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 were evaluated as inhibitors of human placental aromatase. The 19-hydroxy steroids 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-keto inhibitors 4, 6, and 10 to the 17beta-ols 5, 7, and 11, respectively, markedly decreased their affinity to the enzyme. The results suggest that steroids 4 and 9 would bind to the active site in a similar manner to that involved in the binding of the substrate androstenedione (1).
Numazawa
M
M
Tohoku College of Pharmacy, Sendai, Japan.
Yamada
K
K
Kidokoro
K
K
D000735:Androstenedione / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D001141:Aromatase / Q000378:metabolism; D047072:Aromatase Inhibitors; D001665:Binding Sites; D002384:Catalysis; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D006801:Humans; D010920:Placenta / Q000201:enzymology; D013379:Substrate Specificity
D047072:Aromatase Inhibitors; D004791:Enzyme Inhibitors; C401290:androst-4-ene-6,17-dione; C401289:androst-5-ene-4,17-dione; D000735:Androstenedione; D001141:Aromatase