Catalysts and Reagents for Amide Bond Synthesis

酰胺键合成催化剂和试剂

• 批准号: 1506854
• 负责人: Paramjit Arora
• 金额: $ 49万
• 依托单位: New York University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-01 至 2018-05-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1506854&HistoricalAwards=false
• 关键词: Catalysts; Reagents; Amide; Bond; Synthesis

In this project funded by the Chemical Catalysis program of the Chemistry Division, Professor Paramjit Arora of New York University is developing new catalysts for the synthesis of the amide bond, the linchpin bond in peptides, which are a basic structural building block of proteins. Biological systems make heavy use of peptides and proteins to carry out complex tasks at the molecular level, and they are composed multiple amide bond subunits linked together in a long chain. The use of peptides and proteins as chemical reagents and therapeutics necessitates their production in large amounts; however, the synthesis of these compounds remains inefficient and wasteful. This project is building upon classical and contemporary methods for amide bond formation to enable a more efficient and greener synthesis of proteins and other important compounds that contain amide bonds. This research should yield valuable strategies and reagents for studying chemical processes in biology and for medicinal chemistry. The project also includes teaching activities to train students at the interface of organic chemistry and chemical biology. Students engaged in this work are gaining a broad experience in fundamental chemical and biochemical techniques with potential future applications in biomedical technologies. A collaboration with Professor Amy Brown of Neumann University, Department of Chemistry is making progress on establishing a one-semester research-oriented capstone course at that university. Professor Arora is developing new organocatalysts for amide bond formation that are based upon a chemoselective ligation strategy for the synthesis of native amide bonds in proteins. Chemoselective reactions for amide bond formation have transformed the ability to access synthetic proteins and other bioconjugates through ligation of fragments. In these ligations, amide bond formation is accelerated by transient enforcement of an intramolecular reaction between the carboxyl and the amine termini of two fragments. Building on this principle, Professor Arora is developing aldehyde capture ligation that parlays the high chemoselective reactivity of aldehydes and amines to enforce amide bond formation between amino acid residues and peptides that are difficult to ligate by existing technologies. Aldehyde capture ligation utilizes an o-benzaldehyde selenoester to enforce an intramolecular reaction between the carboxyl and the amine partners. The key advantage of aldehyde capture ligation is that the method is applicable, in principle, to most any N-terminal amino acid residue for amide bond formation, because the capture step is changed from thioester exchange, as in native chemical ligation, to aldehyde-amine condensation. The methodologies are being applied to the synthesis of small ring, cyclic peptides.

在这个由化学部化学催化计划资助的项目中，纽约大学的Paramjit Arora教授正在开发用于合成酰胺键的新催化剂，酰胺键是肽中的关键键，肽是蛋白质的基本结构构建块。 生物系统大量使用肽和蛋白质在分子水平上执行复杂的任务，它们由多个酰胺键亚基连接在一起形成长链。 使用肽和蛋白质作为化学试剂和治疗剂需要大量生产它们;然而，这些化合物的合成仍然是低效和浪费的。 该项目是建立在经典和现代的酰胺键形成方法，使蛋白质和其他重要的化合物，含有酰胺键的更有效和更绿色的合成。 这项研究将为生物学和药物化学中的化学过程研究提供有价值的策略和试剂。 该项目还包括在有机化学和化学生物学的接口培训学生的教学活动。 从事这项工作的学生正在获得基础化学和生物化学技术的广泛经验，并在生物医学技术中具有潜在的未来应用。 与诺依曼大学化学系的艾米·布朗教授合作，正在该大学建立一个为期一个学期的研究型顶点课程。 阿罗拉教授正在开发新的有机催化剂，用于酰胺键的形成，这是基于一种化学选择性连接策略，用于蛋白质中天然酰胺键的合成。 用于酰胺键形成的化学选择性反应已经改变了通过片段的连接获得合成蛋白质和其他生物缀合物的能力。 在这些连接中，酰胺键的形成是通过两个片段的羧基和胺末端之间的分子内反应的瞬时实施来加速的。 基于这一原理，Arora教授正在开发醛捕获连接，利用醛和胺的高化学选择性反应性，以加强氨基酸残基和肽之间的酰胺键形成，这些氨基酸残基和肽难以通过现有技术连接。 醛捕获连接利用邻苯甲醛硒酯来加强羧基和胺伴侣之间的分子内反应。 醛捕获连接的关键优点在于，该方法原则上适用于大多数用于酰胺键形成的任何N-末端氨基酸残基，因为捕获步骤从天然化学连接中的硫酯交换改变为脱乙酰基-胺缩合。 这些方法正被应用于合成小的环状肽。