Discovery of novel SERMs with a ferrocenyl entity based on the oxabicyclo[2.2.1]heptene scaffold and evaluation of their antiproliferative effects in breast cancer cells

Org Biomol Chem. 2012 Dec 28;10(48):9689-99. doi: 10.1039/c2ob26226f. Epub 2012 Nov 14.

Abstract

We have synthesized a series of novel SERMs bearing a ferrocenyl unit based on a three-dimensional oxabicyclo[2.2.1]heptene core scaffold. These compounds displayed high receptor binding affinities as well as ERα or ERβ selectivity. In cell proliferation assays, we found that these ligands were cytotoxic at micromolar concentrations in both ER-positive and ER-negative breast cancer cells. On further examination, we found that the antiproliferative effects of compounds 9b, 10h and 11b on MCF-7 cells line does not arise from antiestrogenicity, but rather proceeds through a cytotoxic pathway. Possible mechanisms for the unique activities of these ligands were also investigated by molecular modeling. These new ligands could act as scaffolds for the development of novel anti-breast cancer agents.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Bridged Bicyclo Compounds / chemistry*
  • Cell Proliferation / drug effects*
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Drug Screening Assays, Antitumor
  • Female
  • Ferrous Compounds / chemistry*
  • Humans
  • Ligands
  • MCF-7 Cells
  • Models, Molecular
  • Molecular Structure
  • Protein Binding
  • Receptors, Estrogen / biosynthesis
  • Selective Estrogen Receptor Modulators / chemical synthesis*
  • Selective Estrogen Receptor Modulators / chemistry
  • Selective Estrogen Receptor Modulators / pharmacology
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • Bridged Bicyclo Compounds
  • Ferrous Compounds
  • Ligands
  • Receptors, Estrogen
  • Selective Estrogen Receptor Modulators
  • bicyclo(2.2.1)heptene
  • ferrocenium