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

这项研究的重点是开发新的合成方法，使之适用于固相合成，并应用于组合化学。关键的组成部分将是受保护的磷(III)氨基酸。具体研究将包括：用二氯三苯基膦在溶液中合成模型膦酸酯和膦酰胺二肽，以活化磷(III)氨基酸；评价膦和膦酰胺的苄基保护；这些方法在固相合成膦多肽及其硫代衍生物中的应用；H-膦氨基酸的对映选择性合成；以及对这些新合成化合物的酶抑制的ALD测量。通过这一奖项，合成有机计划和多学科活动办公室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、高产量的方法来制备可应用于组合文库生产的固态程序的膦取代多肽。这种方法将同时提供数以千计的化合物，这些化合物可以被筛选出各种生物活性，例如蛋白酶抑制。

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.