We recently reported the dual (antihormonal and cytotoxic) functionality of ferrocifens, which are organometallic complexes derived from
hydroxytamoxifen, the standard molecule in the treatment of
hormone-dependent breast
cancers. To test the hypothesis that the presence of a ferrocenyl substituent on molecules with an affinity for the
estrogen receptor is sufficient to give them cytotoxic properties in vitro, we prepared complexes derived from
estradiol with a ferrocenyl substituent at positions 7alpha and 17alpha. The complexes thus obtained retain a satisfactory level of affinity for the
estrogen receptor (RBA values higher than 12 %). At low concentrations (0.1-1 microM) the complexes show an
estrogenic effect in vitro equivalent to that of
estradiol on
hormone-dependent (MCF-7)
breast cancer cells, and no cytotoxic effect on
hormone-independent (MDA-MB-231)
breast cancer cells. At high concentrations (up to 50 microM) the 17alpha-ethynylferrocenyl
estradiol and 7alpha-ferrocenylmethylthio
estradiol become cytotoxic (IC(50)=13.2 microM and 18.8 microM, respectively) while the 17alpha-ferrocenylestradiol remains non toxic. The low toxicity of these compounds support our hypothesis that electronic communication between the ferrocenyl and
phenol moieties in the hydroxyferrocifens series is a key parameter in the generation of cytotoxic effects at submicromolar concentrations.