Benzothiepin-derived molecular scaffolds for estrogen receptor modulators: synthesis and antagonistic effects in breast cancer cells

Meegan, Mary J.; Barrett, Irene J.; Zimmermann, Jochen; Knox, Andrew J. S.; Zisterer, Daniela M.; Lloyd, David G.

doi:10.1080/14756360701503232

Cited by 10 publications

(4 citation statements)

References 35 publications

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“…1C). The fluorescent estrogen-ligand bound to ER exhibits a high fluorescence polarization value, whereas displacement of the fluorescent estrogen ligand from ER by the corresponding odorant decreases the fluorescence polarization in a dosedependent manner, which is a well established assay to probe the specific binding of molecules to ER (57,58). Although Polysantol and androstenol specifically competed for the ER binding site, we were not able to reach the same baseline level of ligand displacement as for the other compounds (Fig.…”

Section: Resultsmentioning

confidence: 77%

Dual Activities of Odorants on Olfactory and Nuclear Hormone Receptors

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Baud

et al. 2009

Journal of Biological Chemistry

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We have screened an odorant compound library and discovered molecules acting as chemical signals that specifically activate both G-protein-coupled olfactory receptors (ORs) on the cell surface of olfactory sensory neurons and the human nuclear estrogen receptor ␣ (ER) involved in transcriptional regulation of cellular differentiation and proliferation in a wide variety of tissues. Hence, these apparent dual active odorants induce distinct signal transduction pathways at different subcellular localizations, which affect both neuronal signaling, resulting in odor perception, and the ER-dependent transcriptional control of specific genes. We demonstrate these effects using fluorescence-based in vitro and cellular assays. Among these odorants, we have identified synthetic sandalwood compounds, an important class of molecules used in the fragrance industry. For one estrogenic odorant we have also identified the cognate OR. This prompted us to compare basic molecular recognition principles of odorants on the two structurally and apparent functionally non-related receptors using computational modeling in combination with functional assays. Faced with the increasing evidence that ORs may perform chemosensory functions in a number of tissues outside of the nasal olfactory epithelium, the unraveling of these molecular ligand-receptor interaction principles is of critical importance. In addition the evidence that certain olfactory sensory neurons naturally co-express ORs and ERs may provide a direct functional link between the olfactory and hormonal systems in humans. Our results are therefore useful for defining the structural and functional characteristics of ER-specific odorants and the role of odorant molecules in cellular processes other than olfaction.Our nose detects a large variety of odorant signals relying on about 350 different predicted G-protein-coupled olfactory receptors (ORs) 3 with a conserved seven-transmembrane helical structure (1-3). By binding odorant molecules ORs modulate the conversion of chemical into electrical neuronal signals that are finally decoded in higher brain regions to trigger emotional and behavioral responses (4 -6). Odorants are generally small, hydrophobic organic molecules with highly variable chemical structures and properties (7). They easily pass cell membranes, and, due to their enormous chemical diversity, some of them might, apart from their "conventional" role in olfaction, trigger also yet unknown cellular processes. The role of specific ORs in sperm chemotaxis has been documented (8,9), and the widespread ectopic expression of OR genes in a large number of non-olfactory human tissues implicates additional, unproven functions of ORs in embryonic development and cell-cell recognition (10), and proliferation rates in prostate cancer cells (11). Recent findings indicate that ORs might also have chemosensory functions in kidney (12). Although most present efforts concentrate on matching odorants with their cognate ORs to define their molecular receptive ranges and receptor fu...

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Section: Resultsmentioning

confidence: 77%

Dual Activities of Odorants on Olfactory and Nuclear Hormone Receptors

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Etter

Baud

et al. 2009

Journal of Biological Chemistry

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“…The combined organic layers were washed with 10% NaOH (100 mL), brine (100 mL), dried over sodium sulfate, and the solvent removed under reduced pressure. Compounds 6a (waxy white solid, 35% yield), 6c (yellow oil, 31% yield), and 6d (yellow oil, 77% yield) were prepared and characterized as previously reported.…”

Section: Methodsmentioning

confidence: 99%

Lead Optimization of Benzoxepin-Type Selective Estrogen Receptor (ER) Modulators and Downregulators with Subtype-Specific ERα and ERβ Activity

et al. 2017

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Estrogen receptor ERis an important target for the design of drugs such as tamoxifen (2a) and fulvestrant (5). Three series of ER-ligands based on the benzoxepin scaffold structure were 2 synthesised -series I containing an acrylic acid, series II with an acrylamide and series III with a saturated carboxylic acid substituent. These compounds were shown to be high affinity ligands for the ER with nanomolar IC50 binding values. Series I acrylic acid ligands were generally ER selective. In particular, compound 13e featuring a phenylpenta-2,4-dienoic acid substituent was shown to be antiproliferative and downregulated ERand ER expression in MCF-7 breast cancer cells. Interestingly, from series III, the phenoxybutyric acid derivative compound 22 was not antiproliferative and selectively downregulated ER. A docking study of the benzoxepin ligands was undertaken. Compound 13e is a promising lead for development as a clinically relevant SERD, whilst compound 22 will be a useful experimental probe for helping to elucidate the role of ERβ in cancer cells.

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“…A number of examples where the olefinic group is replaced by a conformationally restricted ring structure have demonstrated significant antiproliferative activity 13 , including those based on coumarin (1) 14,15 , 2(5H)-furanone (2) 16 , imidazole 17 , 1,3-oxazole (3) 17 , furazan (4) 4 and furan (5) 18 , diarylindole 17,19 , and arylthioindole 20 , illustrated in Figure 1. We have previously reported the application of the benzoxepin 21 and benzothiepin scaffolds 22 for the design of antiproliferative agents as estrogen receptor (ER) antagonists. We have now investigated the development of a benzoxepin type scaffold as a conformationally restricted analog for combretastatin CA-4.…”

Section: Introductionmentioning

confidence: 99%