Development of Biologically Active Compounds on the Basis of Phosphonic and Phosphinic Acid Functionalities

Abstract

Phosphonic and phosphinic acids, especially a-heteroatom-substituted ones, possess unique structural and physical features which enable them to act as hydrotically stable analogs to biological phosphates in biological processes. They also act as mimetics in the transition state of the protease-induced hydrolysis of dipeptides. Theˆrst half of this review focuses on selected new synthetic methods developed by our research group for the stereoselective synthesis of aheteroatom-substituted phosphonic and phosphinic acid derivatives, including modiˆed nucleotide analogs and phosphinyl dipeptide isosteres. In the latter half, this review summarizes the utility of di‰uoromethylenephosphonic acids and phosphonic acid esters in the development of enzyme inhibitors against protein tyrosine phosphatases, sphingomyelinases, purine nucleoside phosphorylases and thrombin. The enzyme inhibitors developed were used as probes to elucidate signal transductions and the mechanisms of enzyme actions. Theˆndings of the studies are brie‰y described.