Synthesis of new steroidal isoxazoles: inhibitors of estrogen synthase Original Research Article

A novel class of steroidal A/B ring isoxazoles have been prepared by two independent reaction schemes using 3β,17β-diacetoxyandrost-5-ene (1) and 3β,17β-diacetoxyandrost-4-en-6-one (4) as synthetic precursors. The key common intermediate in these syntheses, 3β,17β-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 3β,17β-dihydroxyandrost-4-eno[6,5,4-c,d] isoxazole (6), androst-3,17-dione-4-eno[6,5,4-c,d] isoxazole (7), and 17β-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 μM; 7, 1.889 μM. 9, 18.57 μM.