Inhibition and inactivation of estrogen synthetase (aromatase) by fluorinated substrate analogues.
19,19-Difluoroandrost-4-ene-3,17-dione (1) and 19-fluorcandrost-4-ene-3,17-dione (2) have been synthesized, and the interaction of these compounds with the estrogen synthetase (aromatase) activity of human placental microsomes has been studied. 1 has been found to cause time-dependent, irreversible inactivation of this enzyme (Ki = 1 micron, kinact = 0.023 min-1). A possible mechanism of this process is enzymatic generation of an acyl fluoride through oxidation of 1. Compound 2 does not cause inactivation, and this substrate analogue has been shown to be converted to estrone in high yield by this enzyme system.
D000735:Androstenedione / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D047072:Aromatase Inhibitors; D055598:Chemical Phenomena; D002621:Chemistry; D005260:Female; D006801:Humans; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008861:Microsomes / Q000201:enzymology; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D010920:Placenta / Q000201:enzymology; D011247:Pregnancy; D013997:Time Factors
D047072:Aromatase Inhibitors; C034066:19-fluoroandrost-4-ene-3,17-dione; D000735:Androstenedione; C034067:19,19-difluoroandrost-4-ene-3,17-dione; D010088:Oxidoreductases