The bioisosteric replacement of the phenol ring, a signature functional group of most estrogen receptor (ER) ligands, with a hydrogen-bonded pseudocyclic ring, led to the development of a novel class of nonsteroidal ER-ligands based on a salicylaldoxime template. A series of structural modifications were applied to selected molecules belonging to the monoaryl-salicylaldoxime chemical class in an attempt to improve further their ERbeta-selective receptor affinity and agonist properties. Among several modifications, the best results were obtained by the simultaneous introduction of a meta-fluorine atom into the para-hydroxyphenyl substituent present in the 4-position of salicylaldoxime, together with the insertion of a chloro group in the 3-position of the central scaffold. The resulting compound showed the best affinity (K(i) = 7.1 nM) and selectivity for ERbeta over ERalpha. Moreover, in transcription assays, it proved to be a selective and potent ERbeta-full agonist with an EC(50) of 4.8 nM.

Structural Evolutions of Salicylaldoximes as Selective Agonists for Estrogen Receptor Beta

MINUTOLO, FILIPPO;BERTINI, SIMONE;GRANCHI, CARLOTTA;RAPPOSELLI, SIMONA;TUCCINARDI, TIZIANO;MARTINELLI, ADRIANO;MACCHIA, MARCO
2009

Abstract

The bioisosteric replacement of the phenol ring, a signature functional group of most estrogen receptor (ER) ligands, with a hydrogen-bonded pseudocyclic ring, led to the development of a novel class of nonsteroidal ER-ligands based on a salicylaldoxime template. A series of structural modifications were applied to selected molecules belonging to the monoaryl-salicylaldoxime chemical class in an attempt to improve further their ERbeta-selective receptor affinity and agonist properties. Among several modifications, the best results were obtained by the simultaneous introduction of a meta-fluorine atom into the para-hydroxyphenyl substituent present in the 4-position of salicylaldoxime, together with the insertion of a chloro group in the 3-position of the central scaffold. The resulting compound showed the best affinity (K(i) = 7.1 nM) and selectivity for ERbeta over ERalpha. Moreover, in transcription assays, it proved to be a selective and potent ERbeta-full agonist with an EC(50) of 4.8 nM.
Minutolo, Filippo; Bertini, Simone; Granchi, Carlotta; Marchitiello, T; Prota, G; Rapposelli, Simona; Tuccinardi, Tiziano; Martinelli, Adriano; GUNTHER J., R; CARLSON K., E; KATZENELLENBOGEN J., A; Macchia, Marco
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11568/196407
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