Improving cytotoxic properties of ferrocenes by incorporation of saturated N-heterocycles

A family of ferrocene derivatives of the general formula [Fe(η5-C5H4CH2(p-C6H4)CH2(N-het))2] bearing saturated six- and five-membered N-heterocycles (N-het) was prepared. Reactions of the selected complexes with acids (HCl, acetic acid) afforded either the corresponding hydrochlorides or led to deprotection of the functionalized pendant N-heterocycles. The reaction of [{Ru(η6-p-cymene)Cl2}2] with the corresponding cyclopentadienide derivatives afforded cationic ruthenium complexes [Ru(η6-p-cymene)(η5-C5H4CH2(p-C6H4)CH2(N-het))]Cl while ruthenocenes [Ru(η5-C5H4CH2(p-C6H4)CH2(N-het))2] were formed as minor byproducts. The prepared complexes (20 examples) were characterized by elemental analysis, melting point, NMR and ESI-MS and the molecular structures of selected ferrocene derivatives were determined by X-ray diffraction analysis. The ferrocene derivatives and the ruthenium complexes were tested in vitro for their cytotoxic properties against three cell lines derived from ovarian cancer (A2780, A2780cis, and SK-OV-3) and against non-tumour embryonic cell line HEK293 (human kidney cells). The most active ferrocene derivatives displayed cytotoxicity in submicromolar and low micromolar concentration against both cisplatin (CisPt) sensitive and resistant cells. The results showed a significant effect of the pendant N-heterocycle on the ferrocene derivative toxicity and selectivity against cancer cells. Ultimately, ferrocene derivatives bearing either piperidine or morpholine groups were proposed to be the most promising substitutes for platinum drugs, as they exhibited comparable or even higher activity (in comparison to CisPt) against cancer cells, whereas these compounds were found to exhibit lower toxicity against embryonic HEK293 cells.