Qualitative and quantitative aspects of the degradation of several tripeptides derived from the antitumour peptide antagonist [Arg 6, D-Trp 7,9, MePhe 8] substance P{6–11}

Abstract

The tripeptides Arg–Trp–Phe, Arg–Trp–Phe–NH 2, Phe–Trp–Arg and Phe–Trp–Arg–NH 2 were subjected to a degradation study to get a more detailed insight into the degradation processes of the antitumor hexapeptide antagonist [Arg 6, D-Trp 7,9, MePhe 8] substance P {6–11} which was investigated in earlier research. Degradation kinetics as well as identities of degradation products of the tripeptides emerging in alkaline and acidic media were studied. The amidated forms (Arg–Trp–Phe–NH 2, Phe–Trp–Arg–NH 2) appear to be less stable than the carboxylic forms (Arg–Trp–Phe, Phe–Trp–Arg). Deamidation of the amide C-terminus, racemization of the Phe and Arg residues, ornithine formation, hydrolysis of the peptide backbone and diketopiperazine formation with elimination of the N-terminal fragments were the major degradative processes. Comparing these reactions with the reactions of antagonist [Arg 6, D-Trp 7,9, MePhe 8] substance P{6–11} it appeared that racemization of Phe and Arg, hydrolysis of the peptide backbone and diketopiperazine formation did not occur in detectable amounts in the hexapeptide, probably due to lower reaction rates of these reactions compared to the overall degradation rate of antagonist [Arg 6, D-Trp 7,9, MePhe 8] substance P{6–11}.