SELECTIVE HYDROLYSIS OF PEPTIDES, PROMOTED BY PALLADIUM AQUA COMPLEXES - KINETIC EFFECTS OF THE LEAVING GROUP, PH, AND INHIBITORS

This study is a step toward a method for selective internal cleavage of peptides and proteins by coordination complexes as artificial metallopeptidases. Palladium(II) aqua complexes attached to the sulfur atom of methionine in peptides promote, under relatively mild conditions, regioselective hydrolysis of the amide bond involving the carboxylic group of the methionine residue to which they are attached. This is a regular amide bond, and no prior activation for cleavage is involved. Kinetics of hydrolysis was studied with the peptides AcMet-Gly, AcMet-Ala, AcMet-Ser, AcMet-Val, AcMet-Leu, and AcMet-Ala-Ser and with the palladium(II) complexes containing aqua, hydroxo, ethylenediamine, and 1,5-dithiacyclooctane ligands. The reactions were followed by H-1 NMR spectroscopy and by two-dimensional thin-layer chromatography. Kinetic effects of pH, temperature, added thioethers, and an added thiol revealed the following. The mononuclear complexes that are initially added to the reaction mixture form binuclear complexes that are the active promoters. The half-lives of hydrolysis reactions are as short as 13 min at 40-degrees-C. Most important, the rate constant for hydrolysis depends on the steric bulk of the leaving fragment in such a way that the reaction is somewhat sequence-selective.