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
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Published:2023-07-03
Issue:7
Volume:15
Page:1875
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ISSN:1999-4923
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Container-title:Pharmaceutics
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language:en
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Short-container-title:Pharmaceutics
Author:
Cseh Klaudia1ORCID, Berasaluce Iker1, Fuchs Valentin1, Banc Alexandra1, Schweikert Andreas12, Prado-Roller Alexander1ORCID, Hejl Michaela1, Wernitznig Debora1, Koellensperger Gunda2, Jakupec Michael A.13ORCID, Kandioller Wolfgang13ORCID, Malarek Michael S.1ORCID, Keppler Bernhard K.13
Affiliation:
1. Institute of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, Waehringer Straße 42, A 1090 Vienna, Austria 2. Institute of Analytical Chemistry, Faculty of Chemistry, University of Vienna, Waehringer Straße 38, A 1090 Vienna, Austria 3. Research Cluster “Translational Cancer Therapy Research”, University of Vienna, Waehringer Straße 42, A 1090 Vienna, Austria
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.
Funder
University of Vienna
Subject
Pharmaceutical Science
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