A bridging thiocarbyne ligand in diiron( i ) complexes enables unconventional isomerization pathways and structural diversity leading to potent cytotoxicity

Eight diiron(i) bis-cyclopentadienyl complexes with a bridging methylthiocarbyne ligand were prepared from the tris-carbonyl precursor [Fe2 Cp2 (CO)2 (μ-CO)(μ-CSMe)]CF3 SO3 (Cp = η5 -C5 H5) through the substitution of one or two terminal carbonyls with a variety of monodentate ligands including phosphanes/phosphite, alkyl/aryl isocyanides or iodide. All compounds were isolated in 57–84% yield and characterized by IR and multinuclear NMR spectroscopy and by X-ray diffraction in five representative cases. Their bonding, stereochemistry and isomerization processes were investigated by NMR and DFT techniques. The water solubility and octanol–water partition coefficient heavily depend on the different monodentate ligands. All cationic complexes displayed substantial inertness in aqueous and cell culture medium solutions at 37 °C over 24–48 h. Their cytotoxicity was assessed on a panel of human cancer cell lines (HCT 116, MCF-7 and A2780). Four compounds showed IC50 values down to the nanomolar range in colorectal, breast and ovarian cancer cell lines. The most potent compound, [Fe2 Cp2 (CO)(PPh3)(μ-CO)(μ-CSMe)]CF3 SO3, revealed enhanced Fe accumulation and significant disruption of cell redox homeostasis in A2780 cells that resulted in caspase-independent apoptotic cell death. The six times higher sensitivity of A2780 cells in comparison to healthy fibroblasts (MRC-5) underlines the potential of this compound to preferably target cancer cells. Overall, the variation of monodentate ligands on a diiron(i) bis-cyclopentadienyl μ-thiocarbyne core represents a simple strategy to obtain robust compounds with tuneable physico-chemical properties and possibly also a remarkable anticancer activity.