Catalytic Methods for Building Block Assembly and for Stereoselective Glycosylation

构建块组装和立体选择性糖基化的催化方法

• 批准号: 9391258
• 负责人: JOHN MONTGOMERY
• 金额: $ 57.97万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9391258
• 关键词: Address; Air; Alcohols; Amino Sugars; Anabolism; Bacteria; Biological; Biological Process; Biology; Carbohydrate Chemistry; Carbohydrates; Catalysis; Chemicals; Collaborations; Collection; Communities; Complex; Copper; Coupled; Development; Engineering; Event; Eye; Filtration; Genome; Glycosides; Goals; Harvest; Health; Human; Hydrolysis; Improve Access; Ketones; Laboratories; Macrolides; Mediating; Metabolic Biotransformation; Methods; Michigan; Mining; Molecular; Monosaccharides; Natural Products; Nickel; Oligosaccharides; Organic Synthesis; Outcome; Oxidation-Reduction; Pathway interactions; Pharmacologic Substance; Phase; Phosphoric Acids; Plant Resins; Play; Positioning Attribute; Process; Property; Reaction; Reagent; Research; Research Personnel; Research Project Grants; Research Proposals; Scientist; Silanes; Site; Solid; Specificity; Structure; Techniques; Technology; Transition Elements; Universities; Work; bioactive natural products; catalyst; design; drug discovery; glycosylation; innovation; interdisciplinary approach; interest; method development; molecular recognition; multidisciplinary; next generation; novel; novel strategies; oxidation; protein folding; small molecule; sugar; synergism; synthetic biology

Project Summary / Abstract (Montgomery, Sherman, Nagorny) Carbohydrates are essential structural motifs that play a key role in many biological processes. They provide the primary structural features that govern many molecular recognition events that are central in biology. Essential molecular properties such as protein folding, biological target recognition, stability, and distribution are governed by glycosidic positioning and structure. Furthermore, alteration of glycosidic functionality has been demonstrated to enhance the potency and specificity of pharmaceutically important compounds. Despite the key role that carbohydrates play in biology and their promise in strategies for the improvement of human health, significant hurdles exist in the efficient access to rare and high-value monosaccharides and their chemical manipulation. Many sugars that are essential in governing the bioactivity of natural products and that hold promise for the discovery of new structures that could impact human health are currently not available to the scientific community. Furthermore, those that are available typically require complex synthetic manipulations that are beyond the expertise of scientists who are not specialists in organic synthesis. The major objective of this research proposal is to develop synergies between methods in biosynthesis and small molecule catalysis to overcome these barriers that are limiting progress in glycoscience. Through innovative biosynthetic strategies, efficient access to rare, high-value monosaccharides will be obtained. The approach brings together state-of-the-art advances in genome mining, synthetic biology, and biotransformation technologies. These advances will partner with novel approaches using transition metal catalysts and organocatalysts to convert biosynthetically derived monosaccharides into versatile and widely available reagents for the stereoselective construction of glycosidic bonds. Additionally, methods will be devised to convert common, widely available monosaccharides into rare sugars through redox manipulations. Innovative techniques in synthesis involving newly devised chiral phosphoric acid catalysts and carbohydrate-derived silane reagents will be developed in the course of the proposed studies. An innovative approach for solid- phase monosaccharide capture and synthetic elaboration will be developed. The unique multidisciplinary perspective of this effort will allow the development of strategies that cannot be addressed by conventional approaches. The outcome will be greatly improved access to valuable reagents and innovative methods for the assembly of glycosylated structural motifs that will enable progress in glycoscience that is currently hindered by limitations and difficulties of current approaches.

项目摘要/摘要(蒙哥马利、谢尔曼、纳戈尔尼) 碳水化合物是重要的结构基序，在许多生物过程中起着关键作用。他们提供了 支配许多分子识别事件的主要结构特征，这些事件在生物学中是核心的。 基本的分子特性，如蛋白质折叠、生物靶标识别、稳定性和分布 是由糖苷的定位和结构决定的。此外，糖苷官能团的改变有 已被证明可以增强重要药用化合物的效力和专一性。尽管 碳水化合物在生物学中的关键作用及其在人类改良策略中的前景 健康方面，在有效获得稀有和高价值的单糖及其 化学操纵。许多糖在控制天然产品的生物活性方面是必不可少的，而且 希望发现可能影响人类健康的新结构目前还不能 科学界。此外，那些可用的通常需要复杂的合成 非有机合成专家的科学家所不具备的专业知识之外的操作。这个 这项研究提案的主要目标是发展生物合成方法和小分子生物合成方法之间的协同效应。 分子催化以克服这些障碍，这些障碍限制了糖科学的进步。通过创新 通过生物合成策略，可以有效地获得稀有、高价值的单糖。该方法 汇集了基因组挖掘、合成生物学和生物转化方面的最新进展 技术。这些进展将与使用过渡金属催化剂和 有机催化剂可将生物合成的单糖转化为用途广泛的多用途单糖 用于糖苷键的立体选择性结构的试剂。此外，还将设计方法来 通过氧化还原操作将常见的、广泛使用的单糖转化为稀有糖。创新型 新型手性磷酸催化剂和碳水化合物的合成技术 在拟议的研究过程中，将开发硅烷试剂。一种创新的固态方法- 将开发相单糖捕获和合成精制。独一无二的多学科 从这一努力的角度来看，将能够制定常规方法无法解决的战略。 接近了。其结果将大大改善获得有价值的试剂和创新方法的机会 糖基化结构基序的组装，这将使目前受阻的糖科学进展成为可能 由于目前方法的局限性和困难。