The cytotoxicity of some ferrocenium salts and the lack of activity of the corresponding ferrocenes has been already demonstrated. The cytotoxic activity in different conditions of decamethylferrocenium tetrafluoroborate (DEMFc(+)) in comparison with four other ferrocenium derivatives on MCF-7 cell line is reported. The relative stability in aqueous solutions with different buffering agents is investigated by means of UV-vis spectroscopy and correlated to the cytotoxic properties of the compounds. DEMFc(+), the most stable compound, shows the highest efficiency in inhibiting cell growth (IC(50) 35 microM, for 48 h treatment). Relaxation time measurements point out the involvement of water molecules in the degradation process. ESR results confirm the ability of ferrocenium cations to produce oxygen radical species as a consequence of their degradation in water. Oxygen-dependent formation of both hydroxyl and superoxide radicals is established by the spin-trapping technique. A direct evidence of the DEMFc(+) radical production into the viable cells is obtained by means of fluorescence-activated cell sorter (FACS) analysis that reveals a dose-dependent growth of 8-oxoguanine, the initial product of the guanine oxidation. This DNA oxidative stress justifies the cytotoxic effect of DEMFc(+). Furthermore, the cytotoxic cooperative effect of bleomycin, an iron-dependent antitumor drug, and DEMFc(+) has been tested. We have demonstrated the synergic effect between the two drugs, that is explained by the complementary oxidative damage inflicted to DNA as well as by the increasing of bleomycin activation by the iron(II/III) species available in the cell compartment from ferrocenium degradation.

This paper describes the synthesis and the spectroscopic characterisation of cis-dichloro[N-(4-(17alpha-ethynylestradiolyl)-benzyl)-ethylenediamine]platinum(II) and cis-diamino[2-(4-(17alpha-ethynylestradiolyl)-benzoylamino)-malonato]platinum(II). These complexes were synthesised in good yield according to multi-step procedures based on the classical and non-classical Sonogashira coupling reaction, respectively. These compounds retain an acceptable degree of relative binding affinity (RBA) for the alpha form of estrogen receptor. Combined treatment of breast cancer cell lines, namely hormone-sensitive MCF-7 and hormone-insensitive MDA-MB-231 cell lines, indicates that these compounds maintain agonistic activity so that the potential advantage in vehiculation of the cytotoxic moiety by means of the receptor system is counteracted by the proliferative effect of the estrogenic component of the entire molecule, especially at low concentrations.

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