Structural evolutions of salicylaldoximes as selective agonists for estrogen receptor β

Filippo Minutolo, 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

Research output: Contribution to journalArticlepeer-review


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 ERβ-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 ERβ over ERa. Moreover, in transcription assays, it proved to be a selective and potent ERS-full agonist with an EC 50 of 4.8 nM.

Original languageEnglish (US)
Pages (from-to)858-867
Number of pages10
JournalJournal of Medicinal Chemistry
Issue number3
StatePublished - Feb 12 2009

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery


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