Anticancer Tungstenocenes with a Diverse Set of (O,O–), (O,S–) and (O,N–) 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 (Corresponding author), Bernhard K. Keppler

Publications: Contribution to journalArticlePeer Reviewed

Abstract

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.

Original languageEnglish
Article number1875
JournalPharmaceutics
Volume15
Issue number7
DOIs
Publication statusPublished - Jul 2023

Austrian Fields of Science 2012

  • 301207 Pharmaceutical chemistry
  • 301904 Cancer research

Keywords

  • 3D cell culture
  • anticancer
  • metal-based drugs
  • multicellular tumor spheroids
  • tungstenocenes

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