Degradation of Azaglycinamido Residues in Model Tripeptides Derived from Goserelin

• Published in: Journal of pharmaceutical sciences Vol. 89; no. 1; pp. 108 - 114
• Main Authors: Hoitink, Marnix A., Beijnen, Jos H., Bult, Auke, Damen, J.Mirjam A., van der Houwen, Oeds A.G.J., Kruijtzer, John A.W., Tibben, Matthijs M., Wiese, Gerard, Underberg, Willy J.M.
• Format: Journal Article
• Language: English
• Published: New York Elsevier Inc 01.01.2000; John Wiley & Sons, Inc; Wiley; American Pharmaceutical Association
• Subjects: Antineoplastic Agents, Hormonal - chemistry; Biological and medical sciences; Buffers; Chromatography, High Pressure Liquid - methods; General pharmacology; Goserelin - chemistry; Hydrazines - chemistry; Hydrogen-Ion Concentration; Kinetics; Mass Spectrometry; Medical sciences; Nuclear Magnetic Resonance, Biomolecular; Oligopeptides - chemistry; Peptide Fragments - chemistry; Pharmacology. Drug treatments; Physicochemical properties. Structure-activity relationships; Protein Denaturation; Thermodynamics; Temperature; Chemical stability; Peptide hormone; Chemical structure; Tripeptide; Degradation; Hypothalamic hormone; Investigation method; pH; Chemical properties; Goserelin; Degradation product; Physicochemical properties; Functional group
• ISSN: 0022-3549; 1520-6017
• DOI: 10.1002/(SICI)1520-6017(200001)89:1<108::AID-JPS11>3.0.CO;2-A

Three model tripeptides, N‐acetyl‐Tyr‐Pro‐azaGly‐NH2 (NYPaG), Tyr‐Pro‐azaGly‐NH2 (YPaG), and Tyr‐Pro‐Gly‐NH2(YPG), were subjected to a systematic degradation study to get information about the degradation of the azaglycinamido residue. The degradation products were characterized with LC‐MS. Main degradation products of NYPaG possess partially or totally eliminated azaglycinamido residues, while YPaG and YPG are exhibit cyclo(Tyr‐Pro) formation, a diketopiperazine. The influence of the pH on the degradation rate constant kobs was investigated for NYPaG and YPaG in the pH range 0.4–11. An U‐shaped profile with an inflexion around pH 9 was found for NYPaG while the degradation rate of YPaG was independent of the pH. NYPaG apparently was subject to proton‐, solvent‐, and hydroxyl‐catalyzed degradation reactions whereas YPaG only underwent solvent‐catalyzed reactions. Some influence of acetate and phosphate ions on kobs was found for YPaG. Arrhenius plots of NYPaG and YPaG were found to be linear. © 2000 Wiley‐Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 89: 108–114, 2000