3β-HYDROXYANDROST-4-EN-6-ONE DERIVATIVES AS AROMATASE INHIBITORS

Article abstract of DOI:10.1016/0039-128X(89)90004-4

The 3-formate (II), 3-acetate (III), 3-bromoacetate (IV), 3-propionate (V), 3-methyl ether (VI), and 3-deoxy-derivative (VII) of 3β-hydroxyandrost-4-ene-6,17-dione (I) were synthesized and tested in human placental microsomes for their ability to inhibit aromatase.II, III, and VII of this series were potent inhibitors of aromatase with the IC₅₀'s (1.7 and 3.3 μM) of the latter two comparable to that (1.2 μM) of 4-hydroxyandrostenedione.Kinetic studies showed that the three steroids are competitive inhibitors of the enzyme with Ki's of 16.0, 5.5, and 0.61 μM for II, III, and VII.Furthermore, II showed a time-dependent, pseudo-first order rate of inactivation of aromatase with Ki of 20.5 μM and k_inact of 1.54 * 10^-2 min^-1, while III gave a time-dependent, biphasic loss of the enzyme activity.NADPH and oxygen were required for the time-dependent inactivation and the substrate, androstenedione, prevented it.