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A- and D-ring androstenedione derivatives were synthesizedandtested for their abilities to inhibit aromatase. In one series, C-3hydroxyl derivatives were studied leading to a very active compound,when the C-3 hydroxyl group assumes 3β stereochemistry (1, IC50= 0.18 μM). In a second series, theinfluence of double bonds or epoxide functions in different positionsalong the A-ring was studied. Among epoxides, the 3,4-epoxide 15showed the best activity (IC50= 0.145 μM)revealing the possibility of the 3,4-oxiran oxygen resembling theC-3 carbonyl group of androstenedione. Among olefins, the 4,5-olefin 12(IC50= 0.135 μM) revealed the best activity,pointing out the importance of planarity in the A,B-ring junctionnear C-5. C-4 acetoxy and acetylsalicyloxy derivatives were also studiedshowing that bulky substituents in C-4 diminish the activity. In addition,IFD simulations helped to explain the recognition of the C-3 hydroxylderivatives (1and 2) as well as 15within the enzyme. [ABSTRACT FROM AUTHOR]