Chemical Synthesis of Beta-Manno and Rehamnopyranosides

β-甘露糖苷和吡喃大黄苷的化学合成

• 批准号: 7433904
• 负责人: JIN K CHA
• 金额: $ 28.24万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-05-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7433904
• 关键词: Address; Appearance; Biological; Biology; Bond-It; Carbohydrate Chemistry; Carbohydrates; Chemistry; Class; Clinical Trials; Complex; Development; Europe; Face; Glycobiology; Link; Macrolide Antibiotics; Mannose; Mannosides; Methodology; Methods; Modification; Nucleotides; Object Attachment; Oligonucleotides; Oligosaccharides; Peptide Synthesis; Peptides; Pharmaceutical Preparations; S Phase; Series; Solutions; Source; Structure; Subgroup; System; Vaccines; base; chemical synthesis; falls; foot; mycosamine; tool

DESCRIPTION (provided by applicant): Contemporary carbohydrate chemistry is being continually challenged by the ever expanding field of glycobiology and, more specifically, by the complexity and diversity of biologically and medically important oligosaccharides uncovered whose synthesis is mandated by their extremely tedious isolation and purification from natural sources in minute quantities. Great strides forward have been made such that the automated synthesis of some of the more straightforward oligosaccharides is now a reality and potential carbohydrate-based antitumor vaccines have been produced by solution phase synthesis on such a scale as to enable clinical trials. A fully synthetic pentasaccharide is now a commercial antithrombotic drug in Europe. Smaller oligosaccharide chains have a profound effect on the biology of many drugs, often in ways not yet fully understood. In spite of these and other remarkable advances, many of which could not have been contemplated a few years ago, there still remain many important problems in carbohydrate chemistry to be addressed before the full potential of glycobiology can even begin to be realized. The aims of this project are to provide enabling chemistry for the direct, stereo-controlled synthesis of some of the more complex types of glycosidic bond found in biology and to illustrate these methods through the total synthesis of specific structures of biological significance. We focus our efforts in this project on the 1,2-cis-equatorial bonds to pyranosides. The most common form of this linkage type is the beta-D-mannopyranoside linkage, although various deoxy forms are also widespread, including the beta-rhamnopyranosides. In macrolide antibiotics this type of glycosidic bond makes it appearance in the form of beta-glycosidic bonds to mycosamine, that is of 3,6-dideoxy-3-amino-beta-mannosides. More recently, the core O-specific IPS from Plesimonas Shigelloides O54 has been found to contain two unusual beta-linked heptopyranosides having the D-glycero-D- manno and 6-deoxyglycero-D-manno configuration. The chemistry described in this proposal has the specific aim of making the synthesis of the 1,2-cis- equatorial glycosidic bonds practical, and efficient, putting it on a similar footing to that of oligonucleotides and peptides, and of demonstrating this through the synthesis of suitably complex, biologically-active oligosaccharides.

描述（由申请人提供）：当代碳水化合物化学正不断受到糖生物学领域不断扩大的挑战，更具体地说，受到生物学和医学上重要的寡糖的复杂性和多样性的挑战，这些寡糖的合成是通过极其繁琐的分离和纯化来完成的。微量的天然来源。已经取得了巨大的进步，一些更简单的寡糖的自动合成现已成为现实，并且已经通过溶液相合成生产了潜在的基于碳水化合物的抗肿瘤疫苗，其规模足以进行临床试验。全合成五糖现已在欧洲成为商业抗血栓药物。较小的寡糖链对许多药物的生物学具有深远的影响，通常其方式尚未完全了解。尽管取得了这些和其他显着的进步，其中许多进步在几年前是无法想象的，但在糖生物学的全部潜力开始实现之前，碳水化合物化学仍然存在许多重要问题需要解决。该项目的目的是为生物学中发现的一些更复杂类型的糖苷键的直接、立体控制合成提供有利的化学方法，并通过具有生物学意义的特定结构的全合成来说明这些方法。我们在这个项目中的重点是吡喃糖苷的 1,2-顺式赤道键。这种连接类型最常见的形式是β-D-吡喃甘露糖苷连接，尽管各种脱氧形式也很普遍，包括β-吡喃鼠李糖苷。在大环内酯类抗生素中，这种类型的糖苷键使其以与海藻糖胺（即 3,6-二脱氧-3-氨基-β-甘露糖苷）的 β-糖苷键的形式出现。最近，发现志贺单胞菌 O54 的核心 O 特异性 IPS 含有两种不寻常的 β 连接吡喃庚糖苷，具有 D-甘油-D-甘露糖和 6-脱氧甘油-D-甘露糖构型。 该提案中描述的化学的具体目标是使 1,2-顺式赤道糖苷键的合成实用且高效，使其与寡核苷酸和肽具有相似的基础，并通过合成证明这一点适当复杂的、具有生物活性的寡糖。