The replacement of a phenol group by an aniline or acetanilide group enhances the cytotoxicity of 2-ferrocenyl-1,1-diphenyl-but-1-ene compounds against breast cancer cells

• Published in: Journal of organometallic chemistry Vol. 694; pp. 895 - 901
• Main Authors: Pigeon, Pascal, Top, Siden, Zekri, Ouardia O., Hillard, Elisabeth A., Vessieres, Anne A., Plamont, M.A., Buriez, Olivier O., Labbé, Eric E., Huché, Michel, Boutamine, Sultana S., Amatore, Christian, Jaouen, G.
• Format: Journal Article
• Language: English
• Published: Elsevier 15-03-2009
• Subjects: Chemical Sciences; Coordination chemistry; Medicinal Chemistry; Bioorganometallic chemistry; Breast cancer; Iron; Anti-cancer drugs; Ferrocene
• ISSN: 0022-328X; 0022-328X
• DOI: 10.1016/j.jorganchem.2008.11.035

We have previously shown that conjugated ferrocenyl p-phenols show strong cytotoxic effects against both the hormone-dependent MCF-7 and hormone-independent MDA-MB-231 breast cancer cell lines, possibly via oxidative quinone methide formation. We now present a series of analogous amine and acetamide compounds: 2-ferrocenyl-1-(4-aminophenyl)-1-phenyl-but-1-ene (Z+E-2), 2-ferrocenyl-1-(4-N-acetylaminophenyl)-1-phenyl-but-1-ene (Z-3), and their corresponding organic molecules 1-(4-aminophenyl)-1,2-bis-phenyl-but-1-ene (Z+E-4) and 1-(4-N-acetamidophenyl)-1,2-bis-phenyl-but-1-ene (Z+E-5). All of the compounds have adequate relative binding affinity values for the estrogen receptor; between 2.8% and 5.7% for ERα, and between 0.18% and 15.5% for ERβ, as well as exothermic ligand binding in in silico ER docking experiments. Compounds 2 and 3 show dual estrogenic/cytotoxic activity on the MCF-7 cell line; they are proliferative at low concentrations (0.1 μM) and antiproliferative at high concentrations (10 μM). On the MDA-MB-231 cell line, the ferrocenyl complexes 2 and 3 are antiproliferative with IC50 values of 0.8 μM for 2 and 0.65 μM for 3, while the purely organic molecules 4 and 5 show no effect. Electrochemical experiments suggest that both 2 and 3 can be transformed to oxidized quinoid-type species, analogous to what had previously been observed for the ferrocene phenols.