Structure-activity relationship study of diphenylamine-based estrogen receptor (ER) antagonists

Bioorg Med Chem. 2015 Feb 15;23(4):861-7. doi: 10.1016/j.bmc.2014.12.022. Epub 2015 Jan 6.

Abstract

We have reported the design and synthesis of novel estrogen receptor (ER) agonists with a diphenylamine skeleton, which has several advantages over the formerly used diphenylmethane skeleton for drug development. Here, we confirmed the versatility of the diphenylamine skeleton by designing and synthesizing ER antagonist candidates bearing a basic alkylamino side chain on one of the two phenol groups of the diphenylamine agonist core structure. Among the tested compounds, cyclic alkylamine-containing derivatives showed more potent ER-antagonistic activity than the corresponding acyclic derivatives in cell proliferation assay using the MCF-7 cell line. Compound 5e showed the most potent antiestrogenic activity (IC50: 1.3×10(-7)M), being 10times more potent than tamoxifen.

Keywords: Antagonist; Diphenylamine; Estrogen receptor; Privileged structure.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / metabolism
  • Cell Proliferation / drug effects
  • Diphenylamine / chemistry*
  • Diphenylamine / pharmacology*
  • Estrogen Receptor Antagonists / chemistry*
  • Estrogen Receptor Antagonists / pharmacology*
  • Estrogen Receptor alpha / metabolism
  • Female
  • Humans
  • MCF-7 Cells
  • Structure-Activity Relationship

Substances

  • Estrogen Receptor Antagonists
  • Estrogen Receptor alpha
  • Diphenylamine