Antiestrogens have long been one of the major therapeutic options for treating estrogen receptor positive breast cancer, but there are still many uncertainties about their mechanism of action and the functional similarities between antiestrogens with significant structural differences. In particular, antiestrogens such as the drug fulvestrant, consisting of estradiol scaffolds with 11-beta or 7-alpha substituents, are believed to be mechanistically and potentially functionally distinct from non-steroidal antiestrogens such as tamoxifen and raloxifene. To better assess these potential differences, a novel fluorescent antiestrogen based on the 11-beta substituted estradiol antiestrogen RU39411 was synthesized and its activity was compared to previously reported fluorescent 4-hydroxytamoxifen derivatives. The 11-beta substituted BODIPY estradiol conjugate bound tightly to full length estrogen receptor alpha in fluorescent polarization assays and provided accurate binding data for other known estrogen receptor ligands when used in competition assays. Both the fluorescent analog and the analog containing the linker but not the fluorophore also inhibited estrogen receptor-mediated transcription from consensus estrogen receptor element-containing promoters in the MCF-7 breast cancer cell line. A key feature of antiestrogens substituted at the 11-beta and 7-alpha positions is their ability to inhibit proliferation of ER-positive cells that have grown resistant to the antiproliferative effects of tamoxifen. Similar to fulvestrant, the non-fluorescent analog inhibited the proliferation of a tamoxifen-resistant MCF-7 cell line, but, surprisingly, the fluorescent analog did not, even though the fluorescent analog was capable of degrading cellular estrogen receptor hours after dosing. Uptake studies showed fluorescence predominantly in the cytoplasm, consistent with previous studies with fluorescent tamoxifen derivatives. These studies demonstrate the utility of the 11-beta substituted fluorescent conjugate as a chemical probe and suggests a complicated structural delineation of the functions of different antiestrogen classes.

Characterization of a novel fluorescent antiestrogen

246th National Meeting (2013)

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