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.
Synthesis of Anthranylaldoxime Derivatives as Estrogen Receptor Ligands and Computational Prediction of Binding Modes
TUCCINARDI, TIZIANO;BERTINI, SIMONE;MARTINELLI, ADRIANO;MINUTOLO, FILIPPO;ORTORE, GABRIELLA MARIA PIA;PLACANICA, GIORGIO;RAPPOSELLI, SIMONA;MACCHIA, MARCO
2006-01-01
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 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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
