包括感染性疾病反应（真菌，例如念珠菌病；病毒性，例如流感；例如，细菌；该建议将开发用于在医学诊断和基础科学研究中首次快速自动组装寡糖的方法。