Design and synthesis of norendoxifen analogues with dual aromatase inhibitory and estrogen receptor modulatory activities

Wei Lv, Jinzhong Liu, Todd Skaar, David A. Flockhart, Mark Cushman

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Both selective estrogen receptor modulators and aromatase inhibitors are widely used for the treatment of breast cancer. Compounds with both aromatase inhibitory and estrogen receptor modulatory activities could have special advantages for treatment of breast cancer. Our previous efforts led to the discovery of norendoxifen as the first compound with dual aromatase inhibitory and estrogen receptor binding activities. To optimize its efficacy and aromatase selectivity versus other cytochrome P450 enzymes, a series of structurally related norendoxifen analogues were designed and synthesized. The most potent compound, 4′-hydroxynorendoxifen (10), displayed elevated inhibitory potency against aromatase and enhanced affinity for estrogen receptors when compared to norendoxifen. The selectivity of 10 for aromatase versus other cytochrome P450 enzymes was also superior to norendoxifen. 4′-Hydroxynorendoxifen is therefore an interesting lead for further development to obtain new anticancer agents of potential value for the treatment of breast cancer.

Original languageEnglish
Pages (from-to)2623-2648
Number of pages26
JournalJournal of Medicinal Chemistry
Volume58
Issue number6
DOIs
StatePublished - Mar 26 2015

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Aromatase
Estrogen Receptors
Cytochrome P-450 Enzyme System
Breast Neoplasms
Selective Estrogen Receptor Modulators
Aromatase Inhibitors
Antineoplastic Agents
N,N-didesmethyl-4-hydroxytamoxifen

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Design and synthesis of norendoxifen analogues with dual aromatase inhibitory and estrogen receptor modulatory activities. / Lv, Wei; Liu, Jinzhong; Skaar, Todd; Flockhart, David A.; Cushman, Mark.

In: Journal of Medicinal Chemistry, Vol. 58, No. 6, 26.03.2015, p. 2623-2648.

Research output: Contribution to journalArticle

Lv, Wei ; Liu, Jinzhong ; Skaar, Todd ; Flockhart, David A. ; Cushman, Mark. / Design and synthesis of norendoxifen analogues with dual aromatase inhibitory and estrogen receptor modulatory activities. In: Journal of Medicinal Chemistry. 2015 ; Vol. 58, No. 6. pp. 2623-2648.
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