Steroidal spiro-gamma-lactones that inhibit 17 beta-hydroxysteroid dehydrogenase activity in human placental microsomes.
Steroidal spiro-gamma-lactones that inhibit 17 beta-hydroxysteroid dehydrogenase activity in human placental microsomes.
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类固醇螺-γ-内酯可抑制人胎盘微粒体中 17 β-羟基类固醇脱氢酶的活性。
DOI：
10.1021/jm00022a018
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发表时间：
1995
影响因子：
7.3
通讯作者：
D. Poirier
中科院分区：
文献类型：
--
作者：
K. Sam;S. Auger;V. Luu‐The;D. Poirier
已知重要的酶17 β-羟基类固醇脱氢酶（17 β-HSD）调节生物活性类固醇（即雄激素和雌激素）的细胞内水平。为了开发有效的17 β-HSD抑制剂以降低活性类固醇的水平，我们发现甾体螺-γ-内酯抑制17 β-HSD活性。在这份报告中，我们描述了11个螺-γ-内酯类似物的合成含有甾体C-18或C-19核，并比较其相对抑制作用对17 β-HSD活性的人胎盘微粒体，催化雄激素和雌激素的相互转化。为了避免对雌酮和雌二醇的相互转化具有特异性的胞质17 β-HSD活性的相互作用，我们使用4-雄烯二酮作为底物。这些类似物对微粒体17 β-HSD活性的抑制作用的分析表明，含有C-18核的螺-γ-内酯是比C-19核类似物更有效的抑制剂。酚螺-γ-内酯7（3-羟基-19-去甲-17 α-孕-1，3，5（10）-三烯-21，17-碳内酯）获得了最佳抑制作用，其IC 50值为0.27 μ M，远低于未标记底物4-雄烯二酮的竞争作用，其IC 50值为1.40 μ M。用内酯7预孵育不抑制17 β-HSD活性。因此，结果表明内酯7是可逆的抑制剂。内酯7对微粒体17 β-HSD活性具有选择性，因为未观察到对胞质17 β-HSD活性的抑制。
The important enzyme 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD) is known to regulate intracellular levels of biologically active steroids, namely, androgens and estrogens. In an effort to develop potent inhibitors of 17 beta-HSD for reducing the levels of active steroids, we found that steroidal spiro-gamma-lactones inhibit 17 beta-HSD activity. In this report, we describe the synthesis of 11 spiro-gamma-lactone analogs containing a steroidal C-18 or C-19 nucleus and compare their relative inhibitory effects on 17 beta-HSD activity in the human placenta microsomes that catalyze the interconversion of androgens and estrogens. To void the interaction of the cytosolic 17 beta-HSD activity that is specific for the interconversion of estrone and estradiol, we used 4-androstenedione as substrate. Analysis of the inhibitory effect exerted by these analogs on microsomal 17 beta-HSD activity indicates that spiro-gamma-lactones containing the C-18 nucleus are more potent inhibitors than C-19 nucleus analogs. The best inhibition was obtained with the phenolic spiro-gamma-lactone 7 (3-hydroxy-19-nor-17 alpha-pregna-1,3,5(10)-triene 21,17-carbolactone), which has an IC50 value of 0.27 microM, and was much lower than the competitive effect of the unlabeled substrate 4-androstenedione, which has an IC50 value of 1.40 microM. Preincubation with lactone 7 did not inactivate 17 beta-HSD activity. The results thus suggest that lactone 7 is a reversible in inhibitor. Lactone 7 is selective for microsomal 17 beta-HSD activity, as no inhibition was observed for cytosolic 17 beta-HSD activity.