When ferrocene and diiron organometallics meet: triiron vinyliminium complexes exhibit strong cytotoxicity and cancer cell selectivity

Cationic triiron complexes resulting from the conjugation of the ferrocenyl skeleton (Fc) with a diiron bis-cyclopentadienyl core through a variable vinyliminium linker, [Fe₂Cp₂(CO)(μ-CO){μ-η¹:η³-C(Fc)CHCN(R)(R′)}]CF₃SO₃ ([2a-i]CF₃SO₃, Cp = η⁵-C₅H₅, R, R′ = alkyl, aryl), were synthesised in 70-94% yield, and the homologous nitrate salt was also prepared in one case ([2h]NO₃). The neutral derivatives [Fe₂Cp₂(CO)(μ-CO){μ-η¹:η³-C(Fc)CHC(CN)NMe₂}], 3, and [FeCp(CO){CN(Me)(Xyl)CHC(Fc)C(=O)}], 4 (Xyl = 2,6-C₆H₃Me₂), were obtained in ca. 70% yield by reactions of the respective precursors [2h]CF₃SO3₃ and [2i]CF₃SO₃ with NBu₄CN and pyrrolidine, respectively. All products were purified by alumina chromatography and fully characterised by analytical and spectroscopic methods, and by single crystal X-ray diffraction in the cases of [2a]CF₃SO₃ and 3. The cytotoxicity of the complexes was assessed on A2780, A2780cisR and BxPC-3 cancer cell lines, and the nontumoral Balb/3T3 clone A31. Most of the cationic complexes display IC₅₀ values in the low micromolar/nanomolar range concerning the cancer cell lines, and up to 35 times higher values on the nontumoral cells. In order to shed light on the mode of action, selected complexes were further characterised by cyclic voltammetry and spectroelectrochemical experiments, and assessed for their potential to trigger ROS production and to interact with a range of biomolecules, i.e. a synthetic dodecapeptide as a simplified model for thioredoxin reductase (TrxR-pept), some model proteins (cytochrome c, hen egg-white lysozyme, ubiquitin, bovine serum albumin, superoxide dismutase and human carbonic anhydrase) and one single-stranded oligonucleotide (ODN2).