3-oxo-17α-pregna-4-ene-7α-(benzoylthia)-21,17-carbolactone

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 类固醇和类固醇衍生物
• 英文名称: 3-oxo-17α-pregna-4-ene-7α-(benzoylthia)-21,17-carbolactone
• 英文别名: S-[(7R,8R,9S,10R,13S,14S,17R)-10,13-dimethyl-3,5'-dioxospiro[2,6,7,8,9,11,12,14,15,16-decahydro-1H-cyclopenta[a]phenanthrene-17,2'-oxolane]-7-yl] benzenecarbothioate
• 化学式: C₂₉H₃₄O₄S
• 分子量: 478.653
• InChiKey: YGSWHYOYVIXSHP-UBUDMHMFSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.6
• 重原子数：
  34
• 可旋转键数：
  3
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.62
• 拓扑面积：
  85.7
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  螺内酯 在 sodium methylate 作用下， 以 四氢呋喃 为溶剂， 反应 21.0h， 生成 3-oxo-17α-pregna-4-ene-7α-(benzoylthia)-21,17-carbolactone
  参考文献：
  名称：

  Spironolactone-related inhibitors of type II 17β-hydroxysteroid dehydrogenase: chemical synthesis, receptor binding affinities, and proliferative/antiproliferative activities

  摘要：

  The family of 17 beta-hydroxysteroid dehydrogenases (17 beta-HSDs) catalyzes the formation and inactivation of testosterone (T), dihydrotestosterone (DHT), and estradiol (E-2), thus playing a crucial role in the regulation of active steroid hormones in target tissues. Among the five known 17 beta-HSD enzymes, type II catalyzes the oxidation of E-2 into estrone (El), T into androstenedione, DHT into androstanedione, and 20 alpha-dihydroprogesterone into progesterone. Specific inhibitors are thus an interesting means to study the regulation and to probe the structure of type II 17 beta-HSD. In this context, we have efficiently synthesized a series of 7 alpha-thioalkyl and 7 alpha-thioaryl derivatives of spironolactone that inhibit type II 17 beta-HSD. These new C19-steroidal inhibitors possess two important pharmacophores, namely 17-spiro-gamma-lactone and a bulky side-chain at the 7 alpha-position. It was found that a para-substituted benzylthio group at the 7 alpha-position enhances the inhibitory potency of spironolactone derivatives on type II 17 beta-HSD. In fact, the compound with a para-hydroxy-benzylthio group showed an IC50 value of 0.5 mu M against type II 17 beta-HSD, whereas the compound with a para-[2-(1-piperidinyl)-ethoxy]-benzylthio group inhibited this enzyme with an IC50 value of 0.7 mu M. The latter inhibitor is more selective than the former because it did not show any inhibitory potency against P450 aromatase as well as any affinity towards four steroid receptors (AR, PR, GR, ER). As a result, this inhibitor did not show any proliferative effect on androgen-sensitive Shionogi cells and estrogen-sensitive ZR-75-1 cells. These findings contribute to a better knowledge of the structure of type II 17 beta-HSD and offer an interesting tool to study the regulation of this enzyme in several biological systems. (C) 1999 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0968-0896(98)00260-0

文献信息

• Spironolactone-related inhibitors of type II 17β-hydroxysteroid dehydrogenase: chemical synthesis, receptor binding affinities, and proliferative/antiproliferative activities
  作者：Martin R. Tremblay、Van Luu-The、Gilles Leblanc、Patricia Noël、Esther Breton、Fernand Labrie、Donald Poirier

  DOI：10.1016/s0968-0896(98)00260-0

  日期：1999.6

  The family of 17 beta-hydroxysteroid dehydrogenases (17 beta-HSDs) catalyzes the formation and inactivation of testosterone (T), dihydrotestosterone (DHT), and estradiol (E-2), thus playing a crucial role in the regulation of active steroid hormones in target tissues. Among the five known 17 beta-HSD enzymes, type II catalyzes the oxidation of E-2 into estrone (El), T into androstenedione, DHT into androstanedione, and 20 alpha-dihydroprogesterone into progesterone. Specific inhibitors are thus an interesting means to study the regulation and to probe the structure of type II 17 beta-HSD. In this context, we have efficiently synthesized a series of 7 alpha-thioalkyl and 7 alpha-thioaryl derivatives of spironolactone that inhibit type II 17 beta-HSD. These new C19-steroidal inhibitors possess two important pharmacophores, namely 17-spiro-gamma-lactone and a bulky side-chain at the 7 alpha-position. It was found that a para-substituted benzylthio group at the 7 alpha-position enhances the inhibitory potency of spironolactone derivatives on type II 17 beta-HSD. In fact, the compound with a para-hydroxy-benzylthio group showed an IC50 value of 0.5 mu M against type II 17 beta-HSD, whereas the compound with a para-[2-(1-piperidinyl)-ethoxy]-benzylthio group inhibited this enzyme with an IC50 value of 0.7 mu M. The latter inhibitor is more selective than the former because it did not show any inhibitory potency against P450 aromatase as well as any affinity towards four steroid receptors (AR, PR, GR, ER). As a result, this inhibitor did not show any proliferative effect on androgen-sensitive Shionogi cells and estrogen-sensitive ZR-75-1 cells. These findings contribute to a better knowledge of the structure of type II 17 beta-HSD and offer an interesting tool to study the regulation of this enzyme in several biological systems. (C) 1999 Elsevier Science Ltd. All rights reserved.
• A safe and practical method for the preparation of 7α-thioether and thioester derivatives of spironolactone
  作者：Géraldine Agusti、Sandrine Bourgeois、Nathalie Cartiser、Hatem Fessi、Marc Le Borgne、Thierry Lomberget

  DOI：10.1016/j.steroids.2012.09.005

  日期：2013.1

  Spironolactone is a renal competitive aldosterone antagonist. One of its most important metabolite is the 7 alpha-methylthio spironolactone: thus it is very important to have an efficient and safe access to this compound, for pharmacokinetic studies. In this context, we synthesized this metabolite by thioalkylation of 7 alpha-thio spironolactone using Hunig's base with a very good yield. We also used our procedure to prepare, with an easy work-up and high yields, 7 alpha-thioether and thioester derivatives of spironolactone, that could be useful for further Structure-Activity Relationships studies. (c) 2012 Elsevier Inc. All rights reserved.