Benzoxepin-Derived Estrogen Receptor Modulators:  A Novel Molecular Scaffold for the Estrogen Receptor

Abstract

We present and examine the efficacy of a novel benzoxepin-based scaffold for modulation of the human estrogen receptor. Receptor tolerance of this new molecular scaffold is examined through presentation of experimentally determined antiproliferative effects on human MCF-7 breast tumor cells and measured binding affinities. The effect of functional group substitution on the benzoxepin scaffold is explored through a brief computational structure-activity relationship investigation with molecular simulation.

Lead identification of conformationally restricted benzoxepin type combretastatin analogs: synthesis, antiproliferative activity, and tubulin effects

“…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.…”

A Fluorescent Chemosensor for Transition‐Metal Ions Based on Optically Active Polybinaphthyl and 2,2′‐Bipyridine

“…Syntheses and Features of the Monomers and Polymer 4-methylphenylboronic acid was synthesized according to the literature, [43][44][45] and 5,5 0 -divinyl-2,2 0 -bipyridine (M-1) was prepared as has been reported previously [38,46,47] (Scheme 1). R-M-2 was synthesized from (R)-BINOL by a six-step reaction (Scheme 2).…”

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

“…All products isolated were homogenous on TLC. Compound 6 was prepared as we previously reported [20]. …”

“…4), dihydrobenzoxathins [17], (e.g. 5), bicyclo[3.3.1]nonene [18] and oxachrysenol [19] while mono [20] and bis-benzo [b ]oxepines [21] have been designed as agonists of the estrogen receptor. The structures of estradiol together with selected SERMs are illustrated in Figure 1.…”

“…We have recently identified a novel estrogen receptor modulator core containing a central benzoxepin scaffold, (e.g. compound 6), [20] which demonstrated some potential as antiproliferative and antagonist ER binding ligands and now report the further development of this novel core scaffold structure as tissue and subtype selective estrogen receptor modulators [22]. The synthesis of benzothiepin derivatives which are substituted at C-4, C-5 and C-8 positions is now described together with an evaluation of their antiproliferative activity and the relative binding affinities for ERa and ERb.…”