Background: Estrogen receptors (ERs) are an important target for the management of
breast cancers. Selective estrogen receptor down-regulators (SERDs) block ER activity, as well as
reduce ERα protein levels in cells, and therefore are promising therapeutic agents for the treatment
of breast cancers.
Objective: In order to develop potent SERDs, we prepared tamoxifen and fulvestrant hybrids and
evaluated their binding activity and down-regulation of ERα.
Methods: We designed and synthesized tamoxifen derivatives, which had a 4,4,5,5,5-
pentafluoropentyl group on the terminal alkyl chain. The oxidation state of the sulfur atom and alkyl
length between the sulfur and nitrogen atoms were varied. Western blotting was performed to determine
the ability to down-regulate ERα. Binding affinities of synthesized compounds were evaluated
by a fluorescence polarization-based competitive binding assay.
Results: We successfully prepared nine compounds. Treatment with 11, 14, and 17 effectively reduced
ERα protein levels in MCF-7 cells in a concentration-dependent manner. This reduction was
inhibited by a proteasome inhibitor. The ability of 14 to down-regulate the ERα protein level was
equal to fulvestrant. All compounds showed a largely equal affinity for ERα.
Conclusion: As indicated by Western blots, the ERα degradation activity was observed only in the
series of butyl linker derivatives, namely, 11, 14, and 17. These findings suggest that the specific
length of the alkyl chain is an important factor in controlling the down-regulation of ER. These results
provide useful information for designing promising SERD candidates.