Synthesis and characterization of fluorescent 4-hydroxytamoxifen conjugates with unique antiestrogenic properties

Emily L. Rickert, Sean Oriana, Cori Hartman-Frey, Xinghua Long, Timothy T. Webb, Kenneth P. Nephew, Ross V. Weatherman

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Membrane receptors for steroid hormones are currently a subject of considerable debate. One approach to selectively target these putative receptors has been to couple ligands to substances that restrict cell permeability. Using this approach, an analogue of the estrogen receptor ligand 4-hydroxytamoxifen was attached to fluorescent dyes with differing degrees of predicted cell permeability. The conjugates bound to estrogen receptor in vitro, but all three conjugates, including one predicted to be cell-impermeable, inhibited estradiol-induced transcriptional activation. Fluorescence microscopy revealed cytoplasmic localization for all three conjugates. We further characterized a 4-hydroxytamoxifen analogue conjugated to a BODIPY fluorophore in breast cancer cell lines. Those experiments suggested a similar, but not identical, mode of action to 4-hydroxytamoxifen, as the fluorescent conjugate was equally effective at inhibiting proliferation of both tamoxifen-sensitive and tamoxifen-resistant breast cancer cell lines. While these findings point to significant complicating factors in designing steroid hormone mimics targeted to the plasma membrane, the results also reveal a possible new direction for designing estrogen receptor modulators.

Original languageEnglish (US)
Pages (from-to)903-910
Number of pages8
JournalBioconjugate Chemistry
Volume21
Issue number5
DOIs
StatePublished - May 19 2010

Fingerprint

Steroid hormones
Tamoxifen
Estrogen Receptors
Permeability
Ligands
Cells
Hormones
Breast Neoplasms
Cell Line
Estrogen Receptor Modulators
Fluorophores
Steroid Receptors
Fluorescence microscopy
Cell membranes
Fluorescent Dyes
Fluorescence Microscopy
Modulators
Transcriptional Activation
Estradiol
Dyes

ASJC Scopus subject areas

  • Biotechnology
  • Bioengineering
  • Biomedical Engineering
  • Pharmacology
  • Pharmaceutical Science
  • Organic Chemistry

Cite this

Synthesis and characterization of fluorescent 4-hydroxytamoxifen conjugates with unique antiestrogenic properties. / Rickert, Emily L.; Oriana, Sean; Hartman-Frey, Cori; Long, Xinghua; Webb, Timothy T.; Nephew, Kenneth P.; Weatherman, Ross V.

In: Bioconjugate Chemistry, Vol. 21, No. 5, 19.05.2010, p. 903-910.

Research output: Contribution to journalArticle

Rickert, Emily L. ; Oriana, Sean ; Hartman-Frey, Cori ; Long, Xinghua ; Webb, Timothy T. ; Nephew, Kenneth P. ; Weatherman, Ross V. / Synthesis and characterization of fluorescent 4-hydroxytamoxifen conjugates with unique antiestrogenic properties. In: Bioconjugate Chemistry. 2010 ; Vol. 21, No. 5. pp. 903-910.
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