High pressure induced hydrolysis at C-terminus of peptide derivatives yielding bioactive peptides

Abstract

If the cyclization of a peptide is associated with a volume reduction, pressure should displace the reaction equilibrium in the direction of a lower volume. Here, results in model solutions are considered, showing a pressure-accelerated transformation of linear dipeptides with reactive C-terminals. The theorised cyclization of dipeptides after hydrolysis of the C-terminal amide H–Leu–Gly–NH 2 or methyl ester groups H–Leu–Gly–OMe and H–Leu–Gly–OtBu was found to be significantly accelerated during application of combined pressure/temperature treatments up to 600–800 MPa and 60–80 °C. Yields were dependent on the nature of the reactive site. Products of those reactions were identified as H–Leu–Gly–OH and cyclo(Leu–Gly), which is a bioactive dipeptide. The dipeptide amide yielded only trace concentrations of the amino acid H–Leu–OH and the linear dipeptide. Steric hindrance prevented a pressure induced cyclisation of a dipeptide with tert-butyl ester at the C-terminus, and only the linear peptide H–Leu–Gly–OH was formed.