Synthesis of Triphenylethylene Bisphenols as Aromatase Inhibitors That Also Modulate Estrogen Receptors

Wei Lv, Jinzhong Liu, Todd Skaar, Elizaveta O'Neill, Ge Yu, David A. Flockhart, Mark Cushman

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

A series of triphenylethylene bisphenol analogues of the selective estrogen receptor modulator (SERM) tamoxifen were synthesized and evaluated for their abilities to inhibit aromatase, bind to estrogen receptor α (ER-α) and estrogen receptor β (ER-β), and antagonize the activity of β-estradiol in MCF-7 human breast cancer cells. The long-range goal has been to create dual aromatase inhibitor (AI)/selective estrogen receptor modulators (SERMs). The hypothesis is that in normal tissue the estrogenic SERM activity of a dual AI/SERM could attenuate the undesired effects stemming from global estrogen depletion caused by the AI activity of a dual AI/SERM, while in breast cancer tissue the antiestrogenic SERM activity of a dual AI/SERM could act synergistically with AI activity to enhance the antiproliferative effect. The potent aromatase inhibitory activities and high ER-α and ER-β binding affinities of several of the resulting analogues, together with the facts that they antagonize β-estradiol in a functional assay in MCF-7 human breast cancer cells and they have no E/Z isomers, support their further development in order to obtain dual AI/SERM agents for breast cancer treatment.

Original languageEnglish (US)
Pages (from-to)157-170
Number of pages14
JournalJournal of Medicinal Chemistry
Volume59
Issue number1
DOIs
StatePublished - Jan 14 2016

Fingerprint

Selective Estrogen Receptor Modulators
Aromatase Inhibitors
Estrogen Receptors
Breast Neoplasms
Aromatase
Estradiol
triphenylethylene
Tamoxifen
Estrogens

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Synthesis of Triphenylethylene Bisphenols as Aromatase Inhibitors That Also Modulate Estrogen Receptors. / Lv, Wei; Liu, Jinzhong; Skaar, Todd; O'Neill, Elizaveta; Yu, Ge; Flockhart, David A.; Cushman, Mark.

In: Journal of Medicinal Chemistry, Vol. 59, No. 1, 14.01.2016, p. 157-170.

Research output: Contribution to journalArticle

Lv, Wei ; Liu, Jinzhong ; Skaar, Todd ; O'Neill, Elizaveta ; Yu, Ge ; Flockhart, David A. ; Cushman, Mark. / Synthesis of Triphenylethylene Bisphenols as Aromatase Inhibitors That Also Modulate Estrogen Receptors. In: Journal of Medicinal Chemistry. 2016 ; Vol. 59, No. 1. pp. 157-170.
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