2-氟-2-丙基戊-4-烯酸乙酯 | 164228-15-3

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 脂肪酰基
• 中文名称: 2-氟-2-丙基戊-4-烯酸乙酯
• 英文名称: ethyl 2-propyl-2-fluoro-4-pentenoate
• 英文别名: ethyl 2-fluoro-2-propyl-4-pentenoate；Ethyl 2-fluoro-2-propylpent-4-enoate；ethyl 2-fluoro-2-propylpent-4-enoate
• CAS: 164228-15-3
• 化学式: C₁₀H₁₇FO₂
• 分子量: 188.242
• InChiKey: MARJODMAYFXORX-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  13
• 可旋转键数：
  7
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.7
• 拓扑面积：
  26.3
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  2-氟-2-丙基戊-4-烯酸乙酯 在 二甲基二环氧乙烷 作用下， 以 水 、 丙酮 为溶剂， 反应 18.0h， 生成 ethyl 2-propyl-2-fluoro-4,5-epoxy-pentanoate
  参考文献：
  名称：

  通过葡糖醛酸糖化作用对丙戊酸（E）-2-丙基-2,4-戊二烯酸的有毒代谢产物进行生物活化。GSH-葡糖醛酸二轭合物的LC / MS / MS表征。

  摘要：

  抗惊厥药丙戊酸的肝毒性可能与潜在反应性代谢物的形成有关，其中之一是（E）-2-丙基-2,4-戊二烯酸（（E）-2,4-二烯VPA）。该报告描述了该二烯新的GSH相关缀合物的表征。通过LC / MS / MS分析从腹膜内注射（E）-2,4-二烯VPA（100 mg / kg）的雄性Sprague-Dawley大鼠收集的胆汁样品。扫描中最初的Q1母体表明，子离子m / z 162和123可以分别来自m / z 624和480的离子。随后这些母离子的碰撞诱导解离（CID）显示了176 Da的常见中性损失，可诊断为葡糖醛酸苷。在大鼠腹腔内注射[2H7] -4-ene VPA产生的胆汁代谢产物的子离子光谱中观察到类似的176 Da中性损失，其中包含VPA部分的离子片段比未标记药物衍生的离子片段高7 amu。离子在m / z 624的CID也给出了GSH共轭物的片段特征，例如甘氨酸和谷氨酸部分的丢失。

  DOI：

  10.1021/tx950120y
• 作为产物：
  描述：

  乙基2-丙基-4-戊烯酸酯 在 lithium diisopropyl amide 、 N-氟苯磺酰胺 作用下， 以 四氢呋喃 、 六甲基磷酰三胺 、 正己烷 为溶剂， 反应 1.0h， 以86%的产率得到2-氟-2-丙基戊-4-烯酸乙酯
  参考文献：
  名称：

  Fluorinated Analogs as Mechanistic Probes in Valproic Acid Hepatotoxicity: Hepatic Microvesicular Steatosis and Glutathione Status

  摘要：

  It is postulated that the hepatotoxicity of valproic acid (VPA) results from the mitochondrial beta-oxidation of its cytochrome P450 metabolite, 2-propyl-4-pentenoic acid (4-ene VPA), to 2-propyl-(E)-2,4-pentadienoic acid ((E)-2,4-diene VPA) which, in the CoA thioester form, either depletes GSH or produces a putative inhibitor of beta-oxidation enzymes. In order to test this hypothesis, 2-fluoro-2-propyl-4-pentenoic acid (alpha-fluoro-4-ene VPA) which was expected to be inert to beta-oxidative metabolism was synthesized and its effect on rat liver studied in comparison with that of 4-ene VPA. Similarly, the known hepatotoxicant 4-pentenoic acid (4-PA) and 2,2-difluoro-4-pentenoic acid (F-2-4-PA) were compared. Male Sprague-Dawley rats (150-180 g, 4 rats per group) were dosed ip with 4-ene VPA (0.7 mmol/kg per day), 4-PA (1.0 mmol/kg per day), or equivalent amounts of their alpha-fluorinated analogues for 5 days. Both 4-ene VPA and 4-PA induced severe hepatic microvesicular steatosis (> 85% affected hepatocytes), and 4-ene VPA produced mitochondrial alterations. By contrast, alpha-fluoro-4-ene VPA and F-2-4-PA were not observed to cause morphological changes in the liver. The major metabolite of 4-ene VPA in the rat urine and serum was the beta-oxidation product (E)-2,4-diene VPA. The N-acetylcysteine (NAC) conjugate of (E)-2,4-diene VPA was also found in the urine. Neither (E)-2,4-diene VPA nor the NAC conjugate could be detected in the rats administered alpha-fluoro-4-ene VPA. In a second set of rats (3 rats per group), total liver GSH levels were determined to be depleted to 56% and 72% of control following doses of 4-ene VPA (1.4 mmol/kg); and equivalent alpha-fluoro-4-ene VPA, respectively. Mitochondrial GSH remained unchanged in the (alpha-fluoro-4-ene VPA treated group but was reduced to 68% of control in the rats administered 4-ene VPA. These results strongly support the theory that hepatotoxicity of 4-ene VPA, and possibly VPA itself, is mediated largely through beta-oxidation of 4-ene VPA to reactive intermediates that are capable of depleting mitochondrial GSH.

  DOI：

  10.1021/tx00047a006

文献信息

• Bioactivation of a Toxic Metabolite of Valproic Acid, (<i>E</i>)-2-Propyl-2,4-pentadienoic Acid, via Glucuronidation. LC/MS/MS Characterization of the GSH−Glucuronide Diconjugates
  作者：Wei Tang、Frank S. Abbott

  DOI：10.1021/tx950120y

  日期：1996.1.1

  of GST enzyme led to the formation of 5-GS-3-ene VPA-glucuronide I which was readily detected by LC/MS/MS, suggesting that in vivo the diconjugate may arise from the reaction of GSH with 2,4-diene VPA-glucuronide. To our knowledge, this is the first recorded instance in which glucuronide formation activates a drug to further conjugate with GSH via a Michael addition reaction.

  抗惊厥药丙戊酸的肝毒性可能与潜在反应性代谢物的形成有关，其中之一是（E）-2-丙基-2,4-戊二烯酸（（E）-2,4-二烯VPA）。该报告描述了该二烯新的GSH相关缀合物的表征。通过LC / MS / MS分析从腹膜内注射（E）-2,4-二烯VPA（100 mg / kg）的雄性Sprague-Dawley大鼠收集的胆汁样品。扫描中最初的Q1母体表明，子离子m / z 162和123可以分别来自m / z 624和480的离子。随后这些母离子的碰撞诱导解离（CID）显示了176 Da的常见中性损失，可诊断为葡糖醛酸苷。在大鼠腹腔内注射[2H7] -4-ene VPA产生的胆汁代谢产物的子离子光谱中观察到类似的176 Da中性损失，其中包含VPA部分的离子片段比未标记药物衍生的离子片段高7 amu。离子在m / z 624的CID也给出了GSH共轭物的片段特征，例如甘氨酸和谷氨酸部分的丢失。
• Fluorinated Analogs as Mechanistic Probes in Valproic Acid Hepatotoxicity: Hepatic Microvesicular Steatosis and Glutathione Status
  作者：Wei Tang、Anthony G. Borel、Tatsuya Fujimiya、Frank S. Abbott

  DOI：10.1021/tx00047a006

  日期：1995.7

  It is postulated that the hepatotoxicity of valproic acid (VPA) results from the mitochondrial beta-oxidation of its cytochrome P450 metabolite, 2-propyl-4-pentenoic acid (4-ene VPA), to 2-propyl-(E)-2,4-pentadienoic acid ((E)-2,4-diene VPA) which, in the CoA thioester form, either depletes GSH or produces a putative inhibitor of beta-oxidation enzymes. In order to test this hypothesis, 2-fluoro-2-propyl-4-pentenoic acid (alpha-fluoro-4-ene VPA) which was expected to be inert to beta-oxidative metabolism was synthesized and its effect on rat liver studied in comparison with that of 4-ene VPA. Similarly, the known hepatotoxicant 4-pentenoic acid (4-PA) and 2,2-difluoro-4-pentenoic acid (F-2-4-PA) were compared. Male Sprague-Dawley rats (150-180 g, 4 rats per group) were dosed ip with 4-ene VPA (0.7 mmol/kg per day), 4-PA (1.0 mmol/kg per day), or equivalent amounts of their alpha-fluorinated analogues for 5 days. Both 4-ene VPA and 4-PA induced severe hepatic microvesicular steatosis (> 85% affected hepatocytes), and 4-ene VPA produced mitochondrial alterations. By contrast, alpha-fluoro-4-ene VPA and F-2-4-PA were not observed to cause morphological changes in the liver. The major metabolite of 4-ene VPA in the rat urine and serum was the beta-oxidation product (E)-2,4-diene VPA. The N-acetylcysteine (NAC) conjugate of (E)-2,4-diene VPA was also found in the urine. Neither (E)-2,4-diene VPA nor the NAC conjugate could be detected in the rats administered alpha-fluoro-4-ene VPA. In a second set of rats (3 rats per group), total liver GSH levels were determined to be depleted to 56% and 72% of control following doses of 4-ene VPA (1.4 mmol/kg); and equivalent alpha-fluoro-4-ene VPA, respectively. Mitochondrial GSH remained unchanged in the (alpha-fluoro-4-ene VPA treated group but was reduced to 68% of control in the rats administered 4-ene VPA. These results strongly support the theory that hepatotoxicity of 4-ene VPA, and possibly VPA itself, is mediated largely through beta-oxidation of 4-ene VPA to reactive intermediates that are capable of depleting mitochondrial GSH.
• Characterization of Thiol-conjugated Metabolites of 2-Propylpent-4-enoic Acid (4-eneVPA), a Toxic Metabolite of Valproic Acid, by Electrospray Tandem Mass Spectrometry
  作者：Wei Tang、Frank S. Abbott

  DOI：10.1002/(sici)1096-9888(199608)31:8<926::aid-jms383>3.0.co;2-p

  日期：1996.8

  The hepatotoxicity of the anticonvulsant drug valproic acid (VPA) is most likely associated with the bioactivation of its metabolite 2-propylpent-4-enoic acid (4-ene VPA), which is known to induce hepatic microvesicular steatosis in rats. This paper presents an on-line liquid chromatographic/tandem mass spectrometric (LC/MS/MS) identification of new glutathione (GSH)-related conjugates of the reactive metabolites of 4-ene VPA. Bile samples collected from male Sprague-Dawley rats dosed intraperitoneally with 4-ene VPA or its [2H7]-analogue (100 mg kg-1) were injected on to an ODS column interfaced to a LC/MS/MS instrument using electrospray ionization. LC was developed such that no overlapping of peaks occurred among those metabolites which may potentially produce common fragment ions of interest. Subsequent comparison of LC retention times and MS/MS full fragment ion spectra generated for putative metabolites with that of authentic reference compounds made available by chemical synthesis confirmed the presence of the GSH, cysteinylglycine, cysteine and N-acetylcysteine (NAC) conjugates of 2-(2'-carboxypentanyl)oxirane (4,5-epoxy VPA) and (E)-2-propylpenta-2,4-dienoic acid ((E)-2,4-diene VPA), respectively. Quantitatively, the biliary thiol conjugates accounted for 5% of the dose. This observation is novel for 4-ene VPA metabolism in terms of the degradation of GSH conjugates to the corresponding mercapturic acids possibly occurring within the liver as opposed to an inter-organ process which involves the kidney. In addition, the GSH- and NAC-glucuronide di-conjugates of (E)-2,4-diene VPA were also identified as the biliary metabolites with the GSH-glucuronide di-conjugate being 10% of the corresponding mono-GSH conjugate. Taken together, these data clearly indicate that reactive metabolites of VPA can react with hepatic GSH via several different metabolic pathways and may subsequently produce depletion of GSH that leads to toxic consequences.