Prodrugs of peptides. 13. Stabilization of peptide amides against alpha-chymotrypsin by the prodrug approach

Abstract

Various derivatives of the C-terminal amide group in N-protected amino acid and peptide amides were synthesized to assess their suitability as prodrug forms with the aim of protecting the amide or peptide bond against cleavage by alpha-chymotrypsin. Whereas N-acetylation, N-hydroxymethylation, and N-phthalidylation did not afford any protection but, in fact, accelerated the terminal amide bond cleavage, condensation with glyoxylic acid to produce peptidyl-alpha-hydroxyglycine derivatives and, to a minor extent, N-aminomethylation were found to improve the stability of the parent amides. Besides protecting the terminal, derivatized amide moiety toward cleavage by alpha-chymotrypsin, alpha-hydroxyglycine derivatization resulted in a significant protection, by a factor ranging from 5 to 75, of the internal peptide bond in various N-protected dipeptide amides. These derivatives are readily bioreversible, the conversion to the parent peptide or amino acid amide taking place either by spontaneous hydrolysis at physiological pH, as demonstrated for the N-Mannich bases, or by catalysis by plasma, as for peptidyl-alpha-hydroxyglycine derivatives.