Anticancer Diiron Vinyliminium Complexes: A Structure-Activity Relationship Study

A series of 16 novel diiron complexes of general formula [Fe2Cp2(CO)(mu-CO){mu-eta(1):eta(3)-C(R ')C(R '')CN(R)(Y)}]CF3SO3 (2-7), bearing different substituents on the bridging vinyliminium ligand, was synthesized in 69-95% yields from the reactions of diiron mu-aminocarbyne precursors with various alkynes. The products were characterized by elemental analysis, IR, H-1 and C-13 NMR spectroscopy; moreover the X-ray structures of 2c (R = Y = CH2Ph, R ' = R '' = Me) and 3a (R = CH2CH=CH2, Y = R ' = Me, R '' = H) were ascertained by single-crystal X-ray diffraction studies. NMR and UV-Vis methods were used to assess the D2O solubility, the stability in aqueous solution at 37 degrees 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).

Automated summary

A series of novel diiron complexes were synthesized and evaluated for their anticancer activity, showing potent cytotoxicity against cancer cell lines with remarkable selectivity and good performance in inhibiting cell proliferation. Additionally, these complexes were capable of inducing significant ROS production and had the potential to inhibit the enzyme thioredoxin reductase.