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Reaction of Zn7metallothionein with cis- and trans-[Pt(N-donor)2Cl2] anticancer complexes: trans-Pt(II) complexes retain their N-donor ligands


Knipp, M; Karotki, A V; Chesnov, S; Natile, G; Sadler, P J; Brabec, V; Vasák, M (2007). Reaction of Zn7metallothionein with cis- and trans-[Pt(N-donor)2Cl2] anticancer complexes: trans-Pt(II) complexes retain their N-donor ligands. Journal of Medicinal Chemistry, 50(17):4075-4086.

Abstract

Intrinsic and acquired resistance are major drawbacks of platinum-based cancer therapy. The protein superfamily of cysteine- and ZnII-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)2Cl2] compounds and [Pt(dien)Cl]Cl, 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 platinum-based anticancer drugs.

Intrinsic and acquired resistance are major drawbacks of platinum-based cancer therapy. The protein superfamily of cysteine- and ZnII-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)2Cl2] compounds and [Pt(dien)Cl]Cl, 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 platinum-based anticancer drugs.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Functional Genomics Center Zurich
08 University Research Priority Programs > Systems Biology / Functional Genomics
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:23 August 2007
Deposited On:28 Dec 2009 07:27
Last Modified:05 Apr 2016 13:35
Publisher:American Chemical Society
ISSN:0022-2623
Publisher DOI:https://doi.org/10.1021/jm070271l
PubMed ID:17665893

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