A series of ruthenocene derivatives, 1-[4-(O(CH(2))(n)()N(CH(3))(2))phenyl]-1-(4-hydroxyphenyl)-2-ruthenocenylbut-1-ene, with n = 2-5, based on the structure of the breast cancer drug tamoxifen has been prepared. These compounds were obtained, via a McMurry cross-coupling reaction, as a mixture of Z and E isomers that could not be separated by HPLC. The relative binding affinity values for estrogen receptor alpha (ERalpha) for n = 2 and 3 were very high (85 and 53%) and surpassed even that of hydroxytamoxifen (38.5%), the active metabolite of tamoxifen. Ruthenocene derivatives act as anti-estrogens as effective (n = 2) or slightly more effective (n = 3-5) than hydroxytamoxifen on ERalpha-positive breast cancer cell lines but, unlike ferrocifens, do not show antiproliferative effects on ERalpha-negative breast cancer cell lines. Electrochemical studies showed that the ruthenocifen radical cations are unstable, which may account for this behavior. Some of these compounds could be useful as radiopharmaceuticals for ERalpha-positive breast cancer tumors.

A series of organometallic antiestrogens based on the OH-tamoxifen (OH-Tam) skeleton and bearing the (eta(5)-C(5)H(4))Re(I)(CO)(3) unit has been prepared by using McMurry coupling for the purpose of studying their biological behaviour. The cyclopentadienylrhenium tricarbonyl moiety is indeed stable in biological media, compact, lipophilic and easy to handle. Furthermore, this study allowed us to select the best candidates for subsequent use as radiopharmaceuticals either for imaging or therapy by using appropriate radionucleides, namely (99m)Tc and (188)Re. In these molecules the beta-phenyl group of OH-Tam has been replaced by the (eta(5)-C(5)H(4))Re(CO)(3) moiety, and the length of the dimethylamino side chain --O(CH(2))(n)N(CH(3))(2) was varied (n=2, 3, 4, 5 and 8). The compounds 7 a-7 e were obtained as mixtures of their Z and E isomers, which could be separated by semipreparative HPLC. Unlike their ferrocene homologues, the compounds do not isomerise in solution. Structural identification was carried out with NMR spectroscopy by using the HMBC and NOE techniques and was confirmed by the X-ray structural determination of (E)-7 a (n=2). These molecules were more lipophilic than OH-Tam (log P(o/w)=4.5-6.3) and they were all reasonably well recognized by the two forms of the estrogen receptor (ERalpha and ERbeta). For example, (Z)-7 b (n=3) has high relative binding affinity (RBA) values of 31 % for ERalpha and 16.8 % for ERbeta. The antiproliferative effects of two pairs of isomers, (Z)- and (E)-7 b (n=3) and (Z)- and (E)-7 d (n=5), were studied at a molarity of 1 microM on two breast-cancer cell lines, MCF7 (ERalpha positive) and MDA-MB231 (ERalpha negative). These molecules had an antiproliferative effect on MCF7 cells slightly higher than that of OH-Tam and no effect on MDA-MB231 cells. Thus, the antiproliferative effect observed on the MCF7 cells seemed essentially to be linked to an antiestrogenic effect. Molecular modelling studies have allowed us to rationalise these effects and select the best compounds for future development of a radioactive series.