title: Deconstructing estradiol: removal of B-ring generates compounds which are potent and subtype-selective estrogen receptor agonists.
abstract: Estradiol and related estrogens have been widely used as supplements to relieve menopausal symptoms, but they lead to an increased risk of breast and endometrial cancer. Here we report the synthesis of a new family of compounds where we have removed the B-ring from the steroid ABCD structure, and functionalized the A-ring. These A-CD compounds show a preferential affinity for the estrogen receptor subtype ERbeta. Some show binding affinities which are greater than estradiol. The presence of electron-withdrawing substituents on the A-ring should reduce the tendency of these compounds to form carcinogenic metabolites, so they might lead to a safer approach to hormone replacement therapy.
authors.affiliation: Department of Chemistry, University of Ottawa, Ottawa, Canada K1N 6N5.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Asim
authors.forename: Mohammud
authors.initials: M
authors.lastname: Asim
authors.forename: Mohamed
authors.initials: M
authors.lastname: El-Salfiti
authors.forename: Yiming
authors.initials: Y
authors.lastname: Qian
authors.forename: Christine
authors.initials: C
authors.lastname: Choueiri
authors.forename: Samira
authors.initials: S
authors.lastname: Salari
authors.forename: James
authors.initials: J
authors.lastname: Cheng
authors.forename: Hooman
authors.initials: H
authors.lastname: Shadnia
authors.forename: Manpartap
authors.initials: M
authors.lastname: Bal
authors.forename: M A
authors.initials: MA
authors.lastname: Christine Pratt
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: Carlson
authors.forename: John A
authors.initials: JA
authors.lastname: Katzenellenbogen
authors.forename: James S
authors.initials: JS
authors.lastname: Wright
authors.forename: Tony
authors.initials: T
authors.lastname: Durst
mesh_terms: D004958:Estradiol / Q000819:agonists / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology; D005260:Female; D020249:Hormone Replacement Therapy / Q000379:methods; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D011959:Receptors, Estradiol / Q000819:agonists*; D013329:Structure-Activity Relationship
chemical_list: D011959:Receptors, Estradiol; D004958:Estradiol