Novel estrogen receptor (ER) modulators containing various hydrophobic bent-core structures

Bioorg Med Chem. 2014 Jul 1;22(13):3508-14. doi: 10.1016/j.bmc.2014.04.022. Epub 2014 Apr 20.

Abstract

We previously discovered m-carborane-containing estrogen receptor (ER) modulator 4, which exhibits weak ER-agonistic and antagonistic activities in transactivation assays. With the aim of developing novel ER partial agonists, we designed and synthesized various analogues of 4 with a bent-core structure, that is, pseudo cyclic structure (5), tetrahydropyrimidinone (6), m-benzene (7), adamantane (8), and 9,10-dimethyl-m-carborane (9), in place of the m-carborane moiety. Compound 9 showed greater binding affinity than 4 in ER-binding assay using [6,7-(3)H]-17β-estradiol and was a more effective partial agonist than 4 in MCF-7 cell proliferation assay. It appears to be a promising candidate as a selective ER modulator (SERM).

Keywords: Bent-core structure; Carborane; Estrogen; Hydrophobic; SERM.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • Estrogen Receptor Modulators / chemistry
  • Estrogen Receptor Modulators / pharmacology*
  • Estrogen Receptor alpha / agonists*
  • Humans
  • Hydrophobic and Hydrophilic Interactions
  • MCF-7 Cells
  • Molecular Structure
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • Estrogen Receptor Modulators
  • Estrogen Receptor alpha