Abul-Hajj Y J
J Med Chem. 1986 Apr;29(4):582-4. doi: 10.1021/jm00154a025.
The synthesis and evaluation of 4-(substituted thio)-4-androstene-3,17-dione derivatives as inhibitors of estrogen synthetase (aromatase) are described. All compounds were prepared by the addition of various thiol reagents to 4 beta,5 beta-epoxyandrostanedione. Inhibitory activity of synthesized compounds was determined with use of a human placental microsomal preparation as the enzyme source and [1 beta-3H]-4-androstene-3,17-dione as substrate. Synthesized compounds exhibiting high inhibitory activity were further evaluated under initial velocity conditions to determine apparent Ki values. Several compounds were effective competitive inhibitors and have apparent Ki values ranging from 36 to 73 nM, with the apparent Km for androstenedione being 53 nM. The results of these studies demonstrate a tightly fitted enzyme pocket that can accommodate bulk up to about 5.5 A.
本文描述了4-(取代硫基)-4-雄烯-3,17-二酮衍生物作为雌激素合成酶(芳香化酶)抑制剂的合成与评价。所有化合物均通过将各种硫醇试剂添加到4β,5β-环氧雄烷二酮中制备而成。使用人胎盘微粒体制剂作为酶源,以[1β-³H]-4-雄烯-3,17-二酮作为底物,测定合成化合物的抑制活性。对表现出高抑制活性的合成化合物在初速度条件下进一步评估,以确定表观Ki值。几种化合物是有效的竞争性抑制剂,表观Ki值范围为36至73 nM,雄烯二酮的表观Km为53 nM。这些研究结果表明存在一个紧密契合的酶口袋,其可容纳高达约5.5埃的体积。