Prodrugs of peptides: III. 5-Oxazolidinones as bioreversible derivatives for the α-amido carboxy moiety in peptides

Abstract

The hydrolysis kinetics of six N-acyl 5-oxazolidinones derived from various N-benzyloxycarbonyl amino acids and aldehydes (formaldehyde, acetaldehyde and benzaldehyde) was studied to assess their suitability as prodrug forms for the α-amido carboxy moiety occurring in peptides. The degradation of the compounds was shown to take place by hydrolytic opening of the lactone ring with the formation of an N-hydroxyalkyl intermediate which subsequently decomposed to the parent N-acylated amino acid and aldehyde. For oxazolidinones derived from formaldehyde and acetaldehyde the latter reaction was rate-limiting whereas for derivatives of benzaldehyde the hydrolysis of the lactone ring was the slowest step at neutral pH. The lactone hydrolysis was catalyzed by human plasma enzymes and influenced by substituents in the 2- and 4-positions. It is suggested that 5-oxazolidinone formation may become a useful approach to bioreversible derivatization of peptides containing an α-amido carboxy function in an effort to protect peptide bonds against enzymatic cleavage and to improve absorption characteristics through increased hpophilicity. The potential utility of the N-hydroxyalkyl derivatives formed upon hydrolysis of the oxazolidinones as useful prodrug forms is also discussed.