Selective estrogen receptor modulators in the ruthenocene series. Synthesis and biological behavior.
A series of ruthenocene derivatives, 1-[4-(O(CH(2))(n)()N(CH(3))(2))phenyl]-1-(4-hydroxyphenyl)-2-ruthenocenylbut-1-ene, with n = 2-5, based on the structure of the breast cancer drug tamoxifen has been prepared. These compounds were obtained, via a McMurry cross-coupling reaction, as a mixture of Z and E isomers that could not be separated by HPLC. The relative binding affinity values for estrogen receptor alpha (ERalpha) for n = 2 and 3 were very high (85 and 53%) and surpassed even that of hydroxytamoxifen (38.5%), the active metabolite of tamoxifen. Ruthenocene derivatives act as anti-estrogens as effective (n = 2) or slightly more effective (n = 3-5) than hydroxytamoxifen on ERalpha-positive breast cancer cell lines but, unlike ferrocifens, do not show antiproliferative effects on ERalpha-negative breast cancer cell lines. Electrochemical studies showed that the ruthenocifen radical cations are unstable, which may account for this behavior. Some of these compounds could be useful as radiopharmaceuticals for ERalpha-positive breast cancer tumors.
Pigeon
Pascal
P
Laboratoire de Chimie et Biochimie des Complexes Moléculaires, Ecole Nationale Supérieure de Chimie de Paris, UMR CNRS 7576, 11, rue Pierre et Marie Curie, 75231 Paris Cedex 05, France.
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Siden
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Vessières
Anne
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Huché
Michel
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Hillard
Elizabeth A
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Salomon
Emmanuel
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Jaouen
Gérard
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D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001943:Breast Neoplasms; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D004563:Electrochemistry; D020847:Estrogen Receptor Modulators / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000378:metabolism; D005260:Female; D006801:Humans; D008958:Models, Molecular; D009376:Neoplasms, Hormone-Dependent; D009942:Organometallic Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012428:Ruthenium; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
D000970:Antineoplastic Agents; D020847:Estrogen Receptor Modulators; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D009942:Organometallic Compounds; D013629:Tamoxifen; C016721:ruthenocene; C016601:afimoxifene; D012428:Ruthenium