PMID: 3761324Oct 1, 1986Paper

Synthesis and estrogen receptor binding of 6,7-dihydro-8-phenyl-9-[4-[2-(dimethylamino)ethoxy] phenyl]-5H-benzocycloheptene, a nonisomerizable analogue of tamoxifen. X-ray crystallographic studies

Journal of Medicinal Chemistry
R McCagueS Stoessel

Abstract

Syntheses of the title compound (5), a novel nonisomerizable antiestrogen containing a seven-membered ring, are described. In one method, 6,7-dihydro-9-(4-methoxyphenyl)-5H-benzocycloheptene was brominated at the 8-position and the bromine displaced by phenylzinc chloride with palladium complex catalysis to introduce the 8-phenyl substituent. Alternatively, benzosuberone was alpha phenylated with tricarbonyl(eta 6-fluorobenzene)chromium (0) and the product treated with the appropriate aryllithium reagent to introduce the 9-aryl group last. The relative binding affinities for estrogen receptors in cell cytosol and whole cells and growth inhibitory activity against the MCF-7 human breast tumor cell line in vitro were for 5 comparable to those of tamoxifen (1) and the corresponding six-membered ring analogue (7). X-ray crystallographic analyses of 10 and 15, which are methoxy derivatives of 5 and 7, show that in some respects 5 bears a closer structural relationship to tamoxifen than does nafoxidine (3) or 7. Thus, the aromatic ring, which is fused in the cyclic analogues, was twisted 64, 45, 20, and 19 degrees out of the plane of the double bond for 1, 10, 3, and 15, respectively. Low-temperature NMR studies indicate that 5 is mo...Continue Reading

Citations

Jan 1, 1994·Cancer Chemotherapy and Pharmacology·C K OsborneA E Wakeling
Oct 1, 1988·Journal of Steroid Biochemistry·J F Miquel, J Gilbert
Oct 1, 1988·Journal of Steroid Biochemistry·R McCagueS Stoessel
Jan 1, 1993·Breast Cancer Research and Treatment·D M Wolf, V C Jordan
Jun 1, 1993·Critical Reviews in Oncology/hematology·V J WiebeM W DeGregorio
Oct 29, 2004·Journal of Medicinal Chemistry·David G LloydMary J Meegan
Jan 5, 2011·Journal of Chemical Information and Modeling·Li GaoLeif A Eriksson
Sep 16, 2005·Journal of Medicinal Chemistry·Nicola J CleggThomas S Scanlan
Jan 19, 2002·The Journal of Organic Chemistry·John F ValliantJames F Britten

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