Synthesis of Complex Carbohydrates.

复杂碳水化合物的合成。

• 批准号: 8826141
• 负责人: Hien M Nguyen
• 金额: $ 28.22万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8826141
• 关键词: Adherence; Advanced Development; Adverse effects; Affinity; Alcohols; Amino Sugars; Antibiotic Resistance; Antibiotics; Antibodies; Anticoagulants; Antithrombins; Applications Grants; Area; Asparagine; Binding; Biochemical Process; Blood coagulation; Calorimetry; Campylobacter jejuni; Carbohydrate Chemistry; Carbohydrates; Cardiovascular system; Cell Surface Receptors; Cells; Cessation of life; Collaborations; Complex; Complication; Coupling; Development; Diagnosis; Diarrhea; Disadvantaged; Discipline; Enzymes; Epithelial Cells; Evaluation; Fluoroquinolones; Glucosamine; Glycoconjugates; Glycosides; Goals; Heparin; Heparin Binding; Human; Infection; Inorganic Sulfates; Institutes; Iowa; Lectin; Ligands; Link; Macrolides; Mass Spectrum Analysis; Measurement; Medicine; Methodology; Methods; Microbiology; Myocardial Infarction; Nickel; Oligosaccharides; Paralysed; Pathogenesis; Pattern; Pharmaceutical Preparations; Platelet Factor 4; Play; Polysaccharides; Preparation; Process; Protein Binding; Protein Glycosylation; Proteins; Reaction; Reactive Arthritis; Relative (related person); Research; Research Personnel; Resistance to infection; Role; Series; Source; Stomach; Stroke; Surface; Surface Plasmon Resonance; System; Techniques; Thrombocytopenia; Titrations; Transition Elements; Universities; Unspecified or Sulfate Ion Sulfates; Variant; analog; catalyst; chemical synthesis; college; design; gastrointestinal; glycosylation; innovation; neuromuscular; novel strategies; novel therapeutics; prevent; tool; trichloroacetamide

DESCRIPTION (provided by applicant): Within the realm of synthetic carbohydrate chemistry, the stereoselective formation of glycosidic bonds is of paramount importance. Efficient manipulation of bond connectivity at the anomeric center opens up new approaches for the synthesis of complex carbohydrates, including the 1,2-cis-2-amino glycosides. These aminosugars make up one of the most important classes of naturally occurring oligosaccharides and glyco-conjugates, which play a crucial role as cell-surface receptor ligands for lectins, antibodies, and enzymes. However, progress toward understanding the specific functions of 1,2-cis-2-aminosugars has been hampered, due to the formidable challenge of obtaining an adequate supply of well-defined glycosides from natural sources. In many cases, high purity 1,2-cis-2-aminosugars can only be obtained by chemical synthesis, which also provides access to structural variants. Although there have been remarkable advances in the synthesis of 1,2-cis-2-amino glycosides, the disadvantages of current methodologies include the use of excess activating agents and unpredictable/poor anomeric selectivity. In this grant application, our goal is to develop a new and innovative strategy for the effective synthesis of 1,2-cis-2-amino glycosides via transition metal-catalyzed a-selective glycosylation (Specific Aim 1). The method that is currently being developed in our group will be broadly applicable and provide products in high yield and with excellent a-selectivity. The successful completion of the proposed method would have broad impact in the carbohydrate field, where catalytic methods for stereoselective glycosylation are still lacking. This transition-metal catalyzed 1,2-cis-2-amino glycosylation methodology will be applied to the synthesis of bioactive carbohydrate targets, including Campylobacter jejuni N-linked glycan (Specific Aim 2) which can be used to block Campylobacter jejuni adherence to human gastric epithelial cells and biding to mammalian lectins, and heparin oligosaccharides which have potent anticoagulant activity and minimal side effect (Specific Aim 3). 1

描述（由申请人提供）：在合成碳水化合物化学领域内，糖苷键的立体选择性形成至关重要。异头中心键连接的有效操纵开辟了合成复杂碳水化合物（包括 1,2-cis-2-氨基糖苷）的新方法。这些氨基糖构成了最重要的一类天然寡糖和糖缀合物，它们作为凝集素、抗体和酶的细胞表面受体配体发挥着至关重要的作用。然而，由于从天然来源获得充足的明确糖苷的巨大挑战，了解 1,2-顺-2-氨基糖的具体功能的进展受到了阻碍。在许多情况下，高纯度的 1,2-顺-2-氨基糖只能通过化学合成获得，这也提供了获得结构变体的途径。尽管 1,2-顺式-2-氨基糖苷的合成已取得显着进展，但当前方法的缺点包括使用过量的活化剂和不可预测/差的异头选择性。 在本次拨款申请中，我们的目标 的目标是开发一种新的创新策略，通过过渡金属催化的α-选择性糖基化有效合成1,2-顺-2-氨基糖苷（具体目标1）。我们小组目前正在开发的方法将具有广泛的适用性，并提供高产率和优异的α选择性的产品。该方法的成功完成将对碳水化合物领域产生广泛影响，该领域仍然缺乏立体选择性糖基化的催化方法。这种过渡金属催化的 1,2-cis-2-氨基糖基化方法将应用于生物活性碳水化合物靶标的合成，包括空肠弯曲杆菌 N 连接聚糖（具体目标 2），可用于阻止空肠弯曲杆菌粘附于人体胃上皮细胞并与哺乳动物凝集素和肝素寡糖结合，具有有效的抗凝活性和最小的副作用（具体目标3）。 1