Rxn Zn7 Metallothionein w cis- & trans-[Pt(N-donor)2Cl2] Anticancer trans-PtII Complexes Retain N-Donor Ligands
Abstract
Intrinsic and acquired resistance are major drawbacks of platinum-based cancer therapy. The protein superfamily of cysteine- and ZnII-rich proteins, metallothioneins (MT), eff inactivate these drugs because of the strong reactivity of Pt compounds with S-donor molecules. In this study the reactions of human Zn7MT-2 with twelve cis/trans-Pt(N-donor)2Cl2 compounds and Pt(dien)ClCl, including new generation drugs, were investigated and the products characterized. A comparison of reaction kinetics revealed that trans-PtII compounds react faster with Zn7MT-2 than cis-PtII compounds. The characterization of the products showed that while all ligands in cis-PtII compounds were replaced by cysteine thiolates, trans-PtII compounds retained their N-donor ligands, thus remaining in a potentially active form. These results provide an increased understanding of the role of MT in the acquired resistance to Pt-based anticancer drugs.
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