1-(8-{[(2R)-2-Hydroxy-3-phenylpropanoyl]oxy}octyl)pyridin-1-ium iodide | 824432-20-4

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 脂肪酰基
• 英文名称: 1-(8-{[(2R)-2-Hydroxy-3-phenylpropanoyl]oxy}octyl)pyridin-1-ium iodide
• 英文别名: 8-pyridin-1-ium-1-yloctyl (2R)-2-hydroxy-3-phenylpropanoate;iodide
• CAS: 824432-20-4
• 化学式: C₂₂H₃₀NO₃*I
• 分子量: 483.39
• InChiKey: RXGDXSPWORZIDM-ZMBIFBSDSA-M

计算性质

• 辛醇/水分配系数(LogP)：
  0.47
• 重原子数：
  27
• 可旋转键数：
  13
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.45
• 拓扑面积：
  50.4
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  D-3-苯乳酸 在 四丁基碘化铵 、 苄基三甲基氢氧化铵 、 sodium iodide 作用下， 以 丙酮 为溶剂， 反应 120.0h， 生成 1-(8-{[(2R)-2-Hydroxy-3-phenylpropanoyl]oxy}octyl)pyridin-1-ium iodide
  参考文献：
  名称：

  Amphiphilic pyridinium salts block TNFα/NFκB signaling and constitutive hypersecretion of interleukin-8 (IL-8) from cystic fibrosis lung epithelial cells

  摘要：

  Cystic fibrosis (CF) is a common, lethal genetic disease, which is due to mutations in the CFTR gene. The CF lung expresses a profoundly proinflammatory phenotype, due to constitutive hypersecretion of IL-8 from epithelial cells lining the airways. In a systematic search for candidate drugs that might be used therapeutically to suppress IL-8 secretion from these cells, we have identified a potent and efficacious series of amphiphilic pyridinium salts. The most potent of these salts is MRS2481, an (R)-1-phenylpropionic acid ester, with an IC50 of ca. 1 mu M. We have synthesized 21 analogues of MRS2481, which have proven sufficient to develop a preliminary structure-activity relationship (SAR). For optimal activity, we have found that the ester must be connected to the pyridinium derivative by an eight-carbon chain. An optical isomer of the lead compound, containing an (S)-1-phenylpropionic acid ester, has been found to be a much less active. The mechanism of action of MRS2481 appears to involve inhibition of signaling of the NF kappa B and AP- I transcription factors to the IL-8 promoter. MRS2481 is a potent inhibitor of TNF alpha-induced phosphorylation and proteosomal destruction Of I kappa B alpha. Inasmuch as I kappa B alpha is the principal inhibitor of the NF kappa B signaling pathway, preservation of intact I kappa B alpha would serve to keep the IL-8 promoter silent. We also find that MRS2481 blocks TNF alpha-activated phosphorylation of JNK, the c-JUN kinase. The IL-8 promoter is also activated by an AP- I site, which requires a phospho-c-JUN/c-FOS dimer for activity. We therefore interpret these data to suggest that the mechanism of MRS2481 action is to inhibit both NF kappa B and AP-1 signaling on the IL-8 promoter. Given the medicinally promising properties of water-solubility, potency in the low mu M concentration range, and high efficacy, we anticipate that MRS2481, or a further optimized derivative, may find an important place in the armamentarium of pharmaceutical strategies yet to be arrayed against the inflammatory phenotype of the CF lung. Published by Elsevier Inc.

  DOI：

  10.1016/j.bcp.2005.05.002

文献信息

• Amphiphilic pyridinium salts block TNFα/NFκB signaling and constitutive hypersecretion of interleukin-8 (IL-8) from cystic fibrosis lung epithelial cells
  作者：Susanna Tchilibon、Jian Zhang、QingFeng Yang、Ofer Eidelman、Haksung Kim、Hung Caohuy、Kenneth A. Jacobson、Bette S. Pollard、Harvey B. Pollard

  DOI：10.1016/j.bcp.2005.05.002

  日期：2005.8

  Cystic fibrosis (CF) is a common, lethal genetic disease, which is due to mutations in the CFTR gene. The CF lung expresses a profoundly proinflammatory phenotype, due to constitutive hypersecretion of IL-8 from epithelial cells lining the airways. In a systematic search for candidate drugs that might be used therapeutically to suppress IL-8 secretion from these cells, we have identified a potent and efficacious series of amphiphilic pyridinium salts. The most potent of these salts is MRS2481, an (R)-1-phenylpropionic acid ester, with an IC50 of ca. 1 mu M. We have synthesized 21 analogues of MRS2481, which have proven sufficient to develop a preliminary structure-activity relationship (SAR). For optimal activity, we have found that the ester must be connected to the pyridinium derivative by an eight-carbon chain. An optical isomer of the lead compound, containing an (S)-1-phenylpropionic acid ester, has been found to be a much less active. The mechanism of action of MRS2481 appears to involve inhibition of signaling of the NF kappa B and AP- I transcription factors to the IL-8 promoter. MRS2481 is a potent inhibitor of TNF alpha-induced phosphorylation and proteosomal destruction Of I kappa B alpha. Inasmuch as I kappa B alpha is the principal inhibitor of the NF kappa B signaling pathway, preservation of intact I kappa B alpha would serve to keep the IL-8 promoter silent. We also find that MRS2481 blocks TNF alpha-activated phosphorylation of JNK, the c-JUN kinase. The IL-8 promoter is also activated by an AP- I site, which requires a phospho-c-JUN/c-FOS dimer for activity. We therefore interpret these data to suggest that the mechanism of MRS2481 action is to inhibit both NF kappa B and AP-1 signaling on the IL-8 promoter. Given the medicinally promising properties of water-solubility, potency in the low mu M concentration range, and high efficacy, we anticipate that MRS2481, or a further optimized derivative, may find an important place in the armamentarium of pharmaceutical strategies yet to be arrayed against the inflammatory phenotype of the CF lung. Published by Elsevier Inc.