Loss of antagonistic activity of tamoxifen by replacement of one N-methyl of its side chain by fluorinated residues

Bioorg Med Chem. 2006 Nov 15;14(22):7531-8. doi: 10.1016/j.bmc.2006.07.012. Epub 2006 Jul 25.

Abstract

Efforts to limit the metabolic alteration of the aminoalkyl side chain of tamoxifen by fluorination largely decrease its ER-mediated antagonistic properties in MCF-7 cells (i.e., ability to inhibit growth, to stabilize ER, and to modulate ERE and AP-1 transcriptional activity). This loss is associated with an enhancement of agonistic activity. Loss of interaction between Asp 351 and the nitrogen atom of tamoxifen provoked by the fluorination of its side chain may explain this property.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Estrogen Antagonists / chemical synthesis*
  • Estrogen Antagonists / chemistry
  • Estrogen Antagonists / pharmacology*
  • Fluorine / chemistry*
  • Humans
  • Methylation
  • Molecular Structure
  • Receptors, Estrogen / genetics
  • Receptors, Estrogen / metabolism
  • Structure-Activity Relationship
  • Tamoxifen / chemical synthesis
  • Tamoxifen / chemistry*
  • Tamoxifen / pharmacology*
  • Transcription Factor AP-1 / metabolism
  • Transcription, Genetic / drug effects
  • Transcription, Genetic / genetics

Substances

  • Estrogen Antagonists
  • Receptors, Estrogen
  • Transcription Factor AP-1
  • Tamoxifen
  • Fluorine