2-(2-(7-(diethylamino)-2-oxo-2H-chromene-3-carboxamido)ethoxy)ethyl 3-((2-(2-(2-aminoethoxy)ethoxy)ethyl)carbamoyl)benzenesulfonate | 1351708-49-0

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 香豆素及其衍生物
• 英文名称: 2-(2-(7-(diethylamino)-2-oxo-2H-chromene-3-carboxamido)ethoxy)ethyl 3-((2-(2-(2-aminoethoxy)ethoxy)ethyl)carbamoyl)benzenesulfonate
• CAS: 1351708-49-0
• 化学式: C₃₁H₄₂N₄O₁₀S
• 分子量: 662.761
• InChiKey: HMFCGDIUZOMDRH-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.51
• 重原子数：
  46.0
• 可旋转键数：
  21.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.45
• 拓扑面积：
  188.73
• 氢给体数：
  3.0
• 氢受体数：
  12.0

反应信息

• 作为反应物：
  描述：

  4-((2-(3,5-bis(trifluoromethyl)phenyl)-4,5-bis(4-methoxyphenyl)-1H-imidazole-1-yl)methyl)benzoic acid 、 2-(2-(7-(diethylamino)-2-oxo-2H-chromene-3-carboxamido)ethoxy)ethyl 3-((2-(2-(2-aminoethoxy)ethoxy)ethyl)carbamoyl)benzenesulfonate 在 1-(3-二甲基氨基丙基)-3-乙基碳二亚胺 、 N,N-二异丙基乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 6.0h， 生成 2-(2-(7-(diethylamino)-2-oxo-2H-chromene-3-carboxamido)ethoxy)ethyl 3-((2-(2-(2-(4-((2-(3,5-bis(trifluoromethyl)phenyl)-4,5-bis(4-methoxyphenyl)-1H-imidazol-1-yl)methyl)benzamido)ethoxy)ethoxy)ethyl)carbamoyl)benzenesulfonate
  参考文献：
  名称：

  A Small Molecule That Binds to an ATPase Domain of Hsc70 Promotes Membrane Trafficking of Mutant Cystic Fibrosis Transmembrane Conductance Regulator

  摘要：

  Cystic fibrosis transmembrane conductance regulator (CFTR) is a cell-surface anion channel that permeates chloride and bicarbonate ions. The most frequent mutation of CFTR that causes cystic fibrosis is the deletion of phenylalanine at position 508 (Delta F508), which leads to defects in protein folding and cellular trafficking to the plasma membrane. The lack of the cell-surface CFTR results in a reduction in the lifespan due to chronic lung infection with progressive deterioration of lung function. Hsc70 plays a crucial role in degradation of mutant CFTR by the ubiquitin-proteasome system. To date, various Hsc70 inhibitors and transcription regulators have been tested to determine whether they correct the defective activity of mutant CFTR However, they exhibited limited or questionable effects on restoring the chloride channel activity in cystic fibrosis cells. Herein, we show that a small molecule apoptozole (Az) has high cellular potency to promote membrane trafficking of mutant CFTR and its chloride channel activity in cystic fibrosis cells. Results from affinity chromatography and ATPase activity assay indicate that Az inhibits the ATPase activity of Hsc70 by binding to its ATPase domain. In addition, a ligand-directed protein labeling and molecular modeling studies also suggest the binding of Az to an ATPase domain, in particular, an ATP-binding pocket. It is proposed that Az suppresses ubiquitination of Delta F508-CFTR maybe by blocking interaction of the mutant with Hsc70 and CHIP, and, as a consequence, it enhances membrane trafficking of the mutant.

  DOI：

  10.1021/ja206762p
• 作为产物：
  描述：

  在 三乙基硅烷 、 三氟乙酸 作用下， 反应 1.0h， 生成 2-(2-(7-(diethylamino)-2-oxo-2H-chromene-3-carboxamido)ethoxy)ethyl 3-((2-(2-(2-aminoethoxy)ethoxy)ethyl)carbamoyl)benzenesulfonate
  参考文献：
  名称：

  A Small Molecule That Binds to an ATPase Domain of Hsc70 Promotes Membrane Trafficking of Mutant Cystic Fibrosis Transmembrane Conductance Regulator

  摘要：

  Cystic fibrosis transmembrane conductance regulator (CFTR) is a cell-surface anion channel that permeates chloride and bicarbonate ions. The most frequent mutation of CFTR that causes cystic fibrosis is the deletion of phenylalanine at position 508 (Delta F508), which leads to defects in protein folding and cellular trafficking to the plasma membrane. The lack of the cell-surface CFTR results in a reduction in the lifespan due to chronic lung infection with progressive deterioration of lung function. Hsc70 plays a crucial role in degradation of mutant CFTR by the ubiquitin-proteasome system. To date, various Hsc70 inhibitors and transcription regulators have been tested to determine whether they correct the defective activity of mutant CFTR However, they exhibited limited or questionable effects on restoring the chloride channel activity in cystic fibrosis cells. Herein, we show that a small molecule apoptozole (Az) has high cellular potency to promote membrane trafficking of mutant CFTR and its chloride channel activity in cystic fibrosis cells. Results from affinity chromatography and ATPase activity assay indicate that Az inhibits the ATPase activity of Hsc70 by binding to its ATPase domain. In addition, a ligand-directed protein labeling and molecular modeling studies also suggest the binding of Az to an ATPase domain, in particular, an ATP-binding pocket. It is proposed that Az suppresses ubiquitination of Delta F508-CFTR maybe by blocking interaction of the mutant with Hsc70 and CHIP, and, as a consequence, it enhances membrane trafficking of the mutant.

  DOI：

  10.1021/ja206762p