Aminophosphonic and Aminoboronic Acids as Key Elements of a Transition State Analogue Inhibitor of Enzymes

Abstract

Amino acid analogues are of considerable interest as inhibitors of enzymes involved in amino acid and peptide metabolism. In particular, α-aminoalkylphosphonic acids and 2-aminoalkylboronic acids, in which the carboxyl group of amino acids is replaced by a phosphonic acid or boronic acid function, respectively, constitute a unique class of amino acid mimics from which a number of potent enzyme inhibitors have been prepared. The inhibitory activity mainly stems from the fact that the tetrahedral phosphonic moiety or the tetrahedral adduct of electrophilic boronic acid is a good mimic of the putative tetrahedral transition state or intermediate encountered in the enzymatic hydrolysis or formation of peptides. Since the peptide hydrolysis and formation invariably involves the tetrahedral high energy species in the course of the reaction, these amino acid mimics serve as a general key element for inhibitors of a broad spectrum of proteases and peptide ligases. The transition state analogy of aminophosphonic- and aminoboronic acid-derived inhibitors also gives a clue to the detailed reaction mechanisms of the enzymes by X-ray crystallographic and NMR analysis of the enzyme-inhibitor complex.