Steric effects on the selectivity of protein labelling with chelate complexes of platinum(II)

Abstract

The Cl − ligand in complexes of the type [Pt(tridentate)Cl] can be displaced by amino-acid side chains in proteins so that the Pt(tridentate) tag becomes covalently attached to the protein. The selectivity in this displacement can be controlled by adjusting the steric properties of the tridentate ligand. In the complex [Pt(dipic)Cl] −, in which dipic represents 2,6-pyridinedicarboxylate, the Cl − ligand is accessible. This complex reacts with methionine and histidine and their derivatives and with the side chain of methionine 65 in cytochrome c. The reactivity of amino-acid side chains toward [Pt(trpy)Cl] − depends mainly on their nucleophilicity; the soft thio-ether ligand in methionine is more reactive than the hard imidazole ligand in histidine. In the complex [Pt(dpes)Cl] +, in which dpes represents di(2-pyridyl-β-ethyl)sulphide, the Cl − ligand is partially shielded. This complex reacts with N-acetylmethionine, N-acetylhistidine, and the side chains of both methionine 65 and histidine 33 in cytochrome c. The reactivity of amino-acid side chains toward [Pt(dpes)Cl] + depends on their steric bulk as well as on their nucleophilicity; the thio-ether ligand in methionine is less reactive than the imidazole ligand in histidine. Principles of stereochemistry can be used in designing metal complexes for selective covalent modification of proteins.