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

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-NH2 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.