Department of Pharmacy, Faculty of Chemistry, National University of Mexico City, Mexico D.F., Mexico.
J Enzyme Inhib Med Chem. 2009 Jun;24(3):655-62. doi: 10.1080/14756360802323720.
The aim of this study was to determine the biological activity of 4 steroidal derivatives (9a, 9b and 10a, 10b) prepared from the commercially available 17alpha acetoxyprogesterone, where 9a, 9b, have the Delta(4)-3-oxo structure and 10a and 10b an epoxy group at C-4 and C-5. These steroids were tested as inhibitors of 5alpha-reductase enzyme, which is present in androgen-dependent tissues and converts testosterone to its more active reduced metabolite dihydrotestosterone. The pharmacological effect of these steroids was demonstrated by the significant decrease of the weight of the prostate gland of gonadectomized hamsters treated with testosterone plus finasteride or with steroids 10a and 10b. For the studies in vitro the IC(50) values were determined by measuring the steroid concentration that inhibits 50% of the activity of-5alpha-reductase. In this study we also determined the capacity of these steroids to bind to the androgen receptor present in the rat prostate cytosol. The results from this work indicated that compounds 9a, 9b, 10a, and 10b inhibited the 5alpha reductase activity with IC(50) values of 360, 370, 13 and 4.9 nM respectively. However these steroids did not bind to the androgen receptors since none competed with labeled mibolerone. Steroid 10b, an epoxy steroidal derivative containing bromine atom in the ester moiety, was the most active inhibitor of 5alpha-reductase enzyme, present in human prostate homogenates with an IC(50) value of 4.9 nM and also showed in vivo pharmacological activity since it decreased the weight of the prostate from hamsters treated with testosterone in a similar way as finasteride.
本研究的目的是确定 4 种甾体衍生物（9a、9b 和 10a、10b）的生物活性，这些衍生物是由市售的 17α-乙酰氧基黄体酮制备的，其中 9a、9b 具有Δ(4)-3-氧代结构，而 10a 和 10b 在 C-4 和 C-5 位具有环氧基团。这些甾体被测试为 5α-还原酶抑制剂，该酶存在于雄激素依赖性组织中，将睾酮转化为其更活跃的还原代谢产物二氢睾酮。这些甾体的药理作用通过以下方式得到证明：用睾酮加非那雄胺或用甾体 10a 和 10b 处理去势仓鼠，前列腺重量显著减少。对于体外研究，通过测量抑制 5α-还原酶活性 50%的甾体浓度来确定 IC(50)值。在这项研究中，我们还确定了这些甾体与存在于大鼠前列腺细胞溶质中的雄激素受体结合的能力。这些结果表明，化合物 9a、9b、10a 和 10b 抑制 5α-还原酶活性的 IC(50)值分别为 360、370、13 和 4.9 nM。然而，这些甾体不与雄激素受体结合，因为没有一种与标记的米非隆竞争。甾体 10b 是一种含有酯部分溴原子的环氧甾体衍生物，是对人前列腺匀浆中 5α-还原酶最有效的抑制剂，IC(50)值为 4.9 nM，并且在体内也表现出药理活性，因为它使用睾酮处理的仓鼠的前列腺重量减少，与非那雄胺相似。
