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 ERα 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 ERβ affinity. The most ERα-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.
|Autori:||TUCCINARDI T; BERTINI S; MARTINELLI A; MINUTOLO F; ORTORE G; PLACANICA G; PROTA G; RAPPOSELLI S; CARLSON KE; KATZENELLENBOGEN JA; MACCHIA M|
|Titolo:||Synthesis of Anthranylaldoxime Derivatives as Estrogen Receptor Ligands and Computational Prediction of Binding Modes|
|Anno del prodotto:||2006|
|Digital Object Identifier (DOI):||10.1021/jm060560u|
|Appare nelle tipologie:||1.1 Articolo in rivista|