Selective Estrogen Receptor Modulators in the Ruthenocene Series. Synthesis and Biological Behavior

Abstract

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.

Sawhorse-type diruthenium tetracarbonyl complexes containing porphyrin-derived ligands as highly selective photosensitizers for female reproductive cancer cells

“…The reasons for this cell specificity remain unknown but must be attributed to the diruthenium structure since the porphyrin alone does not have such specificity properties. Other organometallic compounds conjugated to hydrophobic heterocycles have already been demonstrated to present a specificity to breast estrogen receptors [35,36]. Although, this is not the case for our compounds since both MCF7 (estrogen-receptor positive) and MDA-MB231 (estrogen-receptor negative) breast cancer cell lines were unable to take up our compounds, we hypothesize the targeting of another specific receptor of female reproductive cancer cells since only cervix and ovarian cancers are able to take up the complexes.…”

Tamoxifen: Catalyst for the change to targeted therapy

“…Finally, the importance of understanding the unique pharmacology of tamoxifen can be placed in perspective. In retrospect, tamoxifen could, in fact, be viewed as the lead compound that was essential to initiate the synthesis of a broad range of new SERMs for the treatment of diseases as diverse as osteoporosis (86)(87)(88)(89)(90)(91)(92) and rheumatoid arthritis (93,94) and the subsequent extrapolation of the SERM concept to all members of the nuclear receptor superfamily (76). The advances documented with targeting tamoxifen now offer the promise of designing drugs to treat diseases previously thought to be impossible.…”

The length of the bridging chain in ansa-metallocenes influences their antiproliferative activity against triple negative breast cancer cells (TNBC)

“…In addition, we found that the ruthenocene derivatives are much less active than their ferrocene analogs. 30,41 These characteristics as a whole have been evaluated and contextualized.…”

“…[20][21][22] However, it has not been possible to eradicate a number of serious secondary effects caused by these medications, in particular their high level of general toxicity and tendency to induce resistance. 20 Inspired by the success of platinum compounds, other transition metals have been intensively studied, most recently in organometallic form, for example with Fe, 12,13,16,[23][24][25][26] Ru, 3,[27][28][29][30] Au, 8 Os, 15,31 Ir, 32 rhodium, 33,34 and some of these have now reached the clinical trial stage. Fc-OH-TAM…”