title: Tamoxifen and Fulvestrant Hybrids Showed Potency as Selective Estrogen Receptor Down-Regulators.
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.
  
  
  CONCLUSIONS
  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.
authors: National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan.
authors: Takuji
authors: T
authors: Shoda
authors: School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan.
authors: Masashi
authors: M
authors: Kato
authors: School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan.
authors: Takuma
authors: T
authors: Fujisato
authors: National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan.
authors: Yosuke
authors: Y
authors: Demizu
authors: School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan.
authors: Hideshi
authors: H
authors: Inoue
authors: School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan.
authors: Mikihiko
authors: M
authors: Naito
authors: National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan.
authors: Masaaki
authors: M
authors: Kurihara
mesh_terms: D015536:Down-Regulation / Q000187:drug effects*; D015195:Drug Design; D004958:Estradiol / Q000031:analogs & derivatives* / Q000737:chemistry; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D000077267:Fulvestrant; D006801:Humans; D061986:MCF-7 Cells; D013629:Tamoxifen / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D047628:Estrogen Receptor alpha; D013629:Tamoxifen; D000077267:Fulvestrant; D004958:Estradiol
keywords: ER-positive breast cancer; Tamoxifen; estrogen receptor; fulvestrant; selective estrogen receptor down-regulator