Chemical Synthesis of Beta-Manno and Rehamnopyranosides

β-甘露糖苷和吡喃大黄苷的化学合成

基本信息

批准号：
7619110
负责人：
JIN K CHA
金额：
$ 28.21万
依托单位：
WAYNE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-05-01 至 2011-04-30
项目状态：
已结题

项目摘要

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反应不断地受到糖生物学的不断扩展领域的挑战，更具体地说，是由于生物学和医学上重要的重要寡糖的复杂性和多样性所构成的，其合成是由它们在微小量中从自然来源中极度繁琐的隔离和纯化来授权的。已经实现了巨大的进步，使得一些更直接的寡糖的自动合成现在已成为现实，并且潜在的基于碳水化合物的抗肿瘤疫苗是通过溶液相合成的规模而产生的，以使临床试验成为临床试验。现在，完全合成的五糖是欧洲的一种商业抗血栓药物。较小的寡糖链对许多药物的生物学产生了深远的影响，通常以尚未完全理解的方式。尽管这些和其他显着的进步，但几年前还没有考虑其中的许多进步，但在碳水化学化学方面仍然存在许多重要问题，直到糖生物学的全部潜力甚至可以开始实现。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，立体控制的合成提供促进化学，并通过对生物学意义的特定结构的总合成来说明这些方法。我们将精力集中在该项目上，将1,2-CIS-赤道债券与丙酰糖苷的键合。这种连锁类型的最常见形式是β-D-甘露糖苷连接，尽管各种脱氧形式也广泛，包括β-rhamnopyranosides。在大花环抗生素中，这种类型的糖苷键使其以β-糖苷键与霉菌胺的形式出现，即3,6-二维氧基-3-氨基 - 氨基甲虫甘露糖苷。最近，发现来自shigelloides o54的核心O特异性IP包含两个与D-甘油D- Manno和6-脱氧糖糖糖型构型的不寻常的β链接七吡喃糖苷。该提案中描述的化学旨在使1,2-赤道糖苷键合成实用且有效，这使其与寡核苷酸和肽的基础相似，并通过适当的复杂，生物活性的，具有生物性的活性寡糖的合成来证明这一点。