Kinetics and mechanism of degradation of klerval, a pseudo-tetrapeptide

Abstract

The degradation of klerval ( I) was studied as a function of pH. The extent and routes of degradation were found to be pH-dependent. Under strongly acidic conditions (pH<2), the drug predominantly undergoes specific acid-catalyzed hydrolysis of the side-chain amide bond yielding II. In weakly acidic solutions (2<pH<4), the backbone amide bond was found to be hydrolyzed forming a tripeptide. The cleavage reaction proceeds via intramolecular catalysis by carboxyl group displacement of the nitrogen of the peptide bond. In addition, parallel formation of a small amount of succinimide was observed in acidic solutions (1<pH<5). In neutral solutions (5<pH<8), the peptide isomerizes via the succinimide producing the iso-aspartyl isomer. The isomerization was found to be pH-independent throughout neutral and basic pH regions. In basic solutions (pH>8), the drug undergoes specific base-catalyzed hyrolysis yielding II and epimerization generating d-epimer. The epimerization appears to occur via the succinimide intermediate in neutral pH region. With increasing pH, however, the epimerization rate increases due to direct epimerization of the peptides.