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.
|Autori:||MINUTOLO F; BERTINI S; GRANCHI C; MARCHITIELLO T; PROTA G; RAPPOSELLI S; TUCCINARDI T; MARTINELLI A; GUNTHER J. R; CARLSON K. E; KATZENELLENBOGEN J. A; MACCHIA M|
|Titolo:||Structural Evolutions of Salicylaldoximes as Selective Agonists for Estrogen Receptor Beta|
|Anno del prodotto:||2009|
|Digital Object Identifier (DOI):||10.1021/jm801458t|
|Appare nelle tipologie:||1.1 Articolo in rivista|