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Article Dans Une Revue Journal of Organometallic Chemistry Année : 2007

Organometallic diphenols: The importance of the organometallic moiety on the expression of a cytotoxic effect on breast cancer cells

Résumé

We have recently reported that the ferrocenyl diphenol compound 1,1-di(4-hydroxyphenyl)-2-ferrocenyl-but-1-ene 1 exhibited strong in vitro anti-proliferative effects on both hormone dependent (MCF7, IC50 = 0.7 μM) and hormone independent (MDA-MB231, IC50 = 0.6 μM) breast cancer cells. In order to assess the importance of the ferrocenyl motif, we have prepared a series of analogs using the organometallic fragments (η5-C5H4)Cp∗Fe (7), ((η5-C5H4)(CH3)2phospholyl)Fe (9), (η5-C5H4)CpRu (10), (η5-C5H4)Re(CO)3 (11), and (η5-C5H4)Mn(CO)3 (12), and the chlorinated ferrocenyl derivative 1,1-di(4-hydroxyphenyl)-2-ferrocenyl-4-chloro-but-1-ene (4). The nature of the organometallic moiety had a strong influence on estrogen receptor alpha (ERα) recognition, with relative binding affinity (RBA) values ranging from 0.55% to 10.8%. The second isoform of the estrogen receptor, ERβ, was better able to accommodate these compounds, with RBA values ranging from 8.9% to 17.1%. Molecular modeling studies suggest that the orientation of the compounds and their interactions with the residues of ERα and ERβ binding sites are very similar. A study on the MCF7 hormone dependent breast cancer cell line revealed an anti-proliferative effect for the ferrocenyl phenols 1 and 4, while the other compounds displayed either a proliferative effect (9–12), or no effect (7). The anti-proliferative effect of 1 and 4 is also evident in the MDA-MB231 hormone independent breast cancer cell line (IC50(4) = 1 μM), and can be attributed to the cytotoxicity of these compounds, while the other compounds showed no effect on this cell line. The cytotoxicity of 1 and 4 may arise from electron delocalization in the radical cation in alkaline conditions, possibly resulting in a cytotoxic quinone methide formation, while the other complexes do not undergo the formation of this entity, as evidenced by the electrochemical results
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hal-01230402 , version 1 (15-03-2024)

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Elisabeth A. Hillard, Anne Vessières, Siden Top, Pascal Pigeon, Konrad Kowalski, et al.. Organometallic diphenols: The importance of the organometallic moiety on the expression of a cytotoxic effect on breast cancer cells. Journal of Organometallic Chemistry, 2007, 692 (6), pp.1315-1326. ⟨10.1016/j.jorganchem.2006.10.041⟩. ⟨hal-01230402⟩
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