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

J Med Chem. 1986 Oct;29(10):2053-9. doi: 10.1021/jm00160a044.

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 more rigid than tamoxifen; interconversion between enantiomeric conformers is slow on the NMR time scale at -75 degrees C.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Breast Neoplasms / pathology
  • Cell Line
  • Female
  • Humans
  • Magnetic Resonance Spectroscopy
  • Molecular Conformation
  • Rats
  • Receptors, Estrogen / metabolism*
  • Structure-Activity Relationship
  • Tamoxifen / analogs & derivatives*
  • Tamoxifen / chemical synthesis
  • Tamoxifen / metabolism
  • Tamoxifen / pharmacology
  • Temperature
  • X-Ray Diffraction

Substances

  • Receptors, Estrogen
  • Tamoxifen
  • 6,7-dihydro-8-phenyl-9-(4-(2-(dimethylamino)ethoxy)phenyl)-5-H-benzocycloheptene