Development of New Carbohydrate Synthesis Methodologies

新碳水化合物合成方法的开发

• 批准号: 7623865
• 负责人: Xuefei Huang
• 金额: $ 23.96万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-03-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7623865
• 关键词: Anticoagulants; Anticoagulation; Bacterial Infections; Biological; Biological Process; Carbohydrates; Chemicals; Complex; Coupling; Development; Due Process; Electrons; Event; Glycoconjugates; Heparin; Inflammation; Inorganic Sulfates; Knowledge; Label; Learning; Left; Length; Measures; Mediator of activation protein; Methodology; Methods; Monitor; Nature; Neoplasm Metastasis; Oligonucleotides; Oligopeptides; Oligosaccharides; Pattern; Phase; Physiological Processes; Play; Preparation; Process; Property; Protocols documentation; Reaction; Research; Research Personnel; Role; Route; Sampling; Series; Solid; Solutions; Solvents; Structure; Structure-Activity Relationship; Sulfur; Temperature; Thioglycosides; Time; Unspecified or Sulfate Ion Sulfates; base; cancer cell; chemical synthesis; chitosan sulfate; cold temperature; design; flasks; glycosylation; insight; molecular sieving; novel; novel strategies; programs; promoter; research study; success; sulfation

DESCRIPTION (provided by applicant): A research program devoted to the development of new methods for carbohydrate synthesis and studies of their biological activities is proposed. Carbohydrates and glycoconjugates are mediators of many medicinally important physiological processes, such as cancer metastasis, inflammation, anticoagulation and bacterial infection. Chemical syntheses of oligosaccharides are crucial for providing pure samples for glycobiological studies. Traditional carbohydrate synthesis is a time-consuming process due to tedious protective group manipulation and intermediate purification. Two novel one-pot approaches where multiple glycosylation reactions can be carried out in a single reaction flask without separation of synthetic intermediates are proposed. The first proposed method utilizes glycosyl building blocks with anomeric activities tuned through aglycons with various electron withdrawing power and building blocks with multiple levels of reactivity can be derived from a common intermediate. This will greatly expand the reactivity window and reduce the time and efforts for building block preparation. The second proposed strategy is based on pre-activation of glycosyl donors in the absence of acceptors, which can be carried out iteratively independent of donor anomeric reactivities. The iterative one-pot method represents a general and powerful approach, which can potentially become a fully automated solution-phase based carbohydrate synthesis method. Mechanisms of the two proposed methods will be investigated and the lessons learned will be applied for further development. To demonstrate the broad applicability of proposed strategies, a complex type bi-antennary dodecasaccharide and a series of sulfated chitosanoligosaccharides will be synthesized. The anticoagulant properties of the sulfated chitosanoligosaccharides will be determined for better understanding of their structure-activity relationship and development of more potent anticoagulants.

描述（由申请人提供）：提出了一项致力于开发碳水化合物合成新方法及其生物活性研究的研究计划。碳水化合物和糖缀合物是许多医学上重要的生理过程的介质，如癌症转移、炎症、抗凝和细菌感染。寡糖的化学合成对于为糖生物学研究提供纯净样品至关重要。传统的碳水化合物合成是一个耗时的过程，由于繁琐的保护基操作和中间体纯化。提出了两种新的一锅法，其中多个糖基化反应可以在一个单一的反应烧瓶中进行，而不分离的合成中间体。第一种提出的方法利用具有异头活性的糖基结构单元，该异头活性通过具有各种吸电子能力的糖苷配基进行调节，并且具有多个反应性水平的结构单元可以从共同的中间体衍生。这将极大地扩大反应窗口，并减少构建块制备的时间和精力。第二个提出的策略是基于在不存在受体的情况下糖基供体的预活化，其可以独立于供体异头反应性迭代地进行。迭代一锅法代表了一种通用的和强大的方法，它可能成为一个完全自动化的基于溶液相的碳水化合物合成方法。将对这两种拟议方法的机制进行调查，并将吸取的经验教训用于进一步发展。为了证明所提出的策略的广泛适用性，将合成复合型双触角十二糖和一系列硫酸化壳寡糖。硫酸化壳寡糖的抗凝血性能将被确定，以更好地了解其结构-活性关系和开发更有效的抗凝血剂。