Reaction of Zn(7)Metallothionein with cis- and trans-[Pt(N-donor)(2)Cl-2] anticancer complexes: trans-Pt-II complexes retain their N-donor ligands

Publikace: JOURNAL OF MEDICINAL CHEMISTRY 50, 4075-4086 Autoři: Knipp, M., Karotki, AV., Chesnov, S., Natile, G., Sadler, PJ., Brabec, V., Vasak, M. Rok: 2007


Intrinsic and acquired resistance are major drawbacks of platinum-based cancer therapy. The protein superfamily of cysteine- and Zn-II-rich proteins, metallothioneins (MT), efficiently inactivate these antitumor drugs because of the strong reactivity of platinum compounds with S-donor molecules. In this study the reactions of human Zn7MT-2 with twelve cis/trans-[Pt(N-donor)(2)Cl-2] compounds and [Pt(dien)Cl]Cl, including new generation drugs, were investigated and the products characterized. A comparison of reaction kinetics revealed that trans-Pt-II compounds react faster with Zn7MT-2 than cis-Pt-II compounds. The characterization of the products showed that while all ligands in cis-Pt-II compounds were replaced by cysteine thiolates, trans-Pt-II 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 platinum-based anticancer drugs.