Oxidative Metabolism of Ferrocene Analogues of Tamoxifen: Characterization and Antiproliferative Activities of the Metabolites |
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| Authors: | Dr. Marie‐Aude Richard Dr. Didier Hamels Dr. Pascal Pigeon Dr. Siden Top Dr. Patrick M. Dansette Hui Zhi Shirley Lee Dr. Anne Vessières Dr. Daniel Mansuy Prof. Gérard Jaouen |
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| Affiliation: | 1. PSL, Chimie ParisTech, 11 rue Pierre et Marie Curie, 75005 Paris (France);2. Sorbonne Universités, UPMC Univ. Paris 6, UMR 8232, IPCM, 4 place Jussieu, 75005 Paris (France);3. CNRS, UMR 8232, IPCM, 75005 Paris (France);4. Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, UMR 8601 CNRS, Université Paris Descartes, PRES Paris Cité Sorbonne, 45 rue des Saints Pères, 75270, Paris Cedex 06 (France) |
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| Abstract: | Ferrociphenols have been found to have high antiproliferative activity against estrogen‐independent breast cancer cells. The rat and human liver microsome‐mediated metabolism of three compounds of the ferrocifen ( FC ) family, 1,1‐bis(4‐hydroxyphenyl)‐2‐ferrocenyl‐but‐1‐ene ( FC1 ), 1‐(4‐hydroxyphenyl)‐1‐(phenyl)‐2‐ferrocenyl‐but‐1‐ene ( FC2 ), and 1‐[4‐(3‐dimethylaminopropoxy)phenyl]‐1‐(4‐hydroxyphenyl)‐2‐ferrocenyl‐but‐1‐ene ( FC3 ), was studied. Three main metabolite classes were identified: quinone methides ( QM s) deriving from two‐electron oxidation of FC s, cyclic indene products ( CP s) deriving from acid‐catalyzed cyclization of QM s, and allylic alcohols ( AA s) deriving from hydroxylation of FC s. These metabolites are generated by cytochromes P450 (P450s), as shown by experiments with either N‐benzylimidazole as a P450 inhibitor or recombinant human P450s. Such P450‐dependent oxidation of the phenol function and hydroxylation of the allylic CH2 group of FC s leads to the formation of QM and AA metabolites, respectively. Some of the new ferrociphenols obtained in this study were found to exhibit remarkable antiproliferative effects toward MDA‐MB‐231 hormone‐independent breast cancer cells. |
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| Keywords: | breast cancer ferrocifen indene metabolites P450‐dependent oxidation quinone methides |
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