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

这项研究的重点是开发普遍适用的、可靠的和快速的长肽和小蛋白(结合氨基酸范围为75-100或更高)的化学合成程序。将对分段缩合和分步方法进行平行研究，以期最终详细阐述后一种技术，以便能够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-偶氮苯并三氮唑(HOAT)的新型偶联技术。由于邻基效应，后者提供了将氨基甲酸酯保护的氨基酸和多肽片段偶联的机会，而不需要外消旋。组氨酸和精氨酸将得到稳定的Fmoc保护的氨基酸氟化物衍生物。当全系列酸性氟化物可用时，29-、41-和76-氨基酸多肽的模型合成将作为新方法的测试而被检验。同样的模型将通过Hoat衍生的试剂使用分步和分段耦合协议进行组装。有了这个奖项，合成有机计划将支持马萨诸塞大学阿默斯特分校化学系的Louis A.Carpino博士的研究。卡皮诺教授将把他的工作重点放在开发普遍适用、可靠和快速的长肽和小蛋白化学合成程序上。将对分段缩合和分步方法进行平行研究，以期最终制定后一种技术，以便能够快速合成高纯度的产品，而不需要繁琐的提纯。随着这些物质在药物化学、药物发现和材料科学领域中越来越多的使用，需要快速、可靠的方法来化学合成高级多肽。

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.