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Benzimidazol-2-ylidene Gold(I) Complexes Are Thioredoxin Reductase Inhibitors with Multiple Antitumor Properties

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    Benzimidazol-2-ylidene Gold(I) Complexes Are Thioredoxin Reductase Inhibitors with Multiple Antitumor Properties
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    † Institute of Pharmaceutical Chemistry, Technische Universität Braunschweig, Beethovenstrasse 55, 38106 Braunschweig, Germany
    ‡ Institut für Pharmazie und Molekulare Biotechnologie, Ruprecht-Karls-Universität Heidelberg, Im Neuenheimer Feld 364, 69120 Heidelberg, Germany
    § Department of Paedriatric Oncology, Childrens Hospital Cologne, Amsterdamer Strasse 59, 50735 Cologne, Germany
    ∥ Lehrstuhl für Analytische Chemie, Ruhr-Universität Bochum, 44780 Bochum, Germany
    ⊥ Institute of Pharmacy, Freie Universität Berlin, Königin-Luise-Strasse 2 + 4, 14195 Berlin, Germany
    *To whom correspondence should be addressed. Phone: +49 531 3912743. Fax: +495313918456. E-mail: [email protected]
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    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2010, 53, 24, 8608–8618
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    https://doi.org/10.1021/jm100801e
    Published November 17, 2010
    Copyright © 2010 American Chemical Society
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    Abstract

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    Gold(I) complexes such as auranofin have been used for decades to treat symptoms of rheumatoid arthritis and have also demonstrated a considerable potential as new anticancer drugs. The enzyme thioredoxin reductase (TrxR) is considered as the most relevant molecular target for these species. The here investigated gold(I) complexes with benzimidazole derived N-heterocyclic carbene (NHC) ligands 1a−4a represent a promising class of gold coordination compounds with a good stability against the thiol glutathione. TrxR was selectively inhibited by 1a−4a in comparison to the closely related enzyme glutathione reductase, and all complexes triggered significant antiproliferative effects in cultured tumor cells. More detailed studies on a selected complex (2a) revealed a distinct pharmacodynamic profile including the high increase of reactive oxygen species formation, apoptosis induction, strong effects on cellular metabolism (related to cell surface properties, respiration, and glycolysis), inhibition of mitochondrial respiration and activity against resistant cell lines.

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    More details on the reaction of a gold(I) phosphine complex with glutathione (31P NMR and ESI-MS experiments), additional data on the effects on cell proliferation of non tumorigenic cells, video microscopic imaging, ROS formation, inhibition of disulfide reductases in cells, DNA fragmentation, cell viability, and effects in resistant cell lines are presented as a PDF file and as two video files. This material is available free of charge via the Internet at http://pubs.acs.org.

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    Cite this: J. Med. Chem. 2010, 53, 24, 8608–8618
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