Deconstructing estradiol: removal of B-ring generates compounds which are potent and subtype-selective estrogen receptor agonists.
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.
Asim
Muhammad
M
Department of Chemistry, University of Ottawa, Ottawa, Canada K1N 6N5.
Asim
Mohammud
M
El-Salfiti
Mohamed
M
Qian
Yiming
Y
Choueiri
Christine
C
Salari
Samira
S
Cheng
James
J
Shadnia
Hooman
H
Bal
Manpartap
M
Christine Pratt
M A
MA
Carlson
Kathryn E
KE
Katzenellenbogen
John A
JA
Wright
James S
JS
Durst
Tony
T
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
D011959:Receptors, Estradiol; D004958:Estradiol