Improved synthesis and molecular modeling of 4beta,19-dihydroxyandrost-5-en-17-one, an excellent inhibitor of aromatase.
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.
Numazawa
Mitsuteru
M
Tohoku Pharmaceutical University, Sendai, Japan. numazawa@tohoku-pharm.ac.jp
Yamada
Keiko
K
Watari
Yoko
Y
Ando
Momoko
M
D000736:Androstenes / Q000138:chemical synthesis* / Q000494:pharmacology; D047072:Aromatase Inhibitors; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D006868:Hydrolysis; D007202:Indicators and Reagents; D008958:Models, Molecular; D013055:Spectrophotometry, Infrared; D013329:Structure-Activity Relationship
C468052:4,19-dihydroxyandrost-5-en-17-one; D000736:Androstenes; D047072:Aromatase Inhibitors; D004791:Enzyme Inhibitors; D007202:Indicators and Reagents