Monoaryl-Substituted Salicylaldoximes as Ligands for Estrogen Receptor β

Salicylaldoximes possess a hydrogen-bonded pseudocyclic A′ ring in place of the typical phenolic A ring that is characteristic of most estrogen receptor (ER) ligands. Monoaryl-substituted salicylaldoximes were obtained by replacing the phenol moiety (ring A) of the ERβ pharmacophore with the pseudoc...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2008-03, Vol.51 (5), p.1344-1351
Main Authors: Minutolo, Filippo, Bellini, Rosalba, Bertini, Simone, Carboni, Isabella, Lapucci, Annalina, Pistolesi, Letizia, Prota, Giovanni, Rapposelli, Simona, Solati, Francesca, Tuccinardi, Tiziano, Martinelli, Adriano, Stossi, Fabio, Carlson, Kathryn E, Katzenellenbogen, Benita S, Katzenellenbogen, John A, Macchia, Marco
Format: Article
Language:English
Subjects:
Binding, Competitive
Biological and medical sciences
Cell Line
Drug Partial Agonism
Endometrium - cytology
Estrogen Receptor alpha - genetics
Estrogen Receptor alpha - metabolism
Estrogen Receptor beta - agonists
Estrogen Receptor beta - genetics
Estrogen Receptor beta - metabolism
Female
Genes, Reporter
Hormones. Endocrine system
Humans
Ligands
Medical sciences
Models, Molecular
Oximes - chemical synthesis
Oximes - chemistry
Oximes - pharmacology
Pharmacology. Drug treatments
Phenols - chemical synthesis
Phenols - chemistry
Phenols - pharmacology
Radioligand Assay
Structure-Activity Relationship
Transcription, Genetic
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Summary:Salicylaldoximes possess a hydrogen-bonded pseudocyclic A′ ring in place of the typical phenolic A ring that is characteristic of most estrogen receptor (ER) ligands. Monoaryl-substituted salicylaldoximes were obtained by replacing the phenol moiety (ring A) of the ERβ pharmacophore with the pseudocycle A′ ring, which has previously been shown to behave as a bioequivalent of phenols in nonselective ER ligands. In this series, small substituents (CH3, CN, Cl) were introduced into the central phenyl scaffold. An efficient sequential halogen-selective double cross-coupling reaction was developed for the synthesis of the methyl-substituted ER ligand. The measured ERβ affinity proved to be very sensitive to the effect of central core substituents. The binding affinities of the compounds herein reported were in good agreement with the results of computational docking analysis. The chloro-substituted derivative showed the highest β affinity and selectivity, and it also proved to be an ERβ partial agonist with an EC50 of 11 nM.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm701396g