title: A-CD estrogens. I. Substituent effects, hormone potency, and receptor subtype selectivity in a new family of flexible estrogenic compounds.
abstract: Long-term use of estrogen supplements by women leads to an increased risk of breast and uterine cancers. Possible mechanisms include metabolism of estradiol and compounds related to tumor-initiating quinones, and ligand-induced activation of the estrogen receptors ERα and ERβ which can cause cancer cell proliferation, depending on the ratio of receptors present. One therapeutic goal would be to create a spectrum of compounds of variable potency for ERα and ERβ, which are resistant to quinone formation, and to determine an optimum point in this spectrum. We describe the synthesis, modeling, binding affinities, hormone potency, and a measure of quinone formation for a new family of A-CD estrogens, where the A-C bond is formed by ring coupling. Some substituents on the A-ring increase hormone potency, and one compound is much less quinone-forming than estradiol. These compounds span a wide range of receptor subtype selectivities and may be useful in hormone replacement therapy.
authors.affiliation: Department of Chemistry, Carleton University, 1125 Colonel By Drive, Ottawa, Ontario, K1S 5B6, Canada. jim_wright@carleton.ca
authors.forename: James S
authors.initials: JS
authors.lastname: Wright
authors.forename: Hooman
authors.initials: H
authors.lastname: Shadnia
authors.forename: James M
authors.initials: JM
authors.lastname: Anderson
authors.forename: Tony
authors.initials: T
authors.lastname: Durst
authors.forename: Muhammad
authors.initials: M
authors.lastname: Asim
authors.forename: Mohamed
authors.initials: M
authors.lastname: El-Salfiti
authors.forename: Christine
authors.initials: C
authors.lastname: Choueiri
authors.forename: M A Christine
authors.initials: MA
authors.lastname: Pratt
authors.forename: Samantha C
authors.initials: SC
authors.lastname: Ruddy
authors.forename: Rosanna
authors.initials: R
authors.lastname: Lau
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: Carlson
authors.forename: John A
authors.initials: JA
authors.lastname: Katzenellenbogen
authors.forename: Peter J
authors.initials: PJ
authors.lastname: O'Brien
authors.forename: Luke
authors.initials: L
authors.lastname: Wan
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D002460:Cell Line; D004958:Estradiol / Q000737:chemistry*; D045166:Estradiol Congeners / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000819:agonists*; D047629:Estrogen Receptor beta / Q000819:agonists*; D005461:Fluorine / Q000737:chemistry; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects; D006801:Humans; D008024:Ligands; D008297:Male; D008958:Models, Molecular; D015394:Molecular Structure; D011809:Quinones / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020218:Response Elements; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: D045166:Estradiol Congeners; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D008024:Ligands; D011809:Quinones; D005461:Fluorine; D004958:Estradiol