title: Synthesis and structure-activity relationships of ferrocenyl tamoxifen derivatives with modified side chains.
abstract: We report here the synthesis and cell-proliferation properties of derivatives of the breast cancer drug tamoxifen, in which the -O(CH(2))(2)N(CH(3))(2) side chain, responsible for the drug's antiestrogenic properties, has been modified by a ferrocenyl moiety. We recently reported the diphenol compound 5, in which this amino chain had been replaced with an acyl-ferrocenyl (-O(CH(2))(2)C(O)[(eta(5)-C(5)H(4))FeCp]) group, and which showed antiproliferative effects against both the hormone-dependent MCF-7 and -independent MDA-MB-231 breast cancer cell lines. We now report the results of a structure-activity relationship (SAR) study, in which the lateral chain length has been varied, the ketone group has been omitted, and the number of phenol groups has been varied. Compounds 1-4, with a side chain lacking the carbonyl function (-O(CH(2))(n)[(eta(5)-C(5)H(4))FeCp], n = 1-4) and which show a decreasing affinity for ERalpha (ER = estrogen receptor) with increasing chain length, act as estrogens on MCF-7 cells, and mild cytotoxics on PC-3 prostate cancer cells, with IC(50) values around 10 microM. The two monophenolic derivatives of 2, 2 a and 2 b, which show a reduced affinity for ERalpha compared to 2, are also estrogenic, but are only slightly cytotoxic. Finally, we have reexamined compound 5 and discovered that its antiproliferative effect against the MCF-7 cell line does not arise from antiestrogenicity as we had originally suspected, but by means of a cytotoxic pathway. This compound is also sensitive to the number of phenol groups as cell death is diminished when one of the hydroxyl groups is omitted (5 a and 5 b). Molecular modeling studies of the ligand-ERalpha binding stability are broadly consistent with the experimental binding affinity results for compounds 2, 2 a, 2 b, 5, 5 a, and 5 b. Electrochemical experiments show that 1-4, 2 a, and 2 b are stable to oxidation on the electrochemical timescale, unlike 5, 5 a, and 5 b, and that cytotoxicity is related to less positive phenol oxidation potentials. The SAR study shows that the presence of a ketone group and two phenol groups is necessary for strong receptor binding and cytotoxic effects, and that all compounds are estrogenic, despite the presence of a bulky side chain.
authors.affiliation: Laboratoire de Chimie et Biochimie des Complexes Moléculaires, UMR CNRS 7576, Ecole Nationale Supérieure de Chimie de Paris, 11 rue Pierre et Marie Curie, 75231 Paris Cedex 05, France.
authors.forename: Anh
authors.initials: A
authors.lastname: Nguyen
authors.forename: Siden
authors.initials: S
authors.lastname: Top
authors.forename: Pascal
authors.initials: P
authors.lastname: Pigeon
authors.forename: Anne
authors.initials: A
authors.lastname: Vessières
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Hillard
authors.forename: Marie-Aude
authors.initials: MA
authors.lastname: Plamont
authors.forename: Michel
authors.initials: M
authors.lastname: Huché
authors.forename: Clara
authors.initials: C
authors.lastname: Rigamonti
authors.forename: Gérard
authors.initials: G
authors.lastname: Jaouen
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D047628:Estrogen Receptor alpha / Q000378:metabolism; D005296:Ferrous Compounds / Q000737:chemistry*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D020128:Inhibitory Concentration 50; D007700:Kinetics; D000075163:Metallocenes; D008958:Models, Molecular; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D018931:Antineoplastic Agents, Hormonal; D047628:Estrogen Receptor alpha; D005296:Ferrous Compounds; D000075163:Metallocenes; D013629:Tamoxifen; C004998:ferrocene