Keywords: breast cancer, ferrocifen, indene metabolites, P450-dependent oxidation, quinone methides Ferrociphenols have been found to have high antiproliferative activity against estrogenindependent breast cancer cells. The rat and human liver microsome-mediated metabolism of three compounds of the ferrocifen (FC) family, 1,1-bis(4-hydroxy-phenyl)-2-ferrocenylbut-1-ene (FC1), 1-(4-hydroxyphenyl)-1-(phenyl)-2-ferrocenyl-but-1-ene (FC2), and 1-[4-(3-dimethylaminopropoxy)phenyl]-1-(4-hydroxyphenyl)-2-ferrocenyl-but-1-ene (FC3), was studied.Three main metabolite classes were identified: quinone methides (QMs) deriving from twoelectron oxidation of FCs, cyclic indene products (CPs) deriving from acid-catalyzed cyclization of QMs, and allylic alcohols (AAs) deriving from hydroxylation of FCs. These metabolites are generated by cytochromes P450 (P450s), as shown by experiments with either N-benzylimidazole as a P450 inhibitor or recombinant human P450s. Such P450-dependent oxidation of the phenol function and hydroxylation of the allylic CH 2 group of FCs leads to the formation of QM and AA metabolites, respectively. Some of the new ferrociphenols obtained in this study were found to exhibit remarkable antiproliferative effects toward MDA-MB-231 hormone-independent breast cancer cells.

Keywords: Drug design / Antitumor agents / Osmium / Ruthenium / Metallocenes / Ferrocifen Three osmium analogues 3a-3c of hydroxytamoxifen were prepared. The antiproliferative effects of these complexes were measured against two breast cancer cell lines (MCF-7 and MDA-MB-231) and compared with those of their homologues of ferrocene (1a-1c) and ruthenocene (2a-2c). The tamoxifen-like complexes 2c and 3c derived from osmium and ruthenium show good cytotoxicities against the two cell lines (IC 50 values between 2 and 3 μM), albeit lower than those of ferrocifen 1c (IC 50 between 0.5 and 0.8 μM). These complexes induce senescence of the cells at low concentration (0.5 μM). The mono-and diphenol complexes of osmium and ruthenium show little cytotoxicity against the two cell lines (2a, 2b, 3a, 3b; IC 50 ≈ 30 μM), whereas the iron analogues show