3-{[(16β,17β)-3-[(ethyl(propyl)amino)methyl]-17-hydroxyestra-1-(10),2,4-trien-16-yl]methyl}benzamide | 1519060-43-5

• 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-{[(16β,17β)-3-[(ethyl(propyl)amino)methyl]-17-hydroxyestra-1-(10),2,4-trien-16-yl]methyl}benzamide
• 英文别名: 3-[[(8R,9S,13S,14S,16R,17S)-3-[[ethyl(propyl)amino]methyl]-17-hydroxy-13-methyl-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthren-16-yl]methyl]benzamide
• CAS: 1519060-43-5
• 化学式: C₃₂H₄₄N₂O₂
• 分子量: 488.714
• InChiKey: QMUYERJYVLZBGK-WNFZKSSUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.1
• 重原子数：
  36
• 可旋转键数：
  8
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.59
• 拓扑面积：
  66.6
• 氢给体数：
  2
• 氢受体数：
  3

反应信息

• 作为产物：
  描述：

  (8R,9S,13S,14S)-13-methyl-17-oxo-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene-3-carboxylic acid 在 sodium tetrahydroborate 、 四溴化碳 、 palladium 10% on activated carbon 、 氢气 、 (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate 、 三乙胺 、 N,N-二异丙基乙胺 、 三苯基膦 、 potassium hydroxide 作用下， 以 四氢呋喃 、 甲醇 、 乙醇 、 二氯甲烷 、 水 为溶剂， 反应 44.67h， 生成 3-{[(16β,17β)-3-[(ethyl(propyl)amino)methyl]-17-hydroxyestra-1-(10),2,4-trien-16-yl]methyl}benzamide
  参考文献：
  名称：

  Discovery of a Non-Estrogenic Irreversible Inhibitor of 17β-Hydroxysteroid Dehydrogenase Type 1 from 3-Substituted-16β-(m-carbamoylbenzyl)-estradiol Derivatives

  摘要：

  17 beta-Hydroxysteroid dehydrogenase type 1 (17 beta-HSD1) is thought to play a pivotal role in the progression of estrogen-sensitive breast cancer by transforming estrone (E1) into estradiol (E2). We designed three successive series of E2-derivatives at position C3 of the potent inhibitor 16 beta-(m-carbamoylbenzy1)-E2 to remove its unwanted estrogenic activity. We report the chemical synthesis and characterization of 20 new E2-derivatives, their evaluation as 17 beta-HSD1 inhibitors, and their proliferative (estrogenic) activity on estrogen-sensitive cells. The structure-activity relationship study provided a new potent and steroidal nonestrogenic inhibitor of 17 beta-HSD1 named 3-{[(16 beta,17 beta)-3-(2-bromoethyl)-17-hydroxyestra-1(10),2,4-trien-16-yl]methyl}benzamide (23b). In fact, this compound inhibited the transformation of E1 into E2 by 17 beta-HSD1 in T-47D cells (IC50 = 83 nM), did not inhibit 17 beta-HSD2, 17 beta-HSD7, 17 beta-HSD12, and CYP3A4, and did not stimulate the proliferation of estrogen-sensitive MCF-7 cells. We also discussed the results of kinetic and molecular modeling (docking) experiments, suggesting that compound 23h is a competitive and irreversible inhibitor of 17 beta-HSD1.

  DOI：

  10.1021/jm401639v

文献信息

• Discovery of a Non-Estrogenic Irreversible Inhibitor of 17β-Hydroxysteroid Dehydrogenase Type 1 from 3-Substituted-16β-(<i>m</i>-carbamoylbenzyl)-estradiol Derivatives
  作者：René Maltais、Diana Ayan、Alexandre Trottier、Xavier Barbeau、Patrick Lagüe、Jean-Emmanuel Bouchard、Donald Poirier

  DOI：10.1021/jm401639v

  日期：2014.1.9

  17 beta-Hydroxysteroid dehydrogenase type 1 (17 beta-HSD1) is thought to play a pivotal role in the progression of estrogen-sensitive breast cancer by transforming estrone (E1) into estradiol (E2). We designed three successive series of E2-derivatives at position C3 of the potent inhibitor 16 beta-(m-carbamoylbenzy1)-E2 to remove its unwanted estrogenic activity. We report the chemical synthesis and characterization of 20 new E2-derivatives, their evaluation as 17 beta-HSD1 inhibitors, and their proliferative (estrogenic) activity on estrogen-sensitive cells. The structure-activity relationship study provided a new potent and steroidal nonestrogenic inhibitor of 17 beta-HSD1 named 3-[(16 beta,17 beta)-3-(2-bromoethyl)-17-hydroxyestra-1(10),2,4-trien-16-yl]methyl}benzamide (23b). In fact, this compound inhibited the transformation of E1 into E2 by 17 beta-HSD1 in T-47D cells (IC50 = 83 nM), did not inhibit 17 beta-HSD2, 17 beta-HSD7, 17 beta-HSD12, and CYP3A4, and did not stimulate the proliferation of estrogen-sensitive MCF-7 cells. We also discussed the results of kinetic and molecular modeling (docking) experiments, suggesting that compound 23h is a competitive and irreversible inhibitor of 17 beta-HSD1.