Bednarski P J, Porubek D J, Nelson S D
J Med Chem. 1985 Jun;28(6):775-9. doi: 10.1021/jm00383a014.
The thiol-containing androgens 17 beta-hydroxy-10 beta-mercaptoestr-4-en-3-one and 19-mercaptoandrost-4-ene-3,17-dione were synthesized and tested in human placental microsomes for their ability to suicide inhibit aromatase. Both compounds showed time-dependent, pseudo-first-order rates of inactivation of aromatase with Ki's of 106 and 34 nM and kcat's of 3.2 X 10(-3) and 1.2 X 10(-3) s-1 respectively for 1 and 2 at 30 degrees C. Diffusion dialysis failed to reactivate aromatase previously inactivated by either compound, and both compounds required that NADPH and O2 be present for the time-dependent inactivation of the enzyme. The presence of the substrate, androst-4-ene-3,17-dione (5.0 microM), protected the enzyme from inactivation while cysteine (1.0 mM) failed to protect aromatase from inactivation by either compound. The above evidence demonstrates that both compounds are potent suicide inhibitors of aromatase.
合成了含硫醇的雄激素17β-羟基-10β-巯基雌甾-4-烯-3-酮和19-巯基雄甾-4-烯-3,17-二酮，并在人胎盘微粒体中测试了它们对芳香化酶的自杀抑制能力。两种化合物均显示出时间依赖性的、准一级的芳香化酶失活速率，在30℃下，化合物1和2的抑制常数（Ki）分别为106和34 nM，催化常数（kcat）分别为3.2×10⁻³和1.2×10⁻³ s⁻¹。扩散透析未能使先前被任何一种化合物失活的芳香化酶重新激活，且两种化合物均需要烟酰胺腺嘌呤二核苷酸磷酸（NADPH）和氧气的存在才能使酶发生时间依赖性失活。底物雄甾-4-烯-3,17-二酮（5.0 microM）的存在可保护酶不被失活，而半胱氨酸（1.0 mM）未能保护芳香化酶不被任何一种化合物失活。上述证据表明这两种化合物都是有效的芳香化酶自杀抑制剂。
