4-((diethoxyphosphoryl)oxy)butyl 2-(4-(1-hydroxy-2-methylpropyl)phenyl)propanoate | 1346752-12-2

• 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: 4-((diethoxyphosphoryl)oxy)butyl 2-(4-(1-hydroxy-2-methylpropyl)phenyl)propanoate
• CAS: 1346752-12-2
• 化学式: C₂₁H₃₅O₇P
• 分子量: 430.478
• InChiKey: FBCVCGITMMTQOE-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.0
• 重原子数：
  29.0
• 可旋转键数：
  14.0
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.67
• 拓扑面积：
  91.29
• 氢给体数：
  1.0
• 氢受体数：
  7.0

反应信息

• 作为反应物：
  描述：

  4-((diethoxyphosphoryl)oxy)butyl 2-(4-(1-hydroxy-2-methylpropyl)phenyl)propanoate 在 porcine liver esterase 作用下， 反应 0.5h， 生成 1-羟基异丁基苯基-1’-甲基丙酸
  参考文献：
  名称：

  Phospho-Ibuprofen (MDC-917) Is a Novel Agent against Colon Cancer: Efficacy, Metabolism, and Pharmacokinetics in Mouse Models

  摘要：

  我们开发了一种对传统非甾体抗炎药进行新型化学修饰，以降低其毒性并增强其疗效。磷酸布洛芬 [(PI) 2-(4-异丁基-苯基)-丙酸-4-(二乙氧基-磷酰氧基)-丁基酯 (MDC-917)] 是布洛芬的一种新型衍生物，可强烈抑制人结肠的生长体外癌细胞和裸鼠 SW480 人结肠癌异种移植物。 PI 被培养的细胞最低程度地代谢，但被肝微粒体和小鼠广泛代谢，经历区域选择性氧化产生 1-OH-PI 和羧基-PI，它们可以分别水解为 1-OH-布洛芬和羧基-布洛芬。 PI还可水解释放布洛芬，布洛芬可生成2-OH-布洛芬、羧基布洛芬和布洛芬葡萄糖醛酸苷。单次口服（400mg/kg）PI后，布洛芬和布洛芬葡萄糖醛酸苷是PI的主要血浆代谢物；它们的 C max 分别为 530 和 215 μM，T max 分别为 1 和 2 小时，消除 t 1/2 分别为 7.7 和 5.3 小时，浓度-时间曲线下面积（0-24 小时）分别为 1816 和 832微米×小时。在多种组织中检测到完整的 PI，但在血浆中未检测到；在较高的 PI 剂量（1200 mg/kg）下，PI 血浆水平为 12.4 μM。 PI 在小鼠血浆中产生与传统布洛芬相同的代谢物，但含量低得多，这可能是 PI 安全性增强的原因。 PI 的抗肿瘤作用与血浆布洛芬水平显着相关 (p = 0.016)，但与异种移植物布洛芬水平无关 (p = 0.08)，表明其具有复杂的抗癌作用。这些结果提供了药理学基础，至少部分地解释了这种有前途的化合物的抗癌功效和安全性，并表明 PI 作为抗癌剂值得进一步评估。

  DOI：

  10.1124/jpet.111.180224
• 作为产物：
  描述：

  磷酸布洛芬132 在 cytochrome P₄₅₀ 1A₂ 、 还原型辅酶II(NADPH)四钠盐 作用下， 反应 20.0h， 生成 4-((diethoxyphosphoryl)oxy)butyl 2-(4-(1-hydroxy-2-methylpropyl)phenyl)propanoate
  参考文献：
  名称：

  Regioselective oxidation of phospho-NSAIDs by human cytochrome P450 and flavin monooxygenase isoforms: implications for their pharmacokinetic properties and safety

  摘要：

  BACKGROUND AND PURPOSEPhospho‐ibuprofen (MDC‐917) and phospho‐sulindac (OXT‐328) are highly effective in cancer and arthritis treatment in preclinical models. Here, we investigated their metabolism by major human cytochrome P450s (CYPs) and flavin monooxygenases (FMOs).EXPERIMENTAL APPROACHThe CYP/FMO‐catalysed metabolism of phospho‐ibuprofen and phospho‐sulindac was studied by using in silico prediction modelling and a direct experimental approach.KEY RESULTSThe CYP isoforms catalyse the oxidation of non‐steroidal anti‐inflammatory drugs (NSAIDs) and phospho‐NSAIDs, with distinct activity and regioselectivity. CYP1A2, 2C19, 2D6 and 3A4 oxidize phospho‐ibuprofen, but not ibuprofen; whereas CYP2C9 oxidizes ibuprofen, but not phospho‐ibuprofen. All CYPs tested oxidize phospho‐sulindac, but not sulindac. Among the five CYPs evaluated, CYP3A4 and 2D6 are the most active in the oxidation of phospho‐ibuprofen and phospho‐sulindac respectively. FMOs oxidized phospho‐sulindac and sulindac, but not phospho‐ibuprofen or ibuprofen. FMOs were more active towards phospho‐sulindac than sulindac, indicating that phospho‐sulindac is a preferred substrate of FMOs. The susceptibility of phospho‐NSAIDs to CYP/FMO‐mediated metabolism was also reflected in their rapid oxidation by human and mouse liver microsomes, which contain a full complement of CYPs and FMOs. Compared with conventional NSAIDs, the higher activity of CYPs towards phospho‐ibuprofen and phospho‐sulindac may be due to their greater lipophilicity, a key parameter for CYP binding.CONCLUSIONS AND IMPLICATIONSCYPs and FMOs play an important role in the metabolism of phospho‐NSAIDs, resulting in differential pharmacokinetic profiles between phospho‐NSAIDs and NSAIDs in vivo. The consequently more rapid detoxification of phospho‐NSAIDs is likely to contribute to their greater safety.

  DOI：

  10.1111/j.1476-5381.2012.01982.x