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Reactivity of Cu(II)-, Zn(II)- and Fe(II)-Thiosemicarbazone Complexes with Glutathione and Metallothionein: from Stability over Dissociation to Transmetallation

Abstract

Thiosemicarbazones (TSCs) are a class of strong metal ion ligands, that are under investigation for several applications, such as anticancer treatment. In addition to the ligands only, supposed to exert their activity upon interaction with metal ions in the cells, also preformed metal-TSC complexes are widely studied, predominantly with the essential metal ions iron, copper and zinc. Currently it is not clear what the active species are, which complexes are present and what are the biological targets. Here we study the complexes of copper(II), zinc(II) and iron(II) with the three TSCs, PT, 3-AP (Triapine) and Dp44mT, (latter two are currently in clinical trials) concerning their reactivity with glutathione (GSH) and Zn7-metallothionein (Zn7MT-1, 2 and 3). These two cysteine-containing molecules could have a major impact on metal-TSC complexes because they are abundant in the cytosol and nucleus, they are strong metal ligands and have the potential to reduce Cu(II) and Fe(III). Our results indicate the Fe(II)-TSC are stable in the presence of typical cytosolic concentrations of GSH and Zn7MT. In contrast, all the three Cu(II)-TSCs react rapidly by reduction of Cu(II) to Cu(I), which is then transferred to MT. This suggests that Cu(II)-TSCs are rapidly dissociated in a cytosolic type environment and the catalytic generation of reactive oxygen species by Cu(II)-TSCs is stopped. Moreover, in the case Cu(II)-Dp44mT, a transmetallation with Zn(II) from MT occurred. The reaction of Zn(II)-TSCs is ligand dependent, from predominant dissociation for PT and 3-AP, to very little dissociation of Zn(II)-Dp44mT2. These results indicate that GSH and Zn7MT can be important factors in the fate of Cu(II)- and Zn(II)-TSCs. In particular for Cu, the chemistry is complex, and such reactions might be also occurring for other families of Cu-complexes used in cancer treatment or for other applications.

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Publication details

The article was received on 15 Mar 2019, accepted on 04 Apr 2019 and first published on 05 Apr 2019


Article type: Paper
DOI: 10.1039/C9MT00061E
Citation: Metallomics, 2019, Accepted Manuscript

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    Reactivity of Cu(II)-, Zn(II)- and Fe(II)-Thiosemicarbazone Complexes with Glutathione and Metallothionein: from Stability over Dissociation to Transmetallation

    A. Santoro, B. Vileno, O. Palacios, M. D. Peris-Diaz, G. Riegel, C. Gaiddon, A. Krezel and P. Faller, Metallomics, 2019, Accepted Manuscript , DOI: 10.1039/C9MT00061E

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