Synthesis of Triphenylethylene Bisphenols as Aromatase Inhibitors That Also Modulate Estrogen Receptors

Abstract

A series of triphenylethylene bisphenol analogues of the selective estrogen receptor modulator (SERM) tamoxifen were synthesized and evaluated for their abilities to inhibit aromatase, bind to estrogen receptor-α (ER-α) and estrogen receptor-β (ER-β), and antagonize the activity of β-estradiol in MCF-7 human breast cancer cells. The long-range goal has been to create dual aromatase inhibitor (AI)/selective estrogen receptor modulators (SERMs). The hypothesis is that in normal tissue the estrogenic SERM activity of a dual AI/SERM could attenuate the undesired effects stemming from global estrogen depletion caused by the AI activity of a dual AI/SERM, while in breast cancer tissue the antiestrogenic SERM activity of a dual AI/SERM could act synergistically with AI activity to enhance the antiproliferative effect. The potent aromatase inhibitory activities and high ER-α and ER-β binding affinities of several of the resulting analogues, together with the facts that they antagonize β-estradiol in a functional assay in MCF-7 human breast cancer cells and they have no E/Z isomers, support their further development in order to obtain dual AI/SERM agents for breast cancer treatment.

A new Suzuki synthesis of triphenylethylenes that inhibit aromatase and bind to estrogen receptors α and β

“…The dianiline 12d was docked in the active sites of aromatase (PDB code 3s79 28 ) and ER-α (PDB code 3ert 29 ) using GOLD 3.0. These studies capitalized on the secure molecular modeling foundation established by previous investigations of the binding of ( E )-norendoxifen and several analogues to both aromatase and ER-α, which involved GOLD 3.0 docking, Amber 10 molecular dynamics simulations and Amber parm99 energy minimizations, as well as MM-PBSA binding energy calculations 18–20 The calculated models were consistent with experimentally determined SAR. As shown in Figure 4, the overall pose of the ligand is close to that present in the previously published models of ( E )-norendoxifen and its analogues bound to aromatase.…”

“…As shown in Figure 4, the overall pose of the ligand is close to that present in the previously published models of ( E )-norendoxifen and its analogues bound to aromatase. 18–20 The amino group on the aniline ring that is trans to the nitrophenyl ring hydrogen bonds to the backbone carbonyl of Asp309. In common with the present situation, all of the previously published models involve hydrogen bonding to Asp309.…”

“…Norendoxifen ( 4 , Figure 1) was found to be an active tamoxifen metabolite that binds to ERs and is also a potent AI, 17, 18 and that discovery has provided a platform for the design and synthesis of dual AI/SERMs based on the structure of norendoxifen. 18–20 Subsequent work proved that installation of a 4′-hydroxy group on norendoxifen to make the metabolite 5 increased potency vs. aromatase and the two estrogen receptors. 19 More recently, it was determined that the aminoethoxy side chain of norendoxifen can be replaced by a phenolic hydroxyl group and the activity vs. all three receptors (AI, ER-α, and ER-β) maintained as long as the ethyl group is replaced by an imidazolylmethyl moiety (e.g.…”

“…compound 6 ) that can coordinate to the iron of aromatases. 20 Initial attempts to install a 4′-amino group in norendoxifen derivatives led to mixed results that were generally disappointing with regard to simultaneous binding to all three receptors. 20 In spite of that, the present investigation was launched in an attempt to simultaneously optimize activity against aromatase, ER-α, and ER-β by replacement of the hydroxyl groups of 4′-hydroxynorendoxifen ( 5 ) derivatives with amino groups or nitro groups and elimination of the 2′-aminoethyl moiety.…”

“…20 Initial attempts to install a 4′-amino group in norendoxifen derivatives led to mixed results that were generally disappointing with regard to simultaneous binding to all three receptors. 20 In spite of that, the present investigation was launched in an attempt to simultaneously optimize activity against aromatase, ER-α, and ER-β by replacement of the hydroxyl groups of 4′-hydroxynorendoxifen ( 5 ) derivatives with amino groups or nitro groups and elimination of the 2′-aminoethyl moiety. The hypothesis was that activity against aromatase, ER-α, and ER-β could be maintained in aminated derivatives even in the absence of imidazole and aminoethyl functionality using a structure-based drug design approach that would take advantage of the known structures of the receptors.…”