Rapid Synthesis of Phosphonate and Phosphonamidate Peptide Analogs from Reduced Phosphorus Intermediates and Determination of their Enzymatic Inhibitory Activity

本研究的重点是开发新的方法来合成磷肽，可以适应固态合成应用于组合化学。关键的构建模块将是受保护的磷（III）氨基酸。具体研究将包括在溶液中使用二氯三苯磷烷活化磷（III）氨基酸合成模型膦酸盐和膦酰胺二肽；膦酸盐和膦酰胺对苯的保护作用评价这些方法在磷酸肽及其硫代衍生物固相合成中的应用h -膦酸氨基酸的对映选择性合成；测定这些新合成化合物的酶抑制作用。通过这个奖项，合成有机项目和多学科活动办公室正在支持路易斯安那州立大学化学系罗伯特·p·哈默博士的研究。Hammer教授将专注于开发新的、通用的和高产的方法来制备膦取代肽，这些方法可以应用于生产组合文库的固态程序。这种方法将同时提供数千种化合物，可以筛选各种生物活性，如蛋白酶抑制。

The focus of this research is the development of new approaches to the synthesis of phosphonopeptides that can be adapted to solid state synthesis for application to combinatorial chemistry. The key building blocks will be protected phosphorus(III) amino acids. Specific studies will include the synthesis of model phosphonate and phosphonamidate dipeptides in solution using dichlorotriphenylphosphorane for activiating the phosphorus(III) amino acids; the evaluation of benzyl protection of phosphonates and phosphonamides; applications of these methods to solid-phase synthesis of phosphonopeptides and their thio derivatives; enantioselective synthesis of H-phosphinate amino acids; ald measurement of enzyme inhibition for these newly synthesized compounds. With this award, the Synthetic Organic Program and the Office of Multidisciplinary Activities are supporting the research of Dr. Robert P. Hammer of the Department of Chemistry at Louisiana State University. Professor Hammer will focus his work on the development of new, general and high-yielding methods for the preparation of phosphono-substituted peptides that can be applied to solid state procedures for the production of combinatorial libraries. This approach will provide thousands of compounds simultaneously which can be screened for a variety of biological activities, such as protease inhibition.