Synthesis and evaluation of 11beta-substituted 21-chloro/iodo-(17alpha,20E/Z)-19-norpregna-1,3,5(10),20-te traene-3, 17beta-diols: high-affinity ligands for the estrogen receptor

J Med Chem. 1998 Nov 19;41(24):4686-92. doi: 10.1021/jm9801051.

Abstract

We have synthesized six new estrogens substituted at the 11beta-position with a methoxy or vinyl group and at the 17alpha-position with an (E)- or (Z)-chloro/iodovinyl moiety. The products were obtained in good overall yields from the corresponding tri-n-butylstannylvinyl intermediates using the electrophilic halodestannylation methodology. The six new ligands were compared to the 11beta-unsubstituted chloro/iodovinyl derivatives and the 11beta-methoxy (E)- and (Z)-iodovinyl estrogens to evaluate the effects of 11beta-substitution and 20E/Z-stereochemistry. While all the compounds exhibited high affinity for the estrogen receptor, the 20Z-isomers demonstrated higher affinity than the corresponding 20E-isomers. In addition, the presence of the lipophilic 11beta-substituent was favored over either no substituent or a polar (methoxy) group. Within each isomeric series, the presence of the 21-halo substituent had different effects. For the 20E-series, the 21-chloro products had a higher affinity than the 21-iodo analogue, whereas for the 20Z-series the effect was reversed. These results provide additional insights into the interaction of substituted estradiols with the hormone binding domain of the estrogen receptor.

Publication types

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

MeSH terms

  • Animals
  • Binding Sites
  • Cytosol / metabolism
  • Estradiol / analogs & derivatives*
  • Estradiol / chemical synthesis
  • Estradiol / chemistry
  • Estradiol / metabolism
  • Female
  • Ligands
  • Receptors, Estrogen / metabolism*
  • Sheep
  • Stereoisomerism
  • Structure-Activity Relationship
  • Uterus / metabolism
  • Uterus / ultrastructure

Substances

  • Ligands
  • Receptors, Estrogen
  • Estradiol