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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.

寡糖的固相合成方法改进主要研究者：Matthew Brichacek，缅因州大学化学系摘要与基因组学或蛋白质组学相比，对细胞中所有聚糖结构的系统研究（糖组学）受到的关注相当少。然而，这并不是因为缺乏生物重要性;其中碳水化合物在细胞信号传导、免疫反应、微生物发病机制、肿瘤转移和蛋白质活性的调节。相反，知识差距是由于糖组的巨大复杂性，由大量的单糖组成，组装成许多区域和立体化学组合。因此，天然样品是复杂的防止分离大量纯聚糖的混合物。此外，目前的合成获得寡糖的方法学基本上不如那些用于寡核苷酸（DNA & RNA）和肽，对于它们存在自动化固相方案。通常，低聚糖是通过组合适当的预官能化物质，在溶液中一次构建一个糖苷键糖基供体和受体。这些糖基化反应对空间位阻非常敏感，碳水化合物上的取代基和保护基的电子属性。因此，化学寡糖合成是冗长的，通常只能通过专门的合成碳水化合物来进行化学家一种可以规避与分子间糖基化相关的挑战的方法是将糖基供体和受体的有效分子间偶联与随后的分子内偶联配对，重排以产生所需的天然糖苷键。第一步将解决通过利用快速、稳健的缩合反应来提高效率。当供体和受体连接时，形成糖苷键的分子内重排对保护基的性质不太敏感，这些基团的碳水化合物，并将具有潜在的高度立体选择性。通过应用这种方法，对于固相上的碳水化合物合成，具有完整序列和立体化学控制的聚糖将容易接近。基于高效分子间偶联和高效液相色谱法的聚糖固相合成研究进展立体选择性分子内重排可以提供足够量的明确定义的寡糖。所产生的碳水化合物将使研究许多聚糖结合蛋白，在分子水平上了解聚糖相关疾病，如炎症，病原体感染，和癌症此外，这项技术将使科学家从各种学科感兴趣的，碳水化合物来获得所需的分子，而无需高度专业化的合成训练，就像目前可能用于寡核苷酸和肽。