title: Oxidative metabolism of ferrocene analogues of tamoxifen: characterization and antiproliferative activities of the metabolites.
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 (QMs) deriving from two-electron oxidation of FCs, cyclic indene products (CPs) deriving from acid-catalyzed cyclization of QMs, and allylic alcohols (AAs) deriving from hydroxylation of FCs. 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 FCs 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.
authors.affiliation: PSL, Chimie ParisTech, 11 rue Pierre et Marie Curie, 75005 Paris (France).|Sorbonne Universités, UPMC Univ. Paris 6, UMR 8232, IPCM, 4 place Jussieu, 75005 Paris (France).|CNRS, UMR 8232, IPCM, 75005 Paris (France).
authors.forename: Marie-Aude
authors.initials: MA
authors.lastname: Richard
authors.affiliation: PSL, Chimie ParisTech, 11 rue Pierre et Marie Curie, 75005 Paris (France).
authors.forename: Didier
authors.initials: D
authors.lastname: Hamels
authors.affiliation: PSL, Chimie ParisTech, 11 rue Pierre et Marie Curie, 75005 Paris (France).|Sorbonne Universités, UPMC Univ. Paris 6, UMR 8232, IPCM, 4 place Jussieu, 75005 Paris (France).|CNRS, UMR 8232, IPCM, 75005 Paris (France).
authors.forename: Pascal
authors.initials: P
authors.lastname: Pigeon
authors.affiliation: Sorbonne Universités, UPMC Univ. Paris 6, UMR 8232, IPCM, 4 place Jussieu, 75005 Paris (France). siden.top@upmc.fr.|CNRS, UMR 8232, IPCM, 75005 Paris (France). siden.top@upmc.fr.
authors.forename: Siden
authors.initials: S
authors.lastname: Top
authors.affiliation: 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).
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Dansette
authors.affiliation: PSL, Chimie ParisTech, 11 rue Pierre et Marie Curie, 75005 Paris (France).|Sorbonne Universités, UPMC Univ. Paris 6, UMR 8232, IPCM, 4 place Jussieu, 75005 Paris (France).|CNRS, UMR 8232, IPCM, 75005 Paris (France).
authors.forename: Hui Zhi Shirley
authors.initials: HZ
authors.lastname: Lee
authors.affiliation: Sorbonne Universités, UPMC Univ. Paris 6, UMR 8232, IPCM, 4 place Jussieu, 75005 Paris (France).|CNRS, UMR 8232, IPCM, 75005 Paris (France).
authors.forename: Anne
authors.initials: A
authors.lastname: Vessières
authors.affiliation: 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). Daniel.Mansuy@parisdescartes.fr.
authors.forename: Daniel
authors.initials: D
authors.lastname: Mansuy
authors.affiliation: PSL, Chimie ParisTech, 11 rue Pierre et Marie Curie, 75005 Paris (France). gerad.jaouen@chimie-paristech.fr.|Sorbonne Universités, UPMC Univ. Paris 6, UMR 8232, IPCM, 4 place Jussieu, 75005 Paris (France). gerad.jaouen@chimie-paristech.fr.|CNRS, UMR 8232, IPCM, 75005 Paris (France). gerad.jaouen@chimie-paristech.fr.
authors.forename: Gérard
authors.initials: G
authors.lastname: Jaouen
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003500:Cyclization; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005296:Ferrous Compounds / Q000378:metabolism*; D006801:Humans; D000075163:Metallocenes; D008861:Microsomes / Q000378:metabolism; D010084:Oxidation-Reduction; D013629:Tamoxifen / Q000378:metabolism*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D005296:Ferrous Compounds; D000075163:Metallocenes; D013629:Tamoxifen; D003577:Cytochrome P-450 Enzyme System; C004998:ferrocene
keywords: P450-dependent oxidation; breast cancer; ferrocifen; indene metabolites; quinone methides