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

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.

• Authors: Mitsuteru Numazawa, Keiko Yamada, Yoko Watari, Momoko Ando
• Journal: Chemical & pharmaceutical bulletin (Chem Pharm Bull (Tokyo)) Vol. 50 Issue 5 Pg. 703-5 (May 2002) ISSN: 0009-2363 [Print] Japan
• PMID: 12036037 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

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