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

Author(s): 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
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 W^IV to W^V 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.
Organisation(s): Department of Inorganic Chemistry, Department of Analytical Chemistry, Core Facility Crystal Structure Analysis, Mass Spectrometry Centre
External organisation(s): Research Cluster Translational Cancer Therapy Research
Journal: Pharmaceutics
Volume: 15
DOI: https://doi.org/10.3390/pharmaceutics15071875
Publication date: 07-2023
Peer reviewed: Yes
Austrian Fields of Science 2012: 301207 Pharmaceutical chemistry, 301904 Cancer research
Keywords
ASJC Scopus subject areas: Pharmaceutical Science
Sustainable Development Goals: SDG 3 - Good Health and Well-being
Portal url: https://ucrisportal.univie.ac.at/en/publications/9635d437-5642-4629-af80-dc32b1a58f5b