title: Synthesis and biological evaluation of 4-(hydroxyalkyl)estradiols and related compounds.
abstract: A series of synthetic estrogens containing hydroxyalkyl side chains at the C-4 position of the A ring were designed as metabolically stable analogs of 4-hydroxyestradiol, a catechol estrogen. These synthetic steroids would facilitate investigations on the potential biological role of catechol estrogens and also enable further examination of the structural and electronic constraints on the A ring in the interaction of estrogens with the estrogen receptor. Catechol estrogens are implicated as possible causative agents in estrogen-induced tumorigenesis. 4-Hydroxyestradiol has weaker affinity for the estrogen receptor and exhibits lower estrogenic activity in vivo; on the other hand, the catechol estrogens are prone to further oxidative metabolism and can form reactive intermediates. This report describes the synthesis and initial biochemical evaluation of 4-(hydroxyalkyl)estrogens and 4-(aminoalkyl)estradiols. The 4-(hydroxyalkyl)estrogens were prepared by oxidative hydroboration of 4-alkenylestradiols. The alkenylestradiols were obtained via a Stille cross-coupling between a MOM-protected 4-bromoestradiol and an alkenylstannane. The (4-aminoalkyl)estrogens were prepared from the hydroxyalkyl derivatives with phthalimide under Mitsunobu conditions. The substituted estradiols were evaluated for estrogen receptor binding activity in MCF-7 human mammary carcinoma cells, and 4-(hydroxymethyl)estradiol 1 exhibited the highest affinity with an apparent EC50 value of 364 nM. The relative activities for mRNA induction of the pS2 gene in MCF-7 cell cultures by the 4-(hydroxyalkyl)estrogens closely parallel the relative binding affinities. 4-(Hydroxymethyl)estradiol 1 did not stimulate the growth of MCF-7 cells at concentrations up to 1 microM. Thus, 4-(hydroxymethyl)estradiol 1 exhibited similar estrogen receptor affinity as the catechol estrogen, 4-hydroxyestradiol, and may prove useful in the examination of the biological effects of 4-hydroxyestrogens.
authors.affiliation: Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, Ohio State University, Columbus 43210, USA.
authors.forename: C J
authors.initials: CJ
authors.lastname: Lovely
authors.forename: A S
authors.initials: AS
authors.lastname: Bhat
authors.forename: H D
authors.initials: HD
authors.lastname: Coughenour
authors.forename: N E
authors.initials: NE
authors.lastname: Gilbert
authors.forename: R W
authors.initials: RW
authors.lastname: Brueggemeier
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D002455:Cell Division / Q000187:drug effects; D004958:Estradiol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D002393:Estrogens, Catechol / Q000138:chemical synthesis* / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D009376:Neoplasms, Hormone-Dependent / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D011960:Receptors, Estrogen / Q000378:metabolism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured / Q000187:drug effects
chemical_list: D002393:Estrogens, Catechol; D011960:Receptors, Estrogen; D004958:Estradiol; C014036:4-hydroxyestradiol