Arene Variation of Highly Cytotoxic Tridentate Naphthoquinone-Based Ruthenium(II) Complexes and In-Depth In Vitro Studies
Klaudia Cseh,
Heiko Geisler,
Kristina Stanojkovska,
Julia Westermayr,
Philipp Brunmayr,
Dominik Wenisch,
Natalie Gajic,
Michaela Hejl,
Martin Schaier,
Gunda Koellensperger,
Michael A. Jakupec,
Philipp Marquetand,
Wolfgang Kandioller
Affiliations
Klaudia Cseh
Institute of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, Waehringer Str. 42, 1090 Vienna, Austria
Heiko Geisler
Institute of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, Waehringer Str. 42, 1090 Vienna, Austria
Kristina Stanojkovska
Institute of Theoretical Chemistry, Faculty of Chemistry, University of Vienna, Waehringer Str. 17, 1090 Vienna, Austria
Julia Westermayr
Wilhelm-Ostwald-Institute for Physical and Theoretical Chemistry, Faculty of Chemistry and Mineralogy, University of Leipzig, Linnéstr. 2, 04103 Leipzig, Germany
Philipp Brunmayr
Institute of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, Waehringer Str. 42, 1090 Vienna, Austria
Dominik Wenisch
Institute of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, Waehringer Str. 42, 1090 Vienna, Austria
Natalie Gajic
Institute of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, Waehringer Str. 42, 1090 Vienna, Austria
Michaela Hejl
Institute of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, Waehringer Str. 42, 1090 Vienna, Austria
Martin Schaier
Institute of Analytical Chemistry, Faculty of Chemistry, University of Vienna, Waehringer Str. 38, 1090 Vienna, Austria
Gunda Koellensperger
Institute of Analytical Chemistry, Faculty of Chemistry, University of Vienna, Waehringer Str. 38, 1090 Vienna, Austria
Michael A. Jakupec
Institute of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, Waehringer Str. 42, 1090 Vienna, Austria
Philipp Marquetand
Institute of Theoretical Chemistry, Faculty of Chemistry, University of Vienna, Waehringer Str. 17, 1090 Vienna, Austria
Wolfgang Kandioller
Institute of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, Waehringer Str. 42, 1090 Vienna, Austria
The main purpose of this study was to synthesize a new set of naphthoquinone-based ruthenium(II) arene complexes and to develop an understanding of their mode of action. This study systematically reviews the steps of synthesis, aiming to provide a simplified approach using microwave irradiation. The chemical structures and the physicochemical properties of this novel group of compounds were examined by 1H-NMR and 13C-NMR spectroscopy, X-ray diffractometry, HPLC-MS and supporting DFT calculations. Several aspects of the biological activity were investigated in vitro, including short- and long-term cytotoxicity tests, cellular accumulation studies, detection of reactive oxygen species generation, apoptosis induction and NAD(P)H:quinone oxidoreductase 1 (NQO1) activity as well as cell cycle analysis in A549, CH1/PA-1, and SW480 cancer cells. Furthermore, the DNA interaction ability was studied in a cell-free assay. A positive correlation was found between cytotoxicity, lipophilicity and cellular accumulation of the tested complexes, and the results offer some important insights into the effects of the arene. The most obvious finding to emerge from this study is that the usually very chemosensitive CH1/PA-1 teratocarcinoma cells showed resistance to these phthiocol-based organometallics in comparison to the usually less chemosensitive SW480 colon carcinoma cells, which pilot experiments suggest as being related to NQO1 activity.
