The presence of a ferrocenyl unit on an estrogenic molecule is not always sufficient to generate in vitro cytotoxicity.
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.
Vessières
Anne
A
Laboratoire de Chimie Organométallique, UMR 7576, ENSCP, 11 rue P. et M. Curie, 75231 Paris Cedex 05, France. a-vessieres@enscp.fr
Spera
Daniela
D
Top
Siden
S
Misterkiewicz
Boguslav
B
Heldt
Jan-Martin
JM
Hillard
Elizabeth
E
Huché
Michel
M
Plamont
Marie-Aude
MA
Napolitano
Elio
E
Fiaschi
Rita
R
Jaouen
Gérard
G
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
D000970:Antineoplastic Agents; D004967:Estrogens; D005296:Ferrous Compounds; D000075163:Metallocenes; D011960:Receptors, Estrogen; C004998:ferrocene