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[N,N′-Bis(salicylidene)-1,2-phenylenediamine]metal complexes with cell death promoting properties

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Abstract

We developed N,N′-bis(salicylidene)-1,2-phenylenediamine (salophene, 1) as a chelating agent for metal ions such as Mn(II/III), Fe(II/III), Co(II), Ni(II), Cu(II), and Zn(II). The resulting complexes, from which owing to the carrier ligand a selective mode of action is assumed, were tested for antiproliferative effects on the MCF-7 breast cancer cell line. The cytotoxicity in this assay depended on the nature of the transition metal used. Iron complexes in oxidation states +II and +III (3, 4) strongly reduced cell proliferation in a concentration-dependent manner, whereas, e.g., the manganese analogues 5 and 6 were only marginally active. Therefore, the [N,N′-bis(salicylidene)-1,2-phenylenediamine]iron(II/III) complexes 3 and 4 were selected for studies on the mode of action. Both complexes possessed high activity against various tumor cells, for instance, MDA-MB-231 mammary carcinoma cells as well as HT-29 colon carcinoma cells. They were able to generate reactive oxygen species, showed DNA binding, and induced apoptosis. Exchange of 1 by N,N′-bis(salicylidene)-1,2-cyclohexanediamine (saldach, 2) yielding complexes 7 and 8 reduced the in vitro effects drastically. An unequivocal mode of action cannot be deduced from these results, but it seems to be very likely that cell death is caused by interference with more than one intracellular target.

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Acknowledgment

The financial support of the Deutsche Forschungsgemeinschaft (project FOR 630) is greatly appreciated.

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Authors and Affiliations

  1. Institute of Pharmacy, Freie Universität Berlin, Königin-Luise-Strasse 2+4, 14195, Berlin, Germany

    Annegret Hille, Ingo Ott & Ronald Gust

  2. Institute of Pharmacy and Molecular Biotechnology, Im Neuenheimer Feld 364, 69120, Heidelberg, Germany

    Ana Kitanovic, Igor Kitanovic, Hamed Alborzinia, Elke Lederer & Stefan Wölfl

  3. Inorganic Chemistry I, Bioinorganic Chemistry, Faculty of Chemistry and Biochemistry, Ruhr-Universität Bochum, Universitätsstrasse 150, 44801, Bochum, Germany

    Nils Metzler-Nolte, Caroline Bischof & Ulrich Schatzschneider

  4. Analytical Chemistry, Faculty of Chemistry and Biochemistry, Ruhr-Universität Bochum, Universitätsstrasse 150, 44801, Bochum, Germany

    Sven Schäfer & William S. Sheldrick

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  1. Annegret Hille
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  2. Ingo Ott
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  3. Ana Kitanovic
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  13. Ronald Gust
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Correspondence to Ronald Gust.

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Hille, A., Ott, I., Kitanovic, A. et al. [N,N′-Bis(salicylidene)-1,2-phenylenediamine]metal complexes with cell death promoting properties. J Biol Inorg Chem 14, 711–725 (2009). https://doi.org/10.1007/s00775-009-0485-9

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  • DOI: https://doi.org/10.1007/s00775-009-0485-9

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