Marsh D A, Brodie H J, Garrett W, Tsai-Morris C H, Brodie A M
J Med Chem. 1985 Jun;28(6):788-95. doi: 10.1021/jm00383a017.
The synthesis and biological evaluation of androstenedione derivatives as inhibitors of estrogen biosynthesis are described. The results show that 4-hydroxy analogues are among the most potent in vitro inhibitors of the series. Esterification of the 4-hydroxy steroids generally reduced activity. Further conjugation of the 3-keto 4-ene system to give 4-hydroxy-4,6-androstadiene-3,17-dione caused more rapid inactivation of aromatase in rat ovarian microsomes than 4-hydroxyandrostenedione. Some compounds exhibited differences in activity when tested for inhibition of human placental microsomes vs. rat ovarian microsomes. The 4-hydroxyandrostenedione derivatives and their nonbulky esters were generally more potent in vitro and in vivo inhibitors than other substituted steroids in the series. Several of the synthesized compounds markedly reduce (50-81%) estrogen levels in rats on proestrus and/or had antifertility action. To date, none of the compounds surpassed the in vivo inhibitory action of 4-hydroxy-4-androstene-3,17-dione or its 4-acetate derivative.
本文描述了作为雌激素生物合成抑制剂的雄烯二酮衍生物的合成及生物学评价。结果表明，4-羟基类似物是该系列中体外活性最强的化合物之一。4-羟基甾体的酯化通常会降低活性。将3-酮-4-烯体系进一步共轭得到4-羟基-4,6-雄二烯-3,17-二酮，与4-羟基雄烯二酮相比，其在大鼠卵巢微粒体中使芳香化酶失活的速度更快。当测试对人胎盘微粒体和大鼠卵巢微粒体的抑制作用时，一些化合物表现出活性差异。该系列中的4-羟基雄烯二酮衍生物及其小分子酯在体外和体内通常比其他取代甾体具有更强的抑制活性。几种合成化合物能显著降低（50 - 81%）动情前期大鼠的雌激素水平和/或具有抗生育作用。迄今为止，没有一种化合物在体内的抑制作用超过4-羟基-4-雄烯-3,17-二酮或其4-乙酸酯衍生物。
