Anticancer Diiron Vinyliminium Complexes: A Structure–Activity Relationship Study

A series of 16 novel diiron complexes of general formula [Fe(2)Cp(2)(CO)(μ-CO){μ-η(1):η(3)-C(R′)C(R″)CN(R)(Y)}]CF(3)SO(3) (2–7), bearing different substituents on the bridging vinyliminium ligand, was synthesized in 69–95% yields from the reactions of diiron μ-aminocarbyne precursors with various alkynes. The products were characterized by elemental analysis, IR, (1)H and (13)C NMR spectroscopy; moreover the X-ray structures of 2c (R = Y = CH(2)Ph, R′ = R″ = Me) and 3a (R = CH(2)CH=CH(2), Y = R′ = Me, R″ = H) were ascertained by single-crystal X-ray diffraction studies. NMR and UV–Vis methods were used to assess the D(2)O solubility, the stability in aqueous solution at 37 °C and the octanol–water partition coefficients of the complexes. A screening study evidenced a potent cytotoxicity of 2–7 against the A2780 cancer cell line, with a remarkable selectivity compared to the nontumoral Balb/3T3 cell line; complex 4c (R = Cy, Y = R′ = R″ = Me) revealed as the most performant of the series. The antiproliferative activity of a selection of complexes was also assessed on the cisplatin-resistant A2780cisR cancer cell line, and these complexes were capable of inducing a significant ROS production. Moreover, ESI-MS experiments indicated the absence of interaction of selected complexes with cytochrome c and the potentiality to inhibit the thioredoxin reductase enzyme (TrxR).