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Synthesis of anthranylaldoxime derivatives as estrogen receptor ligands and computational prediction of binding modes.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2006 Aug 10; Vol. 49 (16), pp. 5001-12. - Publication Year :
- 2006
-
Abstract
- N-Me-anthranylaldoximes possess a hydrogen-bonded pseudocyclic A' ring in place of the typical phenolic A-ring that is characteristic of most estrogen receptor (ER) ligands. We have investigated the role played by substituents introduced into either one or both of the peripheral 3- and 4-phenyl rings in modulating ER binding affinity. An efficient synthetic strategy was employed for the preparation of differentially substituted 3- and 4-aryl derivatives that involved exploiting the different reactivity of bromo- versus chloro-aryl groups in palladium-catalyzed cross-couplings. The binding data showed that ERalpha affinity could be improved by a single p-OH group in the 4-phenyl ring, whereas the same substitution on the 3-phenyl ring caused a dramatic reduction of ERbeta affinity. The most ERalpha-selective compound was the one with two p-OH groups on both phenyl substituents. To rationalize these results, ligand docking followed by molecular mechanics Poisson-Boltzmann/surface area (MM-PBSA) studies were carried out. These analyses suggested a molecular basis for the interaction of these compounds with the ERs and enabled the development of models able to predict the mode of ligand binding.
- Subjects :
- Benzene Derivatives chemistry
Benzene Derivatives pharmacology
Binding Sites
Binding, Competitive
Humans
Ligands
Models, Molecular
Molecular Conformation
Oximes chemistry
Oximes pharmacology
Radioligand Assay
Stereoisomerism
Structure-Activity Relationship
Thermodynamics
Benzene Derivatives chemical synthesis
Estrogen Receptor alpha chemistry
Estrogen Receptor alpha metabolism
Estrogen Receptor beta chemistry
Estrogen Receptor beta metabolism
Oximes chemical synthesis
Subjects
Details
- Language :
- English
- ISSN :
- 0022-2623
- Volume :
- 49
- Issue :
- 16
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 16884312
- Full Text :
- https://doi.org/10.1021/jm060560u