3-(4-nitro-3-(trifluoromethyl)phenyl)-4,5,6,6a-tetrahydro-3aH-cyclopenta[d]isoxazole | 1387642-01-4

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 3-(4-nitro-3-(trifluoromethyl)phenyl)-4,5,6,6a-tetrahydro-3aH-cyclopenta[d]isoxazole
• 英文别名: (3aR,6aR)-3-[4-nitro-3-(trifluoromethyl)phenyl]-4,5,6,6a-tetrahydro-3aH-cyclopenta[d][1,2]oxazole
• CAS: 1387642-01-4
• 化学式: C₁₃H₁₁F₃N₂O₃
• 分子量: 300.237
• InChiKey: PHPKNJVMRNRLMZ-GZMMTYOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  21
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.46
• 拓扑面积：
  67.4
• 氢给体数：
  0
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  4-nitro-3-(trifluoromethyl)benzaldehyde oxime 、 环戊烯 在 sodium hypochlorite 、 三乙胺 作用下， 以 二氯甲烷 为溶剂， 反应 24.0h， 生成 3-(4-nitro-3-(trifluoromethyl)phenyl)-4,5,6,6a-tetrahydro-3aH-cyclopenta[d]isoxazole 、 3-(4-nitro-3-(trifluoromethyl)phenyl)-4,5,6,6a-tetrahydro-3aH-cyclopenta[d]isoxazole
  参考文献：
  名称：

  Design, Synthesis, and Biological Evaluation of Nonsteroidal Cycloalkane[d]isoxazole-Containing Androgen Receptor Modulators

  摘要：

  We report here the design, preparation, and systematic evaluation of a novel cycloalkane[d]isoxazole pharmacophoric fragment-containing androgen receptor (AR) modulators. Cycloalkane[d]isoxazoles form new core structures that interact with the hydrophobic region of the AR ligand-binding domain. To systematize and rationalize the RI structure activity relationship of the new fragment, we used molecular modeling to design a molecular library containing over 40 cycloalkane[d]isoxazole derivatives. The most potent compound, 4-(3a,4,5,6,7,7a-hexahydrobenzo[d]isoxazol-3-yl)2-(trifluoromethyl)benzonitrile (6a), exhibits antiandrogenic activity significantly greater than that of the most widely used antiandrogenic prostate cancer drugs bicalutamide (1) and hydroxyflutamide (2) in reporter gene assays measuring the transcriptional activity of AR (decreasing approximately 90% of the total AR activity) and in competitive AR ligand-binding assays (showing over four times higher potency to inhibit radioligand binding in comparison to bicalutamide). Notably, 6a maintains its antiandrogenic activity with AR mutants W741L and T877A commonly observed and activated by bicalutamide and hydroxyflutamide, respectively, in prostate cancer patients.

  DOI：

  10.1021/jm300233k

文献信息

• Design, Synthesis, and Biological Evaluation of Nonsteroidal Cycloalkane[<i>d</i>]isoxazole-Containing Androgen Receptor Modulators
  作者：Pekka K. Poutiainen、Tuomas Oravilahti、Mikael Peräkylä、Jorma J. Palvimo、Janne A. Ihalainen、Reino Laatikainen、Juha T. Pulkkinen

  DOI：10.1021/jm300233k

  日期：2012.7.26

  We report here the design, preparation, and systematic evaluation of a novel cycloalkane[d]isoxazole pharmacophoric fragment-containing androgen receptor (AR) modulators. Cycloalkane[d]isoxazoles form new core structures that interact with the hydrophobic region of the AR ligand-binding domain. To systematize and rationalize the RI structure activity relationship of the new fragment, we used molecular modeling to design a molecular library containing over 40 cycloalkane[d]isoxazole derivatives. The most potent compound, 4-(3a,4,5,6,7,7a-hexahydrobenzo[d]isoxazol-3-yl)2-(trifluoromethyl)benzonitrile (6a), exhibits antiandrogenic activity significantly greater than that of the most widely used antiandrogenic prostate cancer drugs bicalutamide (1) and hydroxyflutamide (2) in reporter gene assays measuring the transcriptional activity of AR (decreasing approximately 90% of the total AR activity) and in competitive AR ligand-binding assays (showing over four times higher potency to inhibit radioligand binding in comparison to bicalutamide). Notably, 6a maintains its antiandrogenic activity with AR mutants W741L and T877A commonly observed and activated by bicalutamide and hydroxyflutamide, respectively, in prostate cancer patients.