title: The presence of a ferrocenyl unit on an estrogenic molecule is not always sufficient to generate in vitro cytotoxicity.
abstract: We recently reported the dual (antihormonal and cytotoxic) functionality of ferrocifens, which are organometallic complexes derived from hydroxytamoxifen, the standard molecule in the treatment of hormone-dependent breast cancers. To test the hypothesis that the presence of a ferrocenyl substituent on molecules with an affinity for the estrogen receptor is sufficient to give them cytotoxic properties in vitro, we prepared complexes derived from estradiol with a ferrocenyl substituent at positions 7alpha and 17alpha. The complexes thus obtained retain a satisfactory level of affinity for the estrogen receptor (RBA values higher than 12 %). At low concentrations (0.1-1 microM) the complexes show an estrogenic effect in vitro equivalent to that of estradiol on hormone-dependent (MCF-7) breast cancer cells, and no cytotoxic effect on hormone-independent (MDA-MB-231) breast cancer cells. At high concentrations (up to 50 microM) the 17alpha-ethynylferrocenyl estradiol and 7alpha-ferrocenylmethylthio estradiol become cytotoxic (IC(50)=13.2 microM and 18.8 microM, respectively) while the 17alpha-ferrocenylestradiol remains non toxic. The low toxicity of these compounds support our hypothesis that electronic communication between the ferrocenyl and phenol moieties in the hydroxyferrocifens series is a key parameter in the generation of cytotoxic effects at submicromolar concentrations.
authors.affiliation: Laboratoire de Chimie Organométallique, UMR 7576, ENSCP, 11 rue P. et M. Curie, 75231 Paris Cedex 05, France. a-vessieres@enscp.fr
authors.forename: Anne
authors.initials: A
authors.lastname: Vessières
authors.forename: Daniela
authors.initials: D
authors.lastname: Spera
authors.forename: Siden
authors.initials: S
authors.lastname: Top
authors.forename: Boguslav
authors.initials: B
authors.lastname: Misterkiewicz
authors.forename: Jan-Martin
authors.initials: JM
authors.lastname: Heldt
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Hillard
authors.forename: Michel
authors.initials: M
authors.lastname: Huché
authors.forename: Marie-Aude
authors.initials: MA
authors.lastname: Plamont
authors.forename: Elio
authors.initials: E
authors.lastname: Napolitano
authors.forename: Rita
authors.initials: R
authors.lastname: Fiaschi
authors.forename: Gérard
authors.initials: G
authors.lastname: Jaouen
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects*; D004563:Electrochemistry; D004967:Estrogens / Q000737:chemistry*; D005296:Ferrous Compounds / Q000737:chemistry*; D006801:Humans; D000075163:Metallocenes; D008958:Models, Molecular; D011960:Receptors, Estrogen / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D004967:Estrogens; D005296:Ferrous Compounds; D000075163:Metallocenes; D011960:Receptors, Estrogen; C004998:ferrocene