Li P K, Brueggemeier R W
College of Pharmacy, Ohio State University, Columbus 43210.
J Steroid Biochem. 1990 Aug 28;36(6):533-9. doi: 10.1016/0022-4731(90)90170-w.
7-Phenyl-1,4,6-androstatriene-3,17-dione (4), 7-benzyl-1,4,6-androstatriene-3,17-dione (5) and 7-phenethyl-1,4,6-androstatriene-3,17-dione (6) were synthesized and evaluated in vitro in human placental microsomes as enzyme-activated irreversible inhibitors of aromatase. The compounds were synthesized from appropriate 7-substituted 4,6-androstadiene-3,17-diones by reaction with DDQ under neutral conditions. All the compounds produced a first order inactivation of aromatase in the presence of NADPH but not in the absence of NADPH. Substrate 4-androstene-3,17-dione protected the enzyme from inactivation by the inhibitors. Furthermore, cysteine failed to protect aromatase from inactivation by compounds 5 and 6. In contrast, cysteine partially protected aromatase from inactivation by compound 4. Irreversibility studies illustrated the covalent nature of the inactivation by 4, 5 and 6. The above experimental evidence demonstrated that compounds 5 and 6 are effective enzyme-activated irreversible inhibitors of aromatase.
合成了7-苯基-1,4,6-雄甾三烯-3,17-二酮（4）、7-苄基-1,4,6-雄甾三烯-3,17-二酮（5）和7-苯乙基-1,4,6-雄甾三烯-3,17-二酮（6），并在人胎盘微粒体中进行体外评估，以研究其作为芳香化酶的酶激活不可逆抑制剂的活性。这些化合物由适当的7-取代4,6-雄甾二烯-3,17-二酮在中性条件下与2,3-二氯-5,6-二氰基-1,4-苯醌（DDQ）反应合成。所有化合物在存在烟酰胺腺嘌呤二核苷酸磷酸（NADPH）的情况下使芳香化酶发生一级失活，但在不存在NADPH的情况下则不会。底物4-雄烯二酮-3,17-二酮可保护该酶不被抑制剂失活。此外，半胱氨酸不能保护芳香化酶不被化合物5和6失活。相比之下，半胱氨酸可部分保护芳香化酶不被化合物4失活。不可逆性研究表明化合物4、5和6的失活具有共价性质。上述实验证据表明化合物5和6是有效的芳香化酶酶激活不可逆抑制剂。
