Prodrugs of peptides. 14. Bioreversible derivatization of the tyrosine phenol group to effect protection of tyrosyl peptides against α-chymotrypsin

Abstract

Various derivatives of the tyrosine phenol group in N-protected tyrosine amides and esters, used as models of tyrosyl peptides, were synthesized to assess their suitability as prodrug forms with the aim of protecting the tyrosyl peptide bond against cleavage by α-chymotrypsin. The derivatives studied included aliphatic and aromatic carboxylic acid esters, a glutarate ester, carbonate esters and carbamates. All derivatives greatly improved the stability of the parent tyrosine compounds toward hydrolysis by α-chymotrypsin but some esters were themselves readily attacked by the enzyme. Thus, the usefulness of this prodrug approach is greatly dependent on the type of derivatization performed. Useful derivatives were found to include aliphatic carboxylic acid and carbonate esters with a short or branched side chain, a glutarate ester and carbamate esters. Most of these esters are readily bioreversible, the conversion to the parent peptide being catalyzed by plasma or liver esterases.