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

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

Research output: Contribution to journalArticle

20 Scopus citations

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

    Fingerprint

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this