SELECTIVE HYDROLYSIS OF UNACTIVATED PEPTIDE-BONDS, PROMOTED BY PLATINUM(II) COMPLEXES ANCHORED TO AMINO-ACID SIDE-CHAINS

Certain platinum(II) complexes attached to the sulfur atom of cysteine, S-methylcysteine, and methionine in peptides and other amino acid derivatives promote, under relatively mild conditions, hydrolysis of unactivated amide bonds involving the platinated amino acid. Kinetics of hydrolysis was studied with the substrates N-acetyl-L-cysteine, S-methyl-L-cysteine, N-acetyl-S-methyl-DL-cysteine, N-(2-mercaptopropionyl)glycine, N-acetylmethionylglycine, leucylglycine, reduced glutathione, S-methyl-glutathione, and oxidized glutathione and with complexes of platinum(II) and platinum(IV) containing chloro, aqua, iodo, ethylenediamine, 2,2'-bipyridine, and 2,2':6',2"-terpyridine ligands. When the substrates and platinum promoters are matched so as to aid hydrolysis, the observed rate constant varies between 2.3 x 10(-4) and 7.4 x 10(-3) min-1 at 40-degrees-C, depending on the substrate, promoter, pH, ionic strength, and chloride concentration. Unplatinated (free) substrates and substrates platinated with complexes designed to hinder hydrolysis do not hydrolyze at a detectable rate under identical conditions. The mechanism involves initial aquation of the platinum(II) complex attached to the substrate and a subsequent rate-determining step within the platinated substrate; details of the mechanism are discussed in terms of kinetic evidence and precedents. Hydrolysis is regioselective-it occurs preferably at the amide bond involving the carboxylic group of the platinated amino acid. This study may point the way toward new methods for selective, perhaps even catalytic, cleavage of peptides and proteins with metal complexes.