Selective estrogen receptor modulators in the ruthenocene series.: Synthesis and biological behavior

A series of ruthenocene derivatives, 1-[4-(O(CH2)(n)N(CH3)(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 (ER alpha) 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 ER alpha-positive breast cancer cell lines but, unlike ferrocifens, do not show antiproliferative effects on ER alpha-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 ER alpha-positive breast cancer tumors.