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Link to original content: https://pubmed.ncbi.nlm.nih.gov/19128016
Structural evolutions of salicylaldoximes as selective agonists for estrogen receptor beta - PubMed Skip to main page content
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. 2009 Feb 12;52(3):858-67.
doi: 10.1021/jm801458t.

Structural evolutions of salicylaldoximes as selective agonists for estrogen receptor beta

Filippo Minutolo  1 , Simone Bertini, Carlotta Granchi, Teresa Marchitiello, Giovanni Prota, Simona Rapposelli, Tiziano Tuccinardi, Adriano Martinelli, Jillian R Gunther, Kathryn E Carlson, John A Katzenellenbogen, Marco Macchia
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Structural evolutions of salicylaldoximes as selective agonists for estrogen receptor beta

Filippo Minutolo et al. J Med Chem. .

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.

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