Chemical stability and plasma-catalyzed dealkylation of peptidyl-alpha-hydroxyglycine derivatives--intermediates in peptide alpha-amidation.
The production of alpha-amidated peptides has recently been shown to occur via a two-step process with peptidyl-alpha-hydroxyglycine being an intermediate. In this study the chemical stability and plasma-catalyzed conversion of various peptidyl-alpha-hydroxyglycine derivatives to their parent amide product have been examined. This conversion was shown to be independent of pH in the range pH 1-5 and to be apparently specific base-catalyzed at pH 6-10. At pH 7.4 and 37 degrees C the half-lives of decomposition of the derivatives ranged from 5.8 to 13.3 h. In 80% human plasma solutions (pH 7.4) the half-lives decreased to 1.3-3.9 h, indicating the occurrence of an enzyme activity in plasma catalyzing the dealkylation of peptidyl-alpha-hydroxyglycine derivatives. The best substrate for the plasma catalytic activity was found to be N-benzyloxycarbonyl-L-alanyl-alpha-hydroxyglycine.
Bundgaard
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Royal Danish School of Pharmacy, Department of Pharmaceutical Chemistry, Copenhagen, Denmark.
Kahns
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AH
D000478:Alkylation; D000577:Amides / Q000737:chemistry*; D001769:Blood; D002384:Catalysis; D002851:Chromatography, High Pressure Liquid; D004355:Drug Stability; D005998:Glycine / Q000031:analogs & derivatives* / Q000737:chemistry; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D010455:Peptides / Q000737:chemistry*
D000577:Amides; D010455:Peptides; D005998:Glycine