Non-hydrolysable Phosphinic Analogues of Dipeptides

Abstract

Peptide analogues 1 in which the phosphonamide group replaces the amide function are thought to mimic the tetrahedral intermediates and transition states in peptide hydrolysis. While pepti-des 1 are potent inhibitors of some peptidases, their unsefulness is limited by rapid hydrolysis of P-N bond in aqueous media. To circumvent the instability problem we designed peptide analogues 2 with a CH₂ group inserted between the phosphorus and nitrogen atoms. Such structures are resistant to hydrolysis but it was interesting to see if they are similar enough to pepti-des to retain any affinity to enzyme active sites.