In defense of platinum: Amino acidic polydentate ligands as a shield against sulphur-donor nucleophilic attacks

Abstract

The interactions of sulfur-containing peptides and proteins with platinum-based anticancer agents are of significant interest in the field of bioinorganic chemistry. We previously modified the lead compound potassium {trichlorido[η2-(but-3-en-1-yl)-2-acetoxybenzoate]platinate(II)} (Pt-butene-ASA) by exchanging two chlorido ligands for an amino acid chelating ligand to improve its stability in aqueous solutions. In the current study, we demonstrate how this amino acid ligand strengthens the inertness of this class of complexes against sulfur-containing compounds. We incubated four complexes, each bearing an amino acid chelating ligand, with various sulfur-containing compounds of biological interest, such as DMSO, methionine, glutathione, and substance P. The reactions were monitored using NMR spectroscopy and mass spectrometry, allowing the identification by combination with IR ion spectroscopy of exotic pentacoordinate platinum(II) complexes as reaction intermediates. The results indicated that the reactivity of complexes 1–4 ((ethene,N-trans)(l-alaninato-N,O)chlorido(η2-ethene)platinate(II), (ethene,O-trans)(β-alaninato-N,O)chlorido(η2-ethene)platinate(II), (l-histidinato-N,N)chlorido(η2-ethene)platinate(II), and (olefin,N-trans)(l-alaninato-N,O)chlorido(η2-(but-3-en-1-yl)-2-acetoxy benzoate)platinate(II), respectively) is determined by the inner coordination sphere, and the addition of an amino acid ligand significantly reduces the rate of nucleophilic substitutions by sulfur-containing nucleophiles. In particular, the N,ethylene-trans isomers reacted only to a low extent with the free thiol in glutathione, while the O,ethylene-trans isomer was completely consumed within 2 h. Complex 4, the new lead compound, showed low reactivity towards S-nucleophiles in general, which confirms the concept of using amino acids as biocompatible bidentate ligands to adjust the reactivity and stability of this kind of metallodrugs.