Li P K, Brueggemeier R W
College of Pharmacy, Ohio State University, Columbus 43210.
J Enzyme Inhib. 1990;4(2):113-20. doi: 10.3109/14756369009040732.
Androstenedione analogs containing 7 alpha-substituents have proven to be potent inhibitors of aromatase both in vitro and in vivo. Several of these agents have exhibited higher affinity for the enzyme complex than the substrate does. In order to examine further the interaction(s) of 7-substituted steroids with aromatase, biochemical and molecular modeling studies were performed on 7-substituted 4,6-androstadiene-3,17-diones. 7-Benzyl- and 7-phenethyl-4,6-androstadiene-3,17-diones effectively inhibited microsomal aromatase, with apparent Kis ranging from 61 to 174 nM. On the other hand, 7-phenyl-4,6-androstadiene-3,17-dione exhibited poor activity, with an apparent Ki of 1.42 microM. Energy minimization calculations and molecular modeling indicated that the 7-substituent is perpendicular to the steroid nucleus in the 7-phenyl analog and can only adopt a pseudo beta position. The 7-benzyl- and 7-phenethyl- groups of 4,6-androstadiene-3,17-diones orient themselves in the minimized structure in a way that the phenyl rings can protrude into the 7 alpha pocket. These orientations are similar to those observed in minimized structures for potent 7 alpha-substituted androstenediones.
含有7α-取代基的雄烯二酮类似物已被证明在体外和体内都是有效的芳香化酶抑制剂。其中几种药物对酶复合物的亲和力高于底物。为了进一步研究7-取代甾体与芳香化酶的相互作用，对7-取代的4,6-雄二烯-3,17-二酮进行了生化和分子模拟研究。7-苄基-和7-苯乙基-4,6-雄二烯-3,17-二酮有效抑制微粒体芳香化酶，表观解离常数（Kis）范围为61至174 nM。另一方面，7-苯基-4,6-雄二烯-3,17-二酮活性较差，表观解离常数（Ki）为1.42 μM。能量最小化计算和分子模拟表明，在7-苯基类似物中，7-取代基与甾体核垂直，且只能采取假β位。4,6-雄二烯-3,17-二酮的7-苄基和7-苯乙基在最小化结构中的取向使得苯环可以伸入7α口袋。这些取向与在有效的7α-取代雄烯二酮的最小化结构中观察到的取向相似。
