Antiestrogens and antiestrogen metabolites: preparation of tritium-labeled (+/-)-cis-3-[p-(1,2,3,4-tetrahydro-6-methoxy-2-phenyl-1-naphthyl)phenoxyl]-1,2-propanediol (U-23469) and characterization and synthesis of a biologically important metabolite

J Med Chem. 1979 Dec;22(12):1509-17. doi: 10.1021/jm00198a015.

Abstract

The Upjohn antiestrogen (+/-)-cis-3-[p-(1,2,3,4-tetrahydro-6-methoxy-2-phenyl-1-naphthyl)phenoxy]-1,2-propanediol (2b, U 23469) has been prepared in tritium-labeled form by reduction of an unsaturated dihydronaphthalene precursor with carrier-free tritium gas over a palladium catalyst followed by alkylation with 3-iodo-1,2-propanediol. After extensive chromatographic purification, the final material was obtained with a specific activity of 13 Ci/mmol and a radiochemical purity of 94%. In vivo studies with immature rats show that [3H]2b is slowly converted to a more polar metabolite that is selectively accumulated in the nuclear fraction of the uterus where it is bound to the estrogen receptor. Chromatographic comparisons indicate that this metabolite is the demethylated analogue 2c, a compound that has an affinity for estrogen receptor more than 300 times greater than that of 2b. These studies suggest that the demethylated analogue 2c may be a biologically important metabolite of 2b that is involved in the action of this antiestrogen.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Estrogen Antagonists / chemical synthesis
  • Estrogen Antagonists / metabolism*
  • Female
  • In Vitro Techniques
  • Isotope Labeling
  • Male
  • Microsomes, Liver / metabolism
  • Naphthalenes / metabolism*
  • Propylene Glycols / chemical synthesis
  • Propylene Glycols / metabolism*
  • Rats
  • Receptors, Estrogen / metabolism
  • Tetrahydronaphthalenes / chemical synthesis
  • Tetrahydronaphthalenes / metabolism*
  • Tritium
  • Uterus / metabolism

Substances

  • Estrogen Antagonists
  • Naphthalenes
  • Propylene Glycols
  • Receptors, Estrogen
  • Tetrahydronaphthalenes
  • Tritium
  • U 23469