Specific displacement of glutathione from the Pt(II)-glutathione adduct by Cu(II) in neutral phosphate buffer

The Pt-S bond of Pt(II)-glutathione (GS-Pt) complex was dissociable in neutral phosphate buffer at room temperature in the presence of Cu(II) ion. In addition, the chloro species, Pt(terpy)Cl+, was isolated and identified as the major cleavage product of Pt(terpy)(GS)(2+) complex when CuCl2 was used. The Pt-S bond dissociation of Pt(terpy)(GS)(2+) mediated by Cu(II) ion was shown to be a pH dependent process in the range of 4.5-8.0. At pH <7, MMR evidence was obtained for a S-bridged heterodinuclear unit formed between Pt(terpy)(GS)(2+) and the Cu(II) ion; however, no Pt-S bond dissociation was observed up to 24 h. At pH greater than or equal to 7, NMR data suggested coordination of the amide nitrogen of GSH of Pt(terpy)(GS)(2+) to the Cu(II) ion. We propose that the coordination of the amide nitrogen to the Cu(II) ion, together with the formation of the S-bridged heterodinuclear unit, induce the Pt-S bond dissociation in Pt(terpy)(GS)(2+). These results may be exploited to develop a molecular activator to regenerate the anticancer activity in cisplatin pro-drugs. (C) 1998 Elsevier Science Inc. All rights reserved.