Am(m)ines Make the Difference: Organoruthenium Am(m)ine Complexes and Their Chemistry in Anticancer Drug Development

Authors

  • Maria V. Babak,

    1. Institute of Inorganic Chemistry, University of Vienna, Waehringer Strasse 42, 1090 Vienna (Austria)
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  • Samuel M. Meier ,

    1. Institute of Inorganic Chemistry, University of Vienna, Waehringer Strasse 42, 1090 Vienna (Austria)
    2. Research Platform “Translational Cancer Therapy Research”, University of Vienna, Waehringer Strasse 42, 1090 Vienna (Austria)
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  • Anton A. Legin,

    1. Institute of Inorganic Chemistry, University of Vienna, Waehringer Strasse 42, 1090 Vienna (Austria)
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  • Mahsa S. Adib Razavi,

    1. Institute of Inorganic Chemistry, University of Vienna, Waehringer Strasse 42, 1090 Vienna (Austria)
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  • Alexander Roller,

    1. Institute of Inorganic Chemistry, University of Vienna, Waehringer Strasse 42, 1090 Vienna (Austria)
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  • Dr. Michael A. Jakupec ,

    1. Institute of Inorganic Chemistry, University of Vienna, Waehringer Strasse 42, 1090 Vienna (Austria)
    2. Research Platform “Translational Cancer Therapy Research”, University of Vienna, Waehringer Strasse 42, 1090 Vienna (Austria)
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  • Prof. Dr. Bernhard K. Keppler ,

    1. Institute of Inorganic Chemistry, University of Vienna, Waehringer Strasse 42, 1090 Vienna (Austria)
    2. Research Platform “Translational Cancer Therapy Research”, University of Vienna, Waehringer Strasse 42, 1090 Vienna (Austria)
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  • Prof. Dr. Christian G. Hartinger 

    Corresponding author
    1. Institute of Inorganic Chemistry, University of Vienna, Waehringer Strasse 42, 1090 Vienna (Austria)
    2. Research Platform “Translational Cancer Therapy Research”, University of Vienna, Waehringer Strasse 42, 1090 Vienna (Austria)
    3. School of Chemical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142 (New Zealand), Fax: (+64) 9-3737-599 ext. 87422
    • Institute of Inorganic Chemistry, University of Vienna, Waehringer Strasse 42, 1090 Vienna (Austria)

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Abstract

With the aim of systematically studying fundamental structure–activity relationships as a basis for the development of RuII arene complexes (arene=p-cymene or biphenyl) bearing mono-, bi-, or tridentate am(m)ine ligands as anticancer agents, a series of ammine, ethylenediamine, and diethylenetriamine complexes were prepared by different synthetic routes. Especially the synthesis of mono-, di-, and triammine complexes was found to be highly dependent on the reaction conditions, such as stoichiometry, temperature, and time. Hydrolysis and protein-binding studies were performed to determine the reactivity of the compounds, and only those containing chlorido ligands undergo aquation or form protein adducts. These properties correlate well with in vitro tumor-inhibiting potency of the compounds. The complexes were found to be active in anticancer assays when meeting the following criteria: stability in aqueous solution and low rates of hydrolysis and binding to proteins. Therefore, the complexes least reactive to proteins were found to be the most cytotoxic in cancer cells. In general, complexes with biphenyl as arene ligand inhibited the growth of tumor cells more effectively than the cymene analogues, consistent with the increase in lipophilicity. This study highlights the importance of finding a proper balance between reactivity and stability in the development of organometallic anticancer agents.

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