title: Synthesis and biological activity of new halo-steroidal antiestrogens.
abstract: 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-micrograms 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-micrograms 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.
authors.affiliation: MRC Group in Molecular Endocrinology, CHUL Research Center, Quebec, Canada.
authors.forename: C
authors.initials: C
authors.lastname: Levesque
authors.forename: Y
authors.initials: Y
authors.lastname: Merand
authors.forename: J M
authors.initials: JM
authors.lastname: Dufour
authors.forename: C
authors.initials: C
authors.lastname: Labrie
authors.forename: F
authors.initials: F
authors.lastname: Labrie
mesh_terms: D000818:Animals; D055598:Chemical Phenomena; D002621:Chemistry; D004958:Estradiol / Q000031:analogs & derivatives*; D004965:Estrogen Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology; D005260:Female; D051379:Mice; D008807:Mice, Inbred BALB C; D013329:Structure-Activity Relationship; D014599:Uterus / Q000187:drug effects
chemical_list: D004965:Estrogen Antagonists; D004958:Estradiol