Tamoxifen and Fulvestrant Hybrids Showed Potency as Selective Estrogen Receptor Down-Regulators

Author(s): Takuji Shoda*, Masashi Kato, Takuma Fujisato, Yosuke Demizu, Hideshi Inoue, Mikihiko Naito, Masaaki Kurihara

Journal Name: Medicinal Chemistry

Volume 13 , Issue 3 , 2017

Become EABM
Become Reviewer
Call for Editor

Graphical Abstract:


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.

Keywords: Tamoxifen, fulvestrant, estrogen receptor, selective estrogen receptor down-regulator, ER-positive breast cancer.

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2017
Published on: 09 April, 2017
Page: [206 - 213]
Pages: 8
DOI: 10.2174/1573406412666160805101408
Price: $65

Article Metrics

PDF: 38