3-carbamoyl-2-phenylpropionaldehyde | 183961-07-1

• 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-carbamoyl-2-phenylpropionaldehyde
• 英文别名: 3-oxo-2-phenylpropyl aminooate；(3-oxo-2-phenylpropyl) carbamate
• CAS: 183961-07-1
• 化学式: C₁₀H₁₁NO₃
• 分子量: 193.202
• InChiKey: XUCMSYZLYLONTH-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.7
• 重原子数：
  14
• 可旋转键数：
  5
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.2
• 拓扑面积：
  69.4
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  3-carbamoyl-2-phenylpropionaldehyde 在 potassium phosphate buffer 作用下， 以 丙酮 为溶剂， 反应 0.25h， 生成 4-hydroxy-5-phenyltetrahydro-1,3-oxazin-2-one
  参考文献：
  名称：

  The Chemistry, Toxicology, and Identification in Rat and Human Urine of 4-Hydroxy-5-phenyl-1,3-oxazaperhydroin-2-one:  A Reactive Metabolite in Felbamate Bioactivation

  摘要：

  4-Hydroxy-5-phenyl-1,3-oxazaperhydroin-2-one has been proposed to be a reactive metabolite of the anti-epileptic drug felbamate [Thompson et al. (1996) Chem. Res. Toxicol. 9, 1225-1229]. 4-Hydroxy-5-phenyl-1,3-oxazaperhydroin-2-one exists in equilibrium with 3-oxo-2-phenylpropyl aminooate, which is known to eliminate to generate 2-phenylpropenal. Thus, this species is postulated to be a latent form of the ultimate reactive metabolite, 2-phenylpropenal. The chemistry of 4-hydroxy-5-phenyl-1,3-oxazaperhydroin-2-one is proposed to parallel that of 4-hydroxycyclophosphamide, the bioactivated form of cyclophosphamide that undergoes ring-opening to aldophosphamide and subsequent elimination to afford 2-propenal (acrolein). The work presented here reports the chemical synthesis of 4-hydroxy-5-phenyl-1,3-oxazaperhydroin-2-one and demonstrates that under buffered conditions it exists in equilibrium with 3-oxo-2-phenylpropyl aminooate. The rate-limiting step in the decomposition of 4-hydroxy-5-phenyl-1,3-oxazaperhydroin-2-one is the irreversible fl-elimination from 3-oxo-2-phenylpropyl aminooate to 2-phenylpropenal. We have found the half-life of 4-hydroxy-5-phenyl-1,3-oxazaperhydroin-2-one to be 4.6 +/- 0.4 h under in vitro conditions that mimic the physiological setting. As a consequence of the relatively long half-life of 4-hydroxy-5-phenyl-1,3-oxazaperhydroin-2-one, we have sought evidence for the significance of this pathway in experimental and clinical conditions. We report here the observation of this metabolite in the urine of rats being treated with 3-hydroxy-2-phenylpropyl aminooate, the esterase-mediated metabolite of felbamate, and in the urine of patients undergoing felbamate therapy. In addition, we have shown that 4-hydroxy-5-phenyl-1,3-oxazaperhydroin-2-one is toxic to cultured cells in a time-dependent manner, most likely as a result of its decomposition to 2-phenylpropenal. Taken together, the data support the hypothesis that 4-hydroxy-5-phenyl-1,3-oxazaperhydroin-2-one represents a "time-release" form of 2-phenylpropenal capable of traveling to distal sites from its locus of bioactivation and thereby mediates felbamate associated toxicities.

  DOI：

  10.1021/tx000139n
• 作为产物：
  描述：

  3,3-Diaethoxy-2-phenyl-propanol-(1) 在 Amberlyst 15 、 氨 作用下， 以 四氢呋喃 、 丙酮 为溶剂， 反应 4.0h， 生成 3-carbamoyl-2-phenylpropionaldehyde
  参考文献：
  名称：

  Synthesis and in Vitro Reactivity of 3-Carbamoyl-2-phenylpropionaldehyde and 2-Phenylpropenal:  Putative Reactive Metabolites of Felbamate

  摘要：

  We propose that 3-carbamoyl-2-phenylpropionaldehyde is an intermediate in the metabolism of felbamate, an anti-epileptic drug with a unique profile of therapeutic activity, and undergoes a cascade of chemical reactions responsible for the toxic properties of the parent drug. To test this hypothesis, we have synthesized 3-carbamoyl-2-phenylpropionaldehyde and evaluated its in vitro reactivity. This molecule was found to be highly unstable at physiological pH (t(1/2) less than or equal to 30 s) and to undergo facile elimination to 2-phenylpropenal, an a,P-unsaturated aldehyde commonly termed atropaldehyde. However, the predominant reaction pathway for 3-carbamoyl-2-phenylpropionaldehyde was reversible cyclization to generate 4-hydroxy-5-phenyltetrahydro-1,3-oxazin-2-one, a urethane that has a considerably longer half-life at physiological pH (t(1/2) greater than or equal to 5 h) and may serve as a stable reservoir of the reactive aldehyde both in, vitro and in vivo. Atropaldehyde is a potent electrophile and was found to exhibit cytotoxicity to cultured fibroblasts (50% growth inhibition (GI(50)) = 4.1 +/- 1.1 mu M) comparable to the known unsaturated aldehyde toxins, 4-hydroxy-2-nonenal and acrolein. 3-Carbamoyl-2-phenylpropionaldehyde also exhibited significant cytotoxicity (GI(50) = 53 +/- 8 mu M), whereas 2-phenyl-1,3-propanediol monocarbamate (GI(50) > 500 mu M) and 3-carbamoyl-2-phenylpropionic acid (GI(50) > 500 mu M) were nontoxic. We have additionally demonstrated the formation of a glutathione-atropaldehyde conjugate from the in vitro incubation of 3-carbamoyl-2-phenylpropionaldehyde with glutathione. Thus, the potent cytotoxicity and potential allergenicity of atropaldehyde implicate this unsaturated aldehyde as a possible causative agent in the toxicities observed with felbamate treatment.

  DOI：

  10.1021/tx9601566

文献信息

• Synthesis and <i>in Vitro</i> Reactivity of 3-Carbamoyl-2-phenylpropionaldehyde and 2-Phenylpropenal:  Putative Reactive Metabolites of Felbamate
  作者：Charles D. Thompson、Michael T. Kinter、Timothy L. Macdonald

  DOI：10.1021/tx9601566

  日期：1996.1.1

  We propose that 3-carbamoyl-2-phenylpropionaldehyde is an intermediate in the metabolism of felbamate, an anti-epileptic drug with a unique profile of therapeutic activity, and undergoes a cascade of chemical reactions responsible for the toxic properties of the parent drug. To test this hypothesis, we have synthesized 3-carbamoyl-2-phenylpropionaldehyde and evaluated its in vitro reactivity. This molecule was found to be highly unstable at physiological pH (t(1/2) less than or equal to 30 s) and to undergo facile elimination to 2-phenylpropenal, an a,P-unsaturated aldehyde commonly termed atropaldehyde. However, the predominant reaction pathway for 3-carbamoyl-2-phenylpropionaldehyde was reversible cyclization to generate 4-hydroxy-5-phenyltetrahydro-1,3-oxazin-2-one, a urethane that has a considerably longer half-life at physiological pH (t(1/2) greater than or equal to 5 h) and may serve as a stable reservoir of the reactive aldehyde both in, vitro and in vivo. Atropaldehyde is a potent electrophile and was found to exhibit cytotoxicity to cultured fibroblasts (50% growth inhibition (GI(50)) = 4.1 +/- 1.1 mu M) comparable to the known unsaturated aldehyde toxins, 4-hydroxy-2-nonenal and acrolein. 3-Carbamoyl-2-phenylpropionaldehyde also exhibited significant cytotoxicity (GI(50) = 53 +/- 8 mu M), whereas 2-phenyl-1,3-propanediol monocarbamate (GI(50) > 500 mu M) and 3-carbamoyl-2-phenylpropionic acid (GI(50) > 500 mu M) were nontoxic. We have additionally demonstrated the formation of a glutathione-atropaldehyde conjugate from the in vitro incubation of 3-carbamoyl-2-phenylpropionaldehyde with glutathione. Thus, the potent cytotoxicity and potential allergenicity of atropaldehyde implicate this unsaturated aldehyde as a possible causative agent in the toxicities observed with felbamate treatment.
• The Chemistry, Toxicology, and Identification in Rat and Human Urine of 4-Hydroxy-5-phenyl-1,3-oxazaperhydroin-2-one:  A Reactive Metabolite in Felbamate Bioactivation
  作者：Christine M. Dieckhaus、Webster L. Santos、R. Duane Sofia、Timothy L. Macdonald

  DOI：10.1021/tx000139n

  日期：2001.8.1

  4-Hydroxy-5-phenyl-1,3-oxazaperhydroin-2-one has been proposed to be a reactive metabolite of the anti-epileptic drug felbamate [Thompson et al. (1996) Chem. Res. Toxicol. 9, 1225-1229]. 4-Hydroxy-5-phenyl-1,3-oxazaperhydroin-2-one exists in equilibrium with 3-oxo-2-phenylpropyl aminooate, which is known to eliminate to generate 2-phenylpropenal. Thus, this species is postulated to be a latent form of the ultimate reactive metabolite, 2-phenylpropenal. The chemistry of 4-hydroxy-5-phenyl-1,3-oxazaperhydroin-2-one is proposed to parallel that of 4-hydroxycyclophosphamide, the bioactivated form of cyclophosphamide that undergoes ring-opening to aldophosphamide and subsequent elimination to afford 2-propenal (acrolein). The work presented here reports the chemical synthesis of 4-hydroxy-5-phenyl-1,3-oxazaperhydroin-2-one and demonstrates that under buffered conditions it exists in equilibrium with 3-oxo-2-phenylpropyl aminooate. The rate-limiting step in the decomposition of 4-hydroxy-5-phenyl-1,3-oxazaperhydroin-2-one is the irreversible fl-elimination from 3-oxo-2-phenylpropyl aminooate to 2-phenylpropenal. We have found the half-life of 4-hydroxy-5-phenyl-1,3-oxazaperhydroin-2-one to be 4.6 +/- 0.4 h under in vitro conditions that mimic the physiological setting. As a consequence of the relatively long half-life of 4-hydroxy-5-phenyl-1,3-oxazaperhydroin-2-one, we have sought evidence for the significance of this pathway in experimental and clinical conditions. We report here the observation of this metabolite in the urine of rats being treated with 3-hydroxy-2-phenylpropyl aminooate, the esterase-mediated metabolite of felbamate, and in the urine of patients undergoing felbamate therapy. In addition, we have shown that 4-hydroxy-5-phenyl-1,3-oxazaperhydroin-2-one is toxic to cultured cells in a time-dependent manner, most likely as a result of its decomposition to 2-phenylpropenal. Taken together, the data support the hypothesis that 4-hydroxy-5-phenyl-1,3-oxazaperhydroin-2-one represents a "time-release" form of 2-phenylpropenal capable of traveling to distal sites from its locus of bioactivation and thereby mediates felbamate associated toxicities.