SYNTHESIS AND BIOLOGICAL-ACTIVITY OF NEW HALO-STEROIDAL ANTIESTROGENS

Antiestrogen therapy is the most widely used endocrine manipulation for the treatment of breast cancer, especially in postmenopausal women. Unfortunately, the compounds presently available possess mixed agonistic/antagonistic activity, thus potentially limiting their therapeutic efficacy. Following the observations that an aliphatic chain at the 7-alpha-position of 17-beta-estradiol does not prevent binding to the estrogen receptor while halogenation of estradiol can increase the affinity of its binding (expressed as RBA) to the estrogen receptor, we have synthesized a series of new steroidal antiestrogens (6-10) which possess both an 7-alpha-undecanamide group and an halogen atom (Cl, Br, or I) at the 16-alpha-position. The stereochemistry of these compounds was unambiguously established by high-field (400-MHz) nuclear magnetic resonance. Some of the compounds obtained possess potent in vivo antiestrogenic activity. At the low twice daily 3-mu-g dose, 16-alpha-chloro 3,17-beta-diol amide, 16-alpha-iodo 3,17-beta-diol amide, 16-alpha-bromo 3,17-beta-diol amide, 16-alpha-chloro 3,17-alpha-diol amide, and 16-alpha-bromo 3,17-alpha-diol amide inhibit by 74, 63, 52, 35, and 60%, respectively, the estradiol-induced stimulation of uterine weight in ovariectomized Balb/c mice while 78-99% blockade of estradiol action is achieved at the 20-mu-g dose. These new antiestrogens show no estrogenic activity on uterine weight at the doses used while tamoxifen (2-[4-(1,2-diphenyl-1-butenyl)phenoxy]-N,N-dimethylethanamine) shows full estrogenic activity and is only a weak partial antiestrogen in the same assay.