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=H2O or MeOH), in CH2Cl2 and CH3OH solvents, initially provided the kinetic eta(1)-N complexes, cls-4 (OTf- CH3OH) and trans-5 (OTf- CH3OH), which underwent a novel, regioselective, intramolecular N-pi rearrangement to give the cis and trans-eta(6)-phenol substituted complexes, cis-6 and trans-7, via eta(2)-N,O, eta(1)-O, and ether aromatic ring eta(6) intermediates. Recent density functional theory (DFT) calculations showed a preferred ground state for eta(1)-N; eta(2).N,O; eta(1)-O; and the eta(6) complexes, including the prominent roles of the triflate anion (OTf-) and solvent molecules (CH2Cl2 and CH3OH), and provided further steric, electronic, and thermodynamic data on the mechanism of the N-pi rearrangement. The eta(6) complex, cis-6, was shown to be an antagonist for ER alpha 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, ER alpha and ER beta, 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.