Methods and Mechanisms in Carbohydrate Chemistry

碳水化合物化学的方法和机制

• 批准号: 10211071
• 负责人: David Crich
• 金额: $ 31.14万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-30 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10211071
• 关键词: Acids; Active Sites; Address; Affect; Alcohols; Anabolism; Binding; Biological; Carbohydrate Chemistry; Carbohydrates; Carbon; Cations; Cell Wall; Cells; Chemistry; Complex; Coupled; DNA; Dependence; Development; Disease; Empiricism; Enzymes; Funding; Glycoconjugates; Glycoside Hydrolases; Glycosides; Goals; Grant; Investigation; Kinetics; Knowledge; Laboratories; Methods; Modeling; Modernization; Molecular Conformation; Oligonucleotides; Oligosaccharides; Peptide Synthesis; Pharmaceutical Preparations; Process; Production; Rationalization; Reaction; Reproducibility; Role; Series; Sialic Acids; Side; Synthetic Vaccines; Therapeutic Agents; Transferase; Work; base; design; glycosylation; glycosyltransferase; improved; inhibitor/antagonist; innovation; mimetics; novel; predictive modeling; sugar

Although glycochemistry has developed in leaps and bounds in the last two decades, the synthesis of a complex oligosaccharide or of a glycoconjugate remains a very challenging albeit critically important task. The difficulties inherent in such syntheses arise because of numerous reasons that center on the complexity of the chemistry when compared to that of oligonucleotide and peptide synthesis. The most important reactions in any oligosaccharide synthesis are the formation of the glycosidic bonds and there exists many empirical methods toward this end. The longstanding theme of this grant has been that the rationalization of complex oligosaccharide synthesis is best achieved by an improved understanding of the mechanisms of glycosidic bond formation, coupled with the development of more efficient, straightforward and general mechanism-based methods. Progress along these lines has transformed by the way we think about glycosidic bond formation to the extent that predictions can now be made. One aspect of this proposal addresses remaining issues in glycosidation mechanisms through the development of cation clock methods for the determination of reaction kinetics in sialic acid glycosidic bond formation. A further aspect of this proposal is the mechanism-based prediction of reactivity leading to the development of a novel method for the control of anomeric stereoselectivity through the control of side chain conformation. Finally, the knowledge of how side chain conformation affects reactivity is related to transition state stabilization by glycoside hydrolases and glycosyltransferases, resulting in the design of improved inhibitors for such critical carbohydrate processing enzymes.

虽然糖化学在过去的二十年里有了长足的发展， 复合寡糖或糖缀合物的合成仍然是非常困难的 具有挑战性，但至关重要的任务。这种合成中固有的困难 由于许多原因，这些原因集中在化学的复杂性上， 与寡核苷酸和肽合成相比。最重要的 任何寡糖合成中的反应是糖苷键的形成， 为此目的存在许多经验方法。 这项赠款的长期主题是， 低聚糖合成最好通过提高对 糖苷键形成的机制，再加上更多的发展， 高效、直接和通用的基于机制的方法。沿着这些 我们对糖苷键形成的理解已经改变了 现在可以进行预测了。该提案的一个方面涉及剩余的 通过阳离子时钟方法的发展探讨糖苷化机制中的问题 用于测定唾液酸糖苷键形成的反应动力学。一 该建议的另一方面是基于机理的反应性预测， 开发了一种新的方法，用于控制异头立体选择性， 侧链构象的控制。最后是如何侧链的知识 构象影响反应性与糖苷稳定过渡态有关 水解酶和糖基转移酶，导致设计改进的抑制剂， 这些关键的碳水化合物加工酶。