Protection of the peptide bond against α-chymotrypsin by the prodrug approach

• Published in: Bioorganic & medicinal chemistry letters Vol. 3; no. 5; pp. 809 - 812
• Main Authors: Kahns, Anne H., Friis, Gitte J., Bundgaard, Hans
• Format: Journal Article
• Language: English
• Published: Elsevier Ltd 01.05.1993
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/S0960-894X(00)80671-X

N-Hydroxymethylation of the N-terminal peptide bond in N-acetyl-L-phenylalanine amides was found to protect the C-terminal amide bond against cleavage by α-chymotrypsin. The N-hydroxymethyl derivatives are readily bioreversible, undergoing spontaneous hydrolysis at physiological pH, and are thus promising prodrugs to overcome the enzymatic barrier to absorption of various peptides. N-Hydroxymethyl derivatives of N-acetyl-L-phenylalanine amides (R 1 = CH 2OH) were shown to be completely stable toward α-chymotrypsin while undergoing spontaneous decomposition at pH 7.4 and 37°C to the parent N-acetyl-L-phenylalanine amides (R 1 = H).