Improved synthesis and molecular modeling of 4beta,19-dihydroxyandrost-5-en-17-one, an excellent inhibitor of aromatase

Chem Pharm Bull (Tokyo). 2002 May;50(5):703-5. doi: 10.1248/cpb.50.703.

Abstract

4Beta,19-dihydroxyandrost-5-en-17-one (6) is an excellent competitive inhibitor of estrogen synthetase (aromatase). Alternate, improved synthesis of this inhibitor was established. Treatment of 19-(tert-butyldimethylsilyloxy)androst-4-en-17-one (8) with m-chloroperbenzoic acid gave a 1.4:1 mixture of 4alpha,5alpha-epoxide 9 and its 4beta,5beta-isomer 10. The mixture was reacted with diI. HClO4 in dioxane to produce principally 4beta,5alpha-diol 11 (80%) of which acetylation followed by dehydration with SOCl2 yielded 4beta,19-diacetoxy-5-ene compound 14 in good yield. Alkaline hydrolysis of diacetate 14 gave 4beta,19-diol 6. The minimum energy conformation of the powerfull aromatase inhibitor 6 was obtained with the PM3 method and compared with that of the structurally related diol steroid, 4-ene-5beta,19-diol 3, a weak competitive inhibitor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Androstenes / chemical synthesis*
  • Androstenes / pharmacology
  • Aromatase Inhibitors*
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / pharmacology
  • Hydrolysis
  • Indicators and Reagents
  • Models, Molecular
  • Spectrophotometry, Infrared
  • Structure-Activity Relationship

Substances

  • 4,19-dihydroxyandrost-5-en-17-one
  • Androstenes
  • Aromatase Inhibitors
  • Enzyme Inhibitors
  • Indicators and Reagents