Symmetric 4,4'-(piperidin-4-ylidenemethylene)bisphenol derivatives as novel tunable estrogen receptor (ER) modulators

Bioorg Med Chem. 2016 Mar 1;24(5):1089-94. doi: 10.1016/j.bmc.2016.01.035. Epub 2016 Jan 18.

Abstract

We designed and synthesized 4,4'-(piperidin-4-ylidenemethylene)bisphenol derivatives as novel tunable estrogen receptor (ER) modulators. The introduction of hydrophobic substituents on the nitrogen atom of the piperidine ring enhanced ERα binding affinity. In addition, the introduction of four methyl groups adjacent to the piperidine ring nitrogen atom remarkably enhanced ERα binding affinity. N-Acetyl-2,2,6,6-tetramethylpiperidine derivative 3b showed high ERα binding affinity, high MCF-7 cell proliferation inducing activity, and high metabolic stability in rat liver S9 fractions.

Keywords: 2,2,6,6-Tetramethylpiperidine; Estrogen receptor modulator; Hydrophobicity; McMurry coupling; Piperidine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzhydryl Compounds / chemical synthesis
  • Benzhydryl Compounds / chemistry*
  • Benzhydryl Compounds / metabolism
  • Benzhydryl Compounds / pharmacology*
  • Estrogen Receptor Modulators / chemical synthesis
  • Estrogen Receptor Modulators / chemistry*
  • Estrogen Receptor Modulators / metabolism
  • Estrogen Receptor Modulators / pharmacology*
  • Estrogen Receptor alpha / metabolism*
  • Humans
  • Liver / metabolism
  • MCF-7 Cells
  • Phenols / chemical synthesis
  • Phenols / chemistry*
  • Phenols / metabolism
  • Phenols / pharmacology*
  • Piperidines / chemical synthesis
  • Piperidines / chemistry*
  • Piperidines / metabolism
  • Piperidines / pharmacology*
  • Rats
  • Structure-Activity Relationship

Substances

  • Benzhydryl Compounds
  • Estrogen Receptor Modulators
  • Estrogen Receptor alpha
  • Phenols
  • Piperidines
  • 2,2,6,6-tetramethylpiperidide
  • bisphenol A