Synthesis of anthranylaldoxime derivatives as estrogen receptor ligands and computational prediction of binding modes.

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Tuccinardi T, Bertini S, Martinelli A, Minutolo F, Ortore G, Placanica G, Prota G, Rapposelli S, Carlson KE, Katzenellenbogen JA, Macchia M

Synthesis of anthranylaldoxime derivatives as estrogen receptor ligands and computational prediction of binding modes.

J Med Chem. 2006 Aug 10;49(16):5001-12.

PubMed ID

16884312 [ View in PubMed

]

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.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Estradiol	Estrogen receptor alpha	Kd (nM)	0.2	N/A	N/A	Details
Estradiol	Estrogen receptor beta	Kd (nM)	0.5	N/A	N/A	Details