title: Synthesis and characterization of fluorescent 4-hydroxytamoxifen conjugates with unique antiestrogenic properties.
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.
authors.affiliation: Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana, USA.
authors.forename: Emily L
authors.initials: EL
authors.lastname: Rickert
authors.forename: Sean
authors.initials: S
authors.lastname: Oriana
authors.forename: Cori
authors.initials: C
authors.lastname: Hartman-Frey
authors.forename: Xinghua
authors.initials: X
authors.lastname: Long
authors.forename: Timothy T
authors.initials: TT
authors.lastname: Webb
authors.forename: Kenneth P
authors.initials: KP
authors.lastname: Nephew
authors.forename: Ross V
authors.initials: RV
authors.lastname: Weatherman
mesh_terms: D001943:Breast Neoplasms / Q000188:drug therapy; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004965:Estrogen Antagonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D005456:Fluorescent Dyes / Q000138:chemical synthesis / Q000737:chemistry*; D006801:Humans; D011960:Receptors, Estrogen / Q000378:metabolism*; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D004965:Estrogen Antagonists; D005456:Fluorescent Dyes; D011960:Receptors, Estrogen; D013629:Tamoxifen; C016601:afimoxifene