A new Suzuki synthesis of triphenylethylenes that inhibit aromatase and bind to estrogen receptors α and β

Li Ming Zhao, Hai Shan Jin, Jinzhong Liu, Todd Skaar, Joseph Ipe, Wei Lv, David A. Flockhart, Mark Cushman

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

The design and synthesis of dual aromatase inhibitors/selective estrogen receptor modulators (AI/SERMs) is an attractive strategy for the discovery of new breast cancer therapeutic agents. Previous efforts led to the preparation of norendoxifen (4) derivatives with dual aromatase inhibitory activity and estrogen receptor binding activity. In the present study, some of the structural features of the potent AI letrozole were incorporated into the lead compound (norendoxifen) to afford a series of new dual AI/SERM agents based on a symmetrical diphenylmethylene substructure that eliminates the problem of E,Z isomerization encountered with norendoxifen-based AI/SERMs. Compound 12d had good aromatase inhibitory activity (IC50 = 62.2 nM) while also exhibiting good binding activity to both ER-α (EC50 = 72.1 nM) and ER-β (EC50 = 70.8 nM). In addition, a new synthesis was devised for the preparation of norendoxifen and its analogues through a bis-Suzuki coupling strategy.

Original languageEnglish (US)
Pages (from-to)5400-5409
Number of pages10
JournalBioorganic and Medicinal Chemistry
Volume24
Issue number21
DOIs
StatePublished - 2016

Fingerprint

Aromatase
Selective Estrogen Receptor Modulators
Estrogen Receptors
Aromatase Inhibitors
letrozole
Lead compounds
Isomerization
Inhibitory Concentration 50
Breast Neoplasms
Derivatives
triphenylethylene
N,N-didesmethyl-4-hydroxytamoxifen
Therapeutics

Keywords

  • (E,Z)-Norendoxifen synthesis
  • Antiestrogenic activity
  • Aromatase inhibitor
  • Breast cancer
  • Estrogen receptor

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

Cite this

A new Suzuki synthesis of triphenylethylenes that inhibit aromatase and bind to estrogen receptors α and β. / Zhao, Li Ming; Jin, Hai Shan; Liu, Jinzhong; Skaar, Todd; Ipe, Joseph; Lv, Wei; Flockhart, David A.; Cushman, Mark.

In: Bioorganic and Medicinal Chemistry, Vol. 24, No. 21, 2016, p. 5400-5409.

Research output: Contribution to journalArticle

Zhao, Li Ming ; Jin, Hai Shan ; Liu, Jinzhong ; Skaar, Todd ; Ipe, Joseph ; Lv, Wei ; Flockhart, David A. ; Cushman, Mark. / A new Suzuki synthesis of triphenylethylenes that inhibit aromatase and bind to estrogen receptors α and β. In: Bioorganic and Medicinal Chemistry. 2016 ; Vol. 24, No. 21. pp. 5400-5409.
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