Anticancer Tungstenocenes with a Diverse Set of (<i>O,O</i>–), (<i>O</i>,<i>S</i>–) and (<i>O</i>,<i>N</i>–) Chelates—A Detailed Biological Study Using an Improved Evaluation via 3D Spheroid Models
Klaudia Cseh,
Iker Berasaluce,
Valentin Fuchs,
Alexandra Banc,
Andreas Schweikert,
Alexander Prado-Roller,
Michaela Hejl,
Debora Wernitznig,
Gunda Koellensperger,
Michael A. Jakupec,
Wolfgang Kandioller,
Michael S. Malarek,
Bernhard K. Keppler
Affiliations
Klaudia Cseh
Institute of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, Waehringer Straße 42, A 1090 Vienna, Austria
Iker Berasaluce
Institute of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, Waehringer Straße 42, A 1090 Vienna, Austria
Valentin Fuchs
Institute of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, Waehringer Straße 42, A 1090 Vienna, Austria
Alexandra Banc
Institute of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, Waehringer Straße 42, A 1090 Vienna, Austria
Andreas Schweikert
Institute of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, Waehringer Straße 42, A 1090 Vienna, Austria
Alexander Prado-Roller
Institute of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, Waehringer Straße 42, A 1090 Vienna, Austria
Michaela Hejl
Institute of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, Waehringer Straße 42, A 1090 Vienna, Austria
Debora Wernitznig
Institute of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, Waehringer Straße 42, A 1090 Vienna, Austria
Gunda Koellensperger
Institute of Analytical Chemistry, Faculty of Chemistry, University of Vienna, Waehringer Straße 38, A 1090 Vienna, Austria
Michael A. Jakupec
Institute of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, Waehringer Straße 42, A 1090 Vienna, Austria
Wolfgang Kandioller
Institute of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, Waehringer Straße 42, A 1090 Vienna, Austria
Michael S. Malarek
Institute of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, Waehringer Straße 42, A 1090 Vienna, Austria
Bernhard K. Keppler
Institute of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, Waehringer Straße 42, A 1090 Vienna, Austria
The synthesis, characterization and biological activity of tungstenocenes with varying biologically active (O,O–), (S,O–) and (N,O–) chelates are described. Complexes were characterized by 1H and 13C NMR, elemental analysis, ESI-mass spectrometry, FT-IR spectroscopy and X-ray diffraction analysis. The aqueous stability was studied by UV/Vis spectroscopy and the WIV to WV process by cyclic voltammetry. The cytotoxicity was determined by the MTT assay in A549, CH1/PA-1 and SW480 cancer cells as well as in IMR-90 human fibroblasts. Extensive biological evaluation was performed in three other human cancer cell lines (HCT116, HT29 and MCF-7) in monolayer and multicellular tumor spheroid cultures to better understand the mode of action. Lead compounds showed promising in vitro anticancer activity in all cancer cell lines. Further studies yielded important insights into apoptosis induction, ROS generation, different patterns in metal distribution (detected by LA-ICP-TOF-MS), changes in KI67 (proliferation marker) expression and DNA interactions. The results based on qualitative and quantitative research designs show that complexes containing (S,O–) chelates are more active than their (O,O–) and (N,O–) counterparts. The most striking results in spheroid models are the high antiproliferative capacity and the different distribution pattern of two complexes differing only in a W–S or W–O bond.
