Synthesis and biochemical evaluation of analogues of aminoglutethimide based on phenylpyrrolidine-2,5-dione.
A series of (aminophenyl)pyrrolidine-2,5-diones has been prepared that bear structural similarities to aminoglutethimide (1, 3-(4-aminophenyl)-3-ethylpiperidine-2,6-dione). The inhibitory activity of these compounds was evaluated toward human placental aromatase and bovine adrenal cholesterol side chain cleavage (CSCC) enzyme assay systems. Selective, competitive inhibition of the aromatase enzyme system was demonstrated by 5 (3-(4-aminophenyl)-1-methyl-pyrrolidine-2,5-dione, Ki = 1.75 microM), 6 (3-(4-aminophenyl)-1,3-dimethylpyrrolidine-2,5-dione, Ki = 1.75 microM), 7 (3-(4-aminophenyl)-3-methylpyrrolidine-2,5-dione, Ki = 0.8 microM), and 8 (3-(4-aminophenyl)-3-ethylpyrrolidine-2,5-dione, Ki = 1.0 microM). Compound 15 (3-(4-aminophenyl)pyrrolidine-2,5-dione) proved unexpectedly difficult to prepare following standard methods and was only moderately inhibitory toward aromatase (IC50 = 20 microM). Compound 16 (3-(4-aminophenyl)-3-ethyl-1-methylpyrrolidine-2,5-dione) was weakly inhibitory toward testosterone aromatization and totally inactive toward androstenedione aromatization. These compounds were either weak or ineffective inhibitors of the CSCC enzyme systems, while 1 gave Ki values toward aromatase and CSCC enzymes of 0.68 and 14 microM, respectively. The unsubstituted phenylpyrrolidinediones were inactive in either system, and the 4-nitrophenyl derivatives exhibited weak, nonselective inhibition, indicating the importance of the primary amine moiety for potent inhibition of aromatase activity.
D000616:Aminoglutethimide / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D000818:Animals; D047072:Aromatase Inhibitors; D002417:Cattle; D002786:Cholesterol Side-Chain Cleavage Enzyme / Q000037:antagonists & inhibitors*; D006801:Humans; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013739:Testosterone / Q000378:metabolism
D047072:Aromatase Inhibitors; D000616:Aminoglutethimide; D013739:Testosterone; D010088:Oxidoreductases; D002786:Cholesterol Side-Chain Cleavage Enzyme