The Medicinal Chemistry of Nonsteroidal Antiestrogens: A Review

Abstract

Abstract: 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.