Elemental Isomerism: A Boron-Nitrogen Surrogate for a Carbon-Carbon Double Bond Increases the Chemical Diversity of Estrogen Receptor Ligands

Hai Bing Zhou, Kendall W. Nettles, John B. Bruning, Younchang Kim, Andrzej Joachimiak, Sanjay Sharma, Kathryn E. Carlson, Fabio Stossi, Benita S. Katzenellenbogen, Geoffrey L. Greene, John A. Katzenellenbogen

Research output: Contribution to journalArticle

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 ERα-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.

Original languageEnglish (US)
Pages (from-to)659-669
Number of pages11
JournalChemistry and Biology
Volume14
Issue number6
DOIs
StatePublished - Jun 25 2007

Keywords

  • CHEMBIOL

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

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  • Cite this

    Zhou, H. B., Nettles, K. W., Bruning, J. B., Kim, Y., Joachimiak, A., Sharma, S., Carlson, K. E., Stossi, F., Katzenellenbogen, B. S., Greene, G. L., & Katzenellenbogen, J. A. (2007). Elemental Isomerism: A Boron-Nitrogen Surrogate for a Carbon-Carbon Double Bond Increases the Chemical Diversity of Estrogen Receptor Ligands. Chemistry and Biology, 14(6), 659-669. https://doi.org/10.1016/j.chembiol.2007.04.009