Transformative Methods for the Solid Phase Synthesis of Oligosaccharides

低聚糖固相合成的变革方法

基本信息

批准号：
9751331
负责人：
MATTHEW Paul BRICHACEK
金额：
$ 27.44万
依托单位：
UNIVERSITY OF MAINE ORONO
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-01 至 2021-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9751331
关键词：
Acylation Address Alkylation Attention Attributes of Chemicals Bacterial Infections Binding Proteins Biological Biotechnology Carbohydrates Cells Chemicals Chemistry Complex Mixtures Coupling DNA Development Diagnosis Discipline Disease Ethers Future Genomics Glycobiology Glycosides Goals Immune response Infection Inflammation Investigation Knowledge Length Link Maine Malignant Neoplasms Methodology Methods Molecular Monosaccharides Nature Neoplasm Metastasis Nucleic Acids Oligonucleotides Oligosaccharides Oxalates Pathogenesis Pattern Peptides Pharmacologic Substance Phase Physical condensation Play Polysaccharides Principal Investigator Process Production Proteins Proteomics Protocols documentation RNA Reaction Research Role S Phase Sampling Sampling Studies Scientist Signal Transduction Solid Structure Technology Therapeutic Time Training Triazoles Universities Virus Diseases base carbene chemical synthesis cycloaddition design drug discovery glycosylation human disease interest microbial pathogen phosphoramidite prevent reaction rate stereochemistry tumor

项目摘要

Transformative Methods for the Solid Phase Synthesis of Oligosaccharides Principal Investigator: Matthew Brichacek, Department of Chemistry, University of Maine ABSTRACT When compared to genomics or proteomics, the systematic study of all glycan structures in a cell (glycomics) has received considerably less attention. However, this is not due to a lack of biological significance; where carbohydrates play an integral role in cell signaling, immune response, microbial pathogenesis, tumor metastasis, and modulation of protein activity. Instead, the knowledge gap is due to the immense complexity of the glycome, consisting of a large number of monosaccharide building blocks that are assembled in numerous regio- and stereochemical combinations. Consequently, natural samples are complex mixtures that prevent isolation of substantial quantities of pure glycans. Moreover, current synthetic methodology to obtain oligosaccharides is substantially less developed than those for oligonucleotides (DNA & RNA) and peptides, for which automated solid-phase protocols exist. Typically, oligosaccharides are constructed in solution one glycosidic linkage at a time by combination of the appropriate, prefunctionalized glycosyl donors and acceptors. These glycosylation reactions are extremely sensitive to the steric and electronic attributes of the substituents and protecting groups on the carbohydrates. Therefore, the chemical synthesis of oligosaccharides is tedious and generally performed only by specialized synthetic carbohydrate chemists. One approach that could circumvent the challenges associated with an intermolecular glycosylation is to pair an efficient intermolecular coupling of the glycosyl donor and acceptor with a subsequent intramolecular rearrangement to produce the desired natural glycosidic linkage. The first step will address the shortcomings in efficiency by utilizing rapid, robust condensation reactions. When the donor and acceptor are linked, an intramolecular rearrangement to form the glycosidic bond will be less sensitive to the nature of the protecting groups of the carbohydrates and will have the potential to be highly stereoselective. By applying this approach to carbohydrate synthesis on a solid phase, glycans with complete sequence and stereochemical control will be readily accessible. The development of a solid-phase synthesis of glycans based on an efficient intermolecular coupling and a stereoselective intramolecular rearrangement could provide ample quantities of well-defined oligosaccharides. The carbohydrates produced would enable investigations of numerous glycan-binding proteins that will provide a molecular level of understanding of glycan-associated disorders, such as inflammation, pathogen infection, and cancer. In addition, this technology would enable scientists from a wide variety of disciplines interested in carbohydrates to acquire the desired molecules without highly specialized synthetic training, as is currently possible for oligonucleotides and peptides.

寡糖固相合成的变换方法首席研究员：缅因州大学化学系Matthew Brichacek 抽象的与基因组学或蛋白质组学相比，细胞中所有聚糖结构的系统研究（糖果）受到的关注大大减少了。但是，这不是由于缺乏生物学意义;碳水化合物在细胞信号，免疫反应，微生物中起着不可或缺的作用发病机理，肿瘤转移和蛋白质活性的调节。相反，知识差距是由于散热的巨大复杂性，由大量的单糖构建块组成组装成许多区域和立体化学组合。因此，天然样品很复杂防止分离大量纯聚糖的混合物。而且，当前合成获得寡糖的方法比寡核苷酸（DNA＆ RNA）和肽，为其自动固相方案。通常，寡糖为在溶液中构建的一个糖苷连接，通过合适的，预官能化的结合糖基供体和受体。这些糖基化反应对空间非常敏感，碳水化合物上取代基和保护基团的电子属性。因此，化学物质寡糖的合成是乏味的，通常仅通过专门的合成碳水化合物进行化学家。一种可以规避与分子间糖基化相关挑战的方法是将糖基供体和受体的有效分子间耦合与随后的分子内结合重排以产生所需的天然糖苷连接。第一步将解决利用快速，稳健的冷凝反应来效率。当捐助者和受体链接时，分子内重排以形成糖苷键对保护性质的敏感碳水化合物组有可能具有高度立体选择性。通过应用这种方法为了在固相的碳水化合物合成，具有完整序列和立体化学控制的聚糖将会很容易访问。基于有效的分子间耦合和A的固相合成的固相合成的发展立体选择性分子内重排可以提供大量定义明确的寡糖。产生的碳水化合物将使许多聚糖结合蛋白提供研究，这些蛋白将提供分子对聚糖相关疾病的理解水平，例如炎症，病原体感染，和癌症。此外，这项技术将使来自对兴趣的各种学科的科学家能够与目前一样可能用于寡核苷酸和肽。