Novel Techniques for the Solution and Solid Phase Synthesis of Peptide Segments

本研究的重点是开发普遍适用的、可靠的和快速的方法，用于化学合成较长的肽和小的蛋白质（氨基酸掺入范围为75-100或更高）。将对节段缩合和逐步方法进行平行研究，以期最终详细说明后一种技术，以便快速合成高纯度的产品，而不需要精心提纯。重点介绍了基于FMOC氨基酸氟化物和1-羟基-7-偶氮苯并三唑（HOAt）的新型偶联技术。由于邻基效应，后者为氨基保护氨基酸和肽段的偶联提供了机会，而不会发生外消旋。将为组氨酸和精氨酸制备稳定的受fmoc保护的氨基酸氟衍生物。当所有种类的氟化物都可用时，将对29、41和76个氨基酸肽的模型合成进行检查，作为新方法的测试。同样的模型将通过hoat衍生试剂使用逐步和段耦合协议组装。有了这个奖，合成有机项目支持了马萨诸塞大学阿姆赫斯特分校化学系Louis A. Carpino博士的研究。Carpino教授将专注于开发普遍适用、可靠和快速的方法，用于化学合成较长的肽和小蛋白质。将对分段缩合法和分步法进行平行研究，以期最终完善后一种技术，以便快速合成高纯度的产品，而不需要繁琐的纯化。随着高等肽在药物化学、药物发现和材料科学领域的应用越来越广泛，需要一种快速、可靠的化学合成方法。

The focus of this research is the development of generally applicable, reliable and rapid procedures for the chemical synthesis of longer peptides and small proteins (range of incorporated amino acids 75-100 or higher). Parallel studies of the segment condensations and stepwise approaches will be undertaken with a view to eventual elaboration of the latter technique to allow the quick synthesis of products of high purity without the need for elaborate purification. Promising new coupling techniques based on FMOC amino acid fluorides and 1-hydroxy-7-azobenzotriazole (HOAt) will be emphasized. Because of neighboring group effects, the latter offers the opportunity of coupling both urethane-protected amino acids and peptide segments wthout racemization. Stable FMOC-protected amino acid fluoride derivatives will be made for histidine and arginine. When the full range of acid fluorides is available, model syntheses of 29-, 41- and 76-amino acid peptides will be examined as tests of the new methodolgy. The same models will be assembled via HOAt-derived reagents using both stepwise and segment coupling protocols. %%% With this award, the Synthetic Organic Program is supporting the research of Dr. Louis A. Carpino of the Department of Chemistry at the University of Massachusetts Amherst. Professor Carpino will focus his work on the development of generally applicable, reliable and rapid procedures for the chemical synthesis of longer peptides and small proteins. Parallel studies of the segment condensation and stepwise approaches will be undertaken with the view to eventual elaboration of the latter technique to allow the rapid synthesis of products of high purity without the need for tedious purification. Quick, reliable methods for the chemical synthesis of higher peptides are needed in connection with the increasing use of such substances in the fields of medicinal chemistry, drug discovery and material science.