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 [Fe2Cp2(CO)2(μ-CO)(μ-CSMe)]CF3SO3 (Cp = η5-C5H5) 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) and correlates with the lipophilicity. Four compounds showed IC50 values up to the nanomolar range in colorectal, breast, and ovarian cancer cell lines. The most potent compound, [Fe2Cp2(CO)(PPh3)(μ-CO)(μ-CSMe)]CF3SO3, revealed 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.