Synthesis of new steroidal isoxazoles: inhibitors of estrogen synthase.
A novel class of steroidal A/B ring isoxazoles have been prepared by two independent reaction schemes using 3 beta,17 beta-diacetoxyandrost-5-ene (1) and 3 beta,17 beta-diacetoxyandrost-4-en-6-one (4) as synthetic precursors. The key common intermediate in these syntheses, 3 beta,17 beta-diacetoxyandrost-4-eno[6,5,4-c,d] isoxazole (3), was prepared by synthetic methods described in both schemes. Further chemical modification of 3 yielded 3 beta,17 beta-dihydroxyandrost-4-eno[6,5,4-c,d] isoxazole (6), androst-3,17-dione-4-eno[6,5,4-c,d] isoxazole (7), and 17 beta-hydroxyandrost-3-one-4-eno[6,5,4-c,d] isoxazole (9). Human placental estrogen synthase (aromatase) bioassays were conducted to obtain the following IC50 values resulting from a 50% reduction of enzymatic activity: 6, 120.5 microM; 7, 1.889 microM. 9, 18.57 microM.
Li
S
S
Department of Chemistry, Auburn University, AL 36849-5312, USA.
Parish
E J
EJ
Rodriguez-Valenzuela
C
C
Brodie
A M
AM
D047072:Aromatase Inhibitors; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D007555:Isoxazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy
D047072:Aromatase Inhibitors; D004791:Enzyme Inhibitors; D007555:Isoxazoles