Methods and Mechanisms in Carbohydrate Chemistry

碳水化合物化学的方法和机制

• 批准号: 8126453
• 负责人: David Crich
• 金额: $ 30.22万
• 依托单位: WAYNE STATE UNIVERSITY
• 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 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8126453
• 关键词: Anabolism; Binding; Biological; Carbohydrate Chemistry; Cell Wall; Cells; Chemicals; Chemistry; Complex; Coupled; DNA; Detection; Development; Diagnosis; Disease; Enzymes; Esters; Glycopeptides; Glycosides; Goals; Health; Human; Investigation; Ions; Light; Link; Methodology; Methods; Nature; Neuraminic Acids; Oligonucleotides; Oligosaccharides; Peptide Synthesis; Peptides; Pharmaceutical Preparations; Polysaccharides; Positioning Attribute; Preparation; Process; Production; Proteins; Rationalization; Reaction; Role; Sialic Acids; Synthetic Vaccines; Techniques; base; glycosylation; human disease; improved; meetings; method development; mimetics; sound; tumor

DESCRIPTION (provided by applicant): Although oligosaccharide synthesis has developed in leaps and bounds in the last decade or so, this goal is still a long way off. The reasons for this are multiple and reside in the complexity of the chemistry of formation of glycosidic bonds. An absolutely overwhelming number of methods toward this end have been devised, however, the vast majority of these have been developed empirically and they are therefore underpinned by very little detailed understanding of mechanism. The thesis of this proposal is that the rationalization and improvement of oligosaccharide is best be brought about by a two pronged approach. One prong is the detailed investigation of the mechanisms of a few of glycosylation reactions with the aim of providing a sound basis for further development. The second prong, which can not be entirely separated from the first, is the careful development of improved methodology, with a focus on the more challenging problems. In the mechanistic prong we will investigate the underlying basis for possible neighboring group participation by esters at positions other than the familiar 2-position. The emphasis will be on the detection of bridging intermediates by chemical and spectroscopic methods. In the synthetic prong we will build on our extensive preliminary results to develop a method for the stereoselective synthesis of sialic acid glycosides, with an emphasis on the 1-glycosides of N-glycolyl neuraminic acid and KDO. We will also develop methods for the synthesis of glycopeptides linked based on the labile glycosyl ester motif. PUBLIC HEALTH RELEVANCE: The goal of modern oligosaccharide synthesis is the efficient production of natural and unnatural oligosaccharides, and their mimetics, capable of interfering constructively in disease states. This interference may be brought about by the blocking of oligosaccharide processing enzymes, by disruption of bacterial cell wall biosynthesis, by modulating cell-cell recognition, by enhancing binding and selectivity of drugs to DNA, and by the provision of antigenic oligosaccharides in synthetic vaccines. All of these very desirable processes require the highly efficient synthesis of oligosaccharides. The goal of this project is to provide methods for the synthesis of the more challenging classes of glycosidic bond and to display these methods through the synthesis of biologically relevant oligosaccharides and glycopeptides.

描述（由申请人提供）：尽管寡糖合成在过去十年左右有了飞跃式的发展，但这一目标仍有很长的路要走。其原因是多方面的，并且存在于糖苷键形成的化学复杂性中。为此目的设计了绝对压倒性的方法，然而，这些方法中的绝大多数都是经验性的，因此，它们的基础是对机制的详细了解很少。这一建议的论点是，合理化和改善低聚糖最好是通过双管齐下的办法来实现。一方面是对一些糖基化反应的机理进行了详细的研究，为进一步的研究提供了良好的基础。第二个方面与第一个方面不能完全分开，它是认真发展改进的方法，重点放在更具挑战性的问题上。在机械方面，我们将研究酯在熟悉的2-位以外的位置上可能参与相邻基团的潜在基础。重点将放在通过化学和光谱方法检测桥接中间体上。在合成的尖头，我们将建立在我们广泛的初步结果，开发一种方法的唾液酸糖苷的立体选择性合成，重点是1-糖苷的N-羟乙酰神经氨酸和KDO。我们还将开发基于不稳定糖基酯基序连接的糖肽的合成方法。 公共卫生相关性：现代寡糖合成的目标是有效生产天然和非天然寡糖及其模拟物，能够建设性地干预疾病状态。这种干扰可以通过阻断寡糖加工酶、破坏细菌细胞壁生物合成、调节细胞-细胞识别、增强药物与DNA的结合和选择性以及在合成疫苗中提供抗原性寡糖来实现。所有这些非常理想的方法都需要高效合成寡糖。该项目的目标是提供合成更具挑战性的糖苷键类的方法，并通过合成生物相关的寡糖和糖肽来展示这些方法。