Hydrolysis of the phosphonamidate bond in phosphono dipeptide analogues - The influence of the nature of the N-terminal functional group

Phosphonamidate pseudodipeptides, designed as transition state analogue inhibitors of leucine aminopeptidase, revealed unexpected instability in aqueous solutions of pH values varying from acidic up to highly basic. This reaction has been studied in some detail by means of NMR spectroscopy and it was found that the phosphonamidate stability depended strongly on the solution pH, relying on the protonation state of two crucial functional groups of the molecule - the phosphonamidate and amino moieties. Protonation of the free N-terminal amino moiety is required for the occurrence of rapid P-N bond decomposition; N-protected derivatives are significantly more stable. The mechanisms of the cleavage of the phosphonamidate bond have been proposed and discussed. The observed instability of unblocked P-N peptides may be the cause of the substantial limitations of their practical application as aminopeptidase inhibitors. ((C) Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)