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

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.

Anticancer Metallocenes and Metal Complexes of Transition Elements from Groups 4 to 7

“…A wide range of ligands have been utilized, including thiol derivatives of 3-hydroxy-4-pyrones, to improve the stability and the in vitro cytotoxicity. Recently, the synthesis, characterization, and biological studies of ten tungstenocenes containing (O,O–), (S,O–) or (N,O–) chelates, as well as mode-of-action studies, have been reported [ 103 ]. The bidentate ligand scaffolds have been coordinated to the cytotoxic tungstenocene dichloride, enhancing the cytotoxic activity and increasing the stability of the complexes in aqueous media.…”

“…To find the mode of action of the new tungstenocenes, the potential to form ROS and apoptosis induction have been studied in HCT116, HT29, and MCF-7 cell lines. The most active complexes induced apoptosis and necrosis in a concentration-dependent manner in all three cell lines [ 103 ].…”

“…Tungstenocenes were found be more active than molybdenocenes, which was probably due to their lower oxidat potentials and higher redox activity under physiological conditions compared with th Mo analogs. To find the mode of action of the new tungstenocenes, the potential to fo ROS and apoptosis induction have been studied in HCT116, HT29, and MCF-7 cell lin The most active complexes induced apoptosis and necrosis in a concentration-depend manner in all three cell lines [103]. Complexes have been obtained by exchanging the chlorido ligands of the tungstenocene dichloride (Cp 2 WCl 2 ) by the abovementioned ligands, resulting in positively charged complexes [Cp 2 W(L)] + .…”