Synthesis and biological evaluation of guanylhydrazone coactivator binding inhibitors for the estrogen receptor

Bioorg Med Chem. 2008 Dec 1;16(23):10075-84. doi: 10.1016/j.bmc.2008.10.007. Epub 2008 Oct 7.


Most patients with hormone-responsive breast cancer eventually develop resistance to traditional antiestrogens such as tamoxifen, and this has become a major obstacle in their treatment. We prepared and characterized the activity of a series of 16 guanylhydrazone small molecules that are designed to block estrogen receptor (ER) activity through a non-traditional mechanism, by directly interfering with coactivator binding to agonist-liganded ER. The inhibitory activity of these compounds was determined in cell-based transcription assays using ER-responsive reporter gene and mammalian two-hybrid assays. Several of the compounds gave IC(50) values in the low micromolar range. Two secondary assays were used to confirm that these compounds were acting through the proposed non-traditional mode of estrogen inhibitory action and not as conventional antagonists at the ligand binding site.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Estrogen Antagonists / chemical synthesis*
  • Estrogen Antagonists / pharmacology*
  • Female
  • Humans
  • Hydrazones / chemical synthesis*
  • Hydrazones / chemistry
  • Hydrazones / pharmacology*
  • Inhibitory Concentration 50
  • Ligands
  • Receptors, Estrogen / antagonists & inhibitors*
  • Receptors, Estrogen / chemistry
  • Receptors, Estrogen / metabolism
  • Structure-Activity Relationship
  • Tumor Cells, Cultured


  • Estrogen Antagonists
  • Hydrazones
  • Ligands
  • Receptors, Estrogen