BC-spiro-estradiols. Synthesis and estrogen receptor binding affinity of four new estradiol isomers

The synthesis of four new isomers of estradiol in which the ring A to ring C planes are perpendicular to each other as a result of a spiro BC ring junction is described. Heterocyclic analogs and carbocyclic homologs of these compounds are also reported. Estrogen receptor binding studies show that th...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2012-06, Vol.22 (11), p.3713-3717
Main Authors: Asim, Muhammad, Klonowska, Daria, Choueiri, Christine, Korobkov, Ilia, Carlson, Kathryn E., Katzenellenbogen, John A., Durst, Tony
Format: Article
Language:English
Subjects:
BC-spiro-estrogen
binding capacity
Biological and medical sciences
ER binding affinity
Estradiol
Estradiol - analogs & derivatives
Estradiol - chemical synthesis
Estrogen receptors
Heterocyclic Compounds - chemistry
Isomerism
Isomers
Medical sciences
Pharmacology. Drug treatments
Protein Binding
Receptors, Estrogen - chemistry
Receptors, Estrogen - metabolism
Spiro Compounds - chemistry
Stereochemistry
Synthesis
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Summary:The synthesis of four new isomers of estradiol in which the ring A to ring C planes are perpendicular to each other as a result of a spiro BC ring junction is described. Heterocyclic analogs and carbocyclic homologs of these compounds are also reported. Estrogen receptor binding studies show that the spiro compounds with the natural stereochemistry at C9 bind almost as strongly as estradiol but with greater β to α selectivity. These studies show that the estrogen receptors can readily accommodate isomers of estrogen with substantially different fixed shapes than the native ligand
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2012.04.022