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J Med Chem. 1996 Mar 1;39(5):1033-8.

Time-dependent inactivation of aromatase by 6-alkylandrosta-1,4-diene-3,17-diones. Effects of length and configuration of 6-alkyl group.

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Tohoku College of Pharmacy, Sendai, Japan.


Series of 6alpha- and 6beta-alkylandrosta-1,4-diene-3,17-diones (3 and 4) were synthesized and evaluated as time-dependent inactivators of aromatase in human placental microsomes to gain insights to the structure-activity relationship of varying the 6-n-alkyl substituents (C-1--C-7) to the time-dependent inactivation activity. All of the inhibitors synthesized were powerful to good competitive inhibitors of aromatase, with apparent Ki's ranging from 4.7 to 54 nM. The 6beta-ethyl (4b) and 6beta-n-pentyl (4e) compounds were the most potent among them (Ki = 4.7 and 5.0 nM for 4b and 4e, respectively). In a series of the 6alpha-alkyl steroids, the inhibitors 3a-d having C-1--C-4 at the 6-position as well as the 6 alpha-n-heptyl (3g) compounds did not. In contrast, in the 6beta-alkyl steroid series, only the methyl analog 4a inactivated aromatase in a time-dependent manner, and the other alkyl steroids having more than two carbons at C-6beta did not. The inactivations were prevented by the substrate androstenedione, and no significant effects of L-cysteine on the inactivation were observed in each case. These results along with molecular modeling with the PM3 method indicate that both length and stereochemistry of a straight alkyl substituent at the C-6 position of androsta-1.4-diene-3,17-dione (3h) play an important role in the cause of a time-dependent inactivation of aromatase. No significant correlation between affinity for the enzyme and the inactivation ability in the 6-alkylandrosta-1,4-diene-3,17-diones is observed.

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