Synthesis and evaluation of tamoxifen derivatives with a long alkyl side chain as selective estrogen receptor down-regulators. Issue 13 (1st July 2015)

• Record Type: Journal Article
• Authors: Shoda, Takuji; Kato, Masashi; Harada, Rintaro; Fujisato, Takuma; Okuhira, Keiichiro; Demizu, Yosuke; Inoue, Hideshi; Naito, Mikihiko; Kurihara, Masaaki
• Is Part Of: Bioorganic & medicinal chemistry. Volume 23:Issue 13(2015)
• Page Start: 3091
• Page End: 3096
• Publication Date: 2015-07-01
• Subjects: (Boc)2O di-tert-butyl dicarbonate -- E2 17β-estradiol -- ER estrogen receptor -- DIEA N, N-diisopropylethylamine -- DMAP N, N-dimethyl-4-aminopyridine -- DMSO dimethylsulfoxide -- 4-OHT 4-hydroxytamoxifen -- SERD selective estrogen receptor down-regulator -- TBAF tetra-n-butylammonium fluoride -- THF tetrahydrofuran -- TsCl p-toluenesulfonyl chloride; Breast cancer -- Estrogen receptor -- SERD -- Tamoxifen; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2015.05.002
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: Estrogen receptors (ERs) play a major role in the growth of human breast cancer cells. An antagonist that acts as not only an inhibitor of ligand binding but also an inducer of the down-regulation of ER would be useful for the treatment for ER-positive breast cancer. We previously reported the design and synthesis of a selective estrogen receptor down-regulator (SERD), ( E / Z )-4-(1-{4-[2-(dodecylamino)ethoxy]phenyl}-2-phenylbut-1-en-1-yl)phenol (C12), which is a tamoxifen derivative having a long alkyl chain on the amine moiety. This compound induced degradation of ERα via a proteasome-dependent pathway and showed an antagonistic effect in MCF-7 cells. With the aim of increasing the potency of SERDs, we designed and synthesized various tamoxifen derivatives that have various lengths and terminal groups of the long alkyl side chain. During the course of our investigation, C10F having a 10-fluorodecyl group on the amine moiety of 4-OHT was shown to be the most potent compound among the tamoxifen derivatives. Moreover, computational docking analysis suggested that the long alkyl chain interacted with the hydrophobic region on the surface of the ER, which is a binding site of helix 12 and coactivator. These results provide useful information to develop promising candidates as SERDs.