Tamoxifen and fulvestrant hybrids showed potency as selective estrogen receptor down-regulators.

Medicinal chemistry (Shariqah (United Arab Emirates))

PubMedID: 27494038

Shoda T, Kato M, Fujisato T, Demizu Y, Inoue H, Naito M, Kurihara M. Tamoxifen and fulvestrant hybrids showed potency as selective estrogen receptor down-regulators. Med Chem. 2016;.
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 ERa 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 ERa.

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 ERa. 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 ERa 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 ERa protein level was equal to fulvestrant. All compounds showed a largely equal affinity for ERa.

CONCLUSION
As indicated by Western blots, the ERa 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.