19-oxygenated derivatives of androst-4-ene-6,17-dione and androst-5-ene-4,17-dione as catalytic probes for the active site of aromatase

To gain insight into the binding manner of androst-4-ene-6,17-dione (4) and its 5-en-4-one analog 9, good competitive inhibitors of aromatase, in the active site of the enzyme, their 19-oxygenated derivatives Here evaluated a s inhibitors of human placental aromatase, The 19-hydroxysteroids 6, 7, and 10 and the 19-oxo analogs 8 and 12 were much poorer competitive inhibitors than their corresponding parent 19-methyl steroids. Conversion of the 17-k eto inhibitors 4, 6, and 10 to the 17 beta-ols 5, 7, and 11, respectively, markedly decreased their affinity to the enzyme. The results suggest that s teroids 3 and 9 would bind to the active site in a similar manner to that i nvolved in the binding of the substrate androstenedione (1).