Salicylaldoximes and anthranylaldoximes as alternatives to phenol-based estrogen receptor ligands

Filippo Minutolo, Simone Bertini, Adriano Martinelli, Gabriella Ortore, Giorgio Placanica, Giovanni Prota, Simona Rapposelli, Tiziano Tuccinardi, Shubin Sheng, Kathryn E. Carlson, Benita S. Katzenellenbogen, John A. Katzenellenbogen, Marco Macchia

Research output: Contribution to journalArticle

Abstract

Estrogens play a crucial role in the development and function of female reproductive tissues. They have positive effects on the maintenance of bone mineral density, on the liver, and on the cardiovascular and central nervous systems. Selective Estrogen Receptor Modulators (SERMs) are particularly attractive as therapeutic agents because they are able to block estrogen action at those sites where stimulation would be undesirable, such as the breast and uterus, but at the same time stimulate estrogen actions in other tissues where they are desired, such as the bone and liver. Most synthetic estrogen receptor ligands possess a phenolic ring, mimicking the phenolic "Aring" of the natural ligand estradiol. In an attempt to increase the structural diversity of estrogen receptor (ER) ligands, we designed and synthesized molecules containing unprecedented replacements of the prototypical phenolic "A-ring" of estrogens with an oxime and a hydroxy- (salicylaldoximes) or aminomoieties (anthranylaldoximes), forming intramolecularly H-bonded pseudocycles. These new classes of compounds showed interesting ER binding properties on both receptor subtypes (ERα and ERβ). These results proved that the six-membered ring formed by an intramolecular hydrogen bond, and containing an exocyclic oxime OH, is an effective stereoelectronic replacement of the phenolic ring of typical ER ligands.

Original languageEnglish (US)
Pages (from-to)83-94
Number of pages12
JournalArkivoc
Volume2006
Issue number8
StatePublished - Jun 24 2006

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Keywords

  • Binding
  • Estrogen
  • Ligands
  • Nuclear receptors
  • Oximes

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Minutolo, F., Bertini, S., Martinelli, A., Ortore, G., Placanica, G., Prota, G., Rapposelli, S., Tuccinardi, T., Sheng, S., Carlson, K. E., Katzenellenbogen, B. S., Katzenellenbogen, J. A., & Macchia, M. (2006). Salicylaldoximes and anthranylaldoximes as alternatives to phenol-based estrogen receptor ligands. Arkivoc, 2006(8), 83-94.