title: Time-dependent inactivation of aromatase by 6-alkylandrosta-1,4-diene-3,17-diones. Effects of length and configuration of 6-alkyl group.
abstract: 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.
authors.affiliation: Tohoku College of Pharmacy, Sendai, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Numazawa
authors.forename: M
authors.initials: M
authors.lastname: Oshibe
authors.forename: S
authors.initials: S
authors.lastname: Yamaguchi
authors.forename: M
authors.initials: M
authors.lastname: Tachibana
mesh_terms: D000478:Alkylation; D000730:Androstadienes / Q000737:chemistry* / Q000494:pharmacology*; D000735:Androstenedione / Q000378:metabolism / Q000494:pharmacology; D001141:Aromatase / Q000378:metabolism; D047072:Aromatase Inhibitors; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007700:Kinetics; D008861:Microsomes / Q000201:enzymology; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D009249:NADP / Q000494:pharmacology; D010920:Placenta / Q000201:enzymology / Q000648:ultrastructure; D013329:Structure-Activity Relationship; D014316:Tritium
chemical_list: D000730:Androstadienes; D047072:Aromatase Inhibitors; D004791:Enzyme Inhibitors; D014316:Tritium; C006573:1,4-androstadiene-3,17-dione; D000735:Androstenedione; D009249:NADP; D001141:Aromatase