Synthetic and mechanistic pathways of cis and trans-hydroxytamoxifen drug derivatives reacting with Cp*Rh complexes that involve η1-N, η2-N,O, η1-O, and η6 bonding modes, via a novel N-π rearrangement; relative binding affinities and computer docking studies of cis and trans-η6-Cp*Rh-hydroxytamoxifen complexes at the estrogen, ERα and ERβ receptors, and growth inhibition to breast cancer cells.
The reactions of the breast cancer drug metabolite derivatives of tamoxifen, cis and trans-hydroxytamoxifen, cis-1 and trans-2, with [Cp*Rh(L)(3)](2+) complexes (L = H(2)O or MeOH), in CH(2)Cl(2) and CH(3)OH solvents, initially provided the kinetic η(1)-N complexes, cis-4 (OTf(-), CH(3)OH) and trans-5 (OTf(-), CH(3)OH), which underwent a novel, regioselective, intramolecular N-π rearrangement to give the cis and trans-η(6)-phenol substituted complexes, cis-6 and trans-7, via η(2)-N,O, η(1)-O, and ether aromatic ring η(6) intermediates. Recent density functional theory (DFT) calculations showed a preferred ground state for η(1)-N; η(2)-N,O; η(1)-O; and the η(6) complexes, including the prominent roles of the triflate anion (OTf(-)), and solvent molecules (CH(2)Cl(2) and CH(3)OH), and provided further steric, electronic, and thermodynamic data on the mechanism of the N-π rearrangement. The η(6) complex, cis-6, was shown to be an antagonist for ERα estrogen receptor binding, in a competition experiment with the female hormone, estradiol; therefore, computer docking studies of this biologically active complex at the estrogen receptors, ERα and ERβ, also provided information on the binding modes and thermodynamic parameters, while bioassay results provided growth inhibition data on both hormone dependent and independent breast cancer cell lines.
Ecole Nationale Supérieure de Chimie de Paris, Laboratoire Charles Friedel, UMR 7223, 11, rue Pierre et Marie Curie, F-75231 Paris Cedex 05, France.
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D018931:Antineoplastic Agents, Hormonal / Q000138:chemical synthesis / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D047628:Estrogen Receptor alpha / Q000037:antagonists & inhibitors / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000037:antagonists & inhibitors / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism; D005260:Female; D006801:Humans; D008958:Models, Molecular; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000494:pharmacology; D011485:Protein Binding; D012238:Rhodium / Q000737:chemistry; D013237:Stereoisomerism; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D013816:Thermodynamics
D018931:Antineoplastic Agents, Hormonal; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004967:Estrogens; D009942:Organometallic Compounds; D013629:Tamoxifen; C016601:afimoxifene; D012238:Rhodium