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    Development of Ruthenium Antitumor Drugs that Overcome Multidrug Resistance Mechanisms
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    Institut des Sciences et Ingénierie Chimiques, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland, University Institute of Pathology, Centre Hospitalier Universitaire Vaudois (CHUV), CH-1011 Lausanne, Switzerland, Callerio Foundation Onlus, Via A. Fleming 22-31, 34127, Trieste, Italy, and Dipartimento di Scienze Biomediche, Università di Trieste, Via L. Giorgieri 7-9, 34127, Trieste, Italy
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    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2007, 50, 9, 2166–2175
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    https://doi.org/10.1021/jm070039f
    Published April 10, 2007
    Copyright © 2007 American Chemical Society
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    Abstract

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    Organometallic ruthenium(II) complexes of the general formula [Ru(η6-p-cymene)Cl2(L)] and [Ru(η6-p-cymene)Cl(L)2][BPh4] with modified phenoxazine- and anthracene-based multidrug resistance (MDR) modulator ligands (L) have been synthesized, spectroscopically characterized, and evaluated in vitro for their cytotoxic and MDR reverting properties in comparison with the free ligands. For an anthracene-based ligand, coordination to a ruthenium(II) arene fragment led to significant improvement of cytotoxicity as well as Pgp inhibition activity. A similar, but weaker effect was also observed when using a benzimidazole-phenoxazine derivative as Pgp inhibitor. The most active compound in terms of both Pgp inhibition and cytotoxicity is [Ru(η6-p-cymene)Cl2(L)], where L is an anthracene-based ligand. Studies show that it induces cell death via inhibition of DNA synthesis. Moreover, because the complex is fluorescent, its uptake in cells was studied, and relative to the free anthracene-based ligand, uptake of the complex is accelerated and accumulation of the complex in the cell nucleus is observed.

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    †

     Ecole Polytechnique Fédérale de Lausanne.

    ‡

     Centre Hospitalier Universitaire Vaudois.

    *

     To whom correspondence should be addressed. Dr. Lucienne Juillerat-Jeanneret, University Institute of Pathology, CHUV, Rue de Bugnon 25, CH-1011 Lausanne, Switzerland. Tel.:  +41 21 314 7173. Fax:  +41 21 314 7115. E-mail:  [email protected]. Prof. Paul J. Dyson, Institut des Sciences et Ingénierie Chimiques, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland. Tel.:  +41 (0)21 693 98 54. Fax:  +41 (0)21 693 98 85. E-mail:  [email protected].

    §

     Callerio Foundation Onlus.

    ‖

     Università di Trieste.

    Abbreviations:  anthraimid, N-(anthracen-9-yl)-imidazole; EtOAc, ethyl acetate; MDR, multidrug resistance/resistant; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; Pgp, P-glycoprotein; phenoximid, 2-(imidazol-1-yl)-1-(phenoxazin-10-yl)-ethanone; phenoxbenzimid, 2-(benzimidazol-1-yl)-1-(phenoxazin-10-yl)-ethanone; pta, 1,3,5-triaza-7-phosphaadamantane.

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    Crystallographic data for compounds 9, 10, and 12 in CIF format, the structures of amiodarone, fluphenazine, and cyclosporine A, structures for all synthesized compounds with numbering schemes for NMR assignments, and crystallographic tables.. This material is available free of charge via the Internet at http://pubs.acs.org.

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    Cite this: J. Med. Chem. 2007, 50, 9, 2166–2175
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