The inhibition of estrogen is a particularly useful strategy for the treatment of hormone-dependent breast tumors in postmenopausal females and possibly in premenopausal women and as a chemosuppressive in women at high risk of developing breast cancer. Nonsteroidal antiestrogens which exhibit potent antitumor effects represent a major advance in the management of breast cancer. Considerable effort by many research groups has been devoted to the search for novel pure nonsteroidal antiestrogens with the hope of finding antitumor agents that would be useful in estrogen receptor (ER) positive or estrogen receptor (ER) negative disease. The reasoning behind the search for pure antiestrogens is based on the recognition that antiestrogens generally possess the partial estrogenic activity and a complete blockade of estrogen action cannot be achieved by agents like tamoxifen. Novel pure antiestrogens should be more effective than partial agonist in reducing the mitogenic action of estrogen on the growth of breast tumors and complete ablation of hormonal-dependent tumor growth is very desirable since it could provide a more rapid and longer-lasting remission. In addition, pure antiestrogens could be more effective in patients who experience a relapse during tamoxifen therapy, serving as a second-line treatment, and have the potential of demonstrating greater efficacy in first-line treatment of advanced breast cancer. This review covers the chemistry of the experimental and potentially useful nonsteroidal antiestrogens and the only agent, tamoxifen, used in the therapy of breast cancer with special emphasis on structure-activity relationships. Special attention was paid to the structural classes [1,2-bis(hydroxyphenyl)ethane; 2-phenylindoles; indolo[2,1-a] isoquinolines; 2-phenylbenzo[b] thiophenes; dibenzo[a,g]quinolizinones; triarylpropenones (TAPs); 3,4-dihydro-1-naphthalenyl­ methanones; 3-aroyl-2-arylbenzo[b]thiophenes; 2,3-diaryi-2H-1-benzopyrans; triphenyl­ ethylenes (TPEs); dichlorodiarylcyclopropanes (DDACs) and the 1,1-dichloro-2,2,3-triarylcyclo­ propanes (DTACs)] whose agents demonstrated particular activity in the in vitro receptor binding affinity assay and the in vivo uterotrophic and antiuterotrophic assays. Where possible, the in vitro antiproliferative properties of these agents in cell culture assays also were discussed.

Molecular structures and conformational characteristics of a series of 1,1-dichloro-2,2,3-triarylcyclopropanes (DTACs), which were reported previously to be distinctly antiestrogenic and inhibitors of the estrogen-receptor-positive MCF-7 human breast cancer cells in culture, are reported. In addition, structural and conformational features of the DTACs were compared to the first-known nonsteroidal antiestrogen, MER25, and the clinically useful antiestrogen Tamoxifen. The molecular structures of four DTAC compounds were determined by X-ray diffraction. Crystallographic structures show that the DTAC molecules have nearly the same relative conformation for the three aryl rings which is designated as a "nonpropeller" conformation in contrast to the observed "propeller" conformation for the three rings in all known triarylethylenes. Systematic conformational searches were performed to find the conformational preferences of DTACs, MER25, and Tamoxifen using idealized model compounds built from their respective crystal structure. Energy-minimization and conformational-search studies demonstrated that all DTAC molecules have a common, single global minimum energy conformer for their central core containing the dichlorotriarylcyclopropyl system, which is similar to that found in their crystal structures. Conformational search of MER25 showed that the molecule can assume a number of low-energy conformers of which two, one anti (A1) and one gauche (G1A), have about the same energy. The anti conformation is similar to the one observed in its crystal structure and resembles the estrogenic E-isomer of Tamoxifen, while the lowest energy gauche conformer of MER25 resembles more closely the antiestrogenic Z-isomer of Tamoxifen. NMR spectroscopic analysis of MER25 showed that the molecule exists predominantly in the anti conformation in solution. A comparative review of the structural features and bioactivities of Tamoxifen, DTACs, and MER25 provides a possible explanation for their low estrogen receptor binding affinity which is common to these compounds together with their antiestrogenic activity.

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