Elemental isomerism: a boron-nitrogen surrogate for a carbon-carbon double bond increases the chemical diversity of estrogen receptor ligands

Chem Biol. 2007 Jun;14(6):659-69. doi: 10.1016/j.chembiol.2007.04.009.

Abstract

To increase the chemical diversity of bioactive molecules by incorporating unusual elements, we have examined the replacement of a C=C double bond with the isoelectronic, isostructural B-N bond in the context of nonsteroidal estrogen receptor (ER) ligands. While the B-N bond was hydrolytically labile in the unhindered cyclofenil system, the more hindered anilino dimesitylboranes, analogs of triarylethylene estrogens, were easily prepared, hydrolytically stable, and demonstrated substantial affinity for ERs. X-ray analysis of one ERalpha-ligand complex revealed steric clashes with the para methyl groups distorting the receptor; removal of these groups resulted in an increase in affinity, potency, and transcriptional efficacy. These studies define the structural determinants of stability and cellular bioactivity of a B-N for C=C substitution in nonsteroidal estrogens and provide a framework for further exploration of "elemental isomerism" for diversification of drug-like molecules.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Boron / chemistry*
  • Carbon / chemistry*
  • Cell Line, Tumor
  • Crystallography, X-Ray
  • Estrogens, Non-Steroidal* / chemical synthesis
  • Estrogens, Non-Steroidal* / chemistry
  • Estrogens, Non-Steroidal* / pharmacology
  • Humans
  • Isomerism
  • Ligands
  • Models, Molecular
  • Molecular Structure
  • Nitrogen / chemistry*
  • Protein Binding
  • Radioligand Assay
  • Receptors, Estrogen / metabolism*

Substances

  • Estrogens, Non-Steroidal
  • Ligands
  • Receptors, Estrogen
  • Carbon
  • Nitrogen
  • Boron

Associated data

  • PDB/2Q6J