N-acetyl-S-(2-phenylpropan-3-ol)-L-cysteine | 188907-25-7

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: N-acetyl-S-(2-phenylpropan-3-ol)-L-cysteine
• CAS: 188907-25-7
• 化学式: C₁₄H₁₉NO₄S
• 分子量: 297.375
• InChiKey: WHUDPBNTVTZBGH-ABLWVSNPSA-N

物化性质

• 沸点：
  569.9±50.0 °C(Predicted)
• 密度：
  1.268±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.08
• 重原子数：
  20.0
• 可旋转键数：
  8.0
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  86.63
• 氢给体数：
  3.0
• 氢受体数：
  4.0

反应信息

• 作为反应物：
  描述：

  谷胱甘肽 、 N-acetyl-S-(2-phenylpropan-3-ol)-L-cysteine 以100%的产率得到S-(2-phenylpropan-3-ol)-γ-glutathione
  参考文献：
  名称：

  Role of Glutathione S-Transferases A1-1, M1-1, and P1-1 in the Detoxification of 2-Phenylpropenal, a Reactive Felbamate Metabolite

  摘要：

  Felbamate has proven to be an effective therapy for treating refractory epilepsy. However, felbamate therapy has been limited due to the associated reports of hepatotoxicity and aplastic anemia. Previous research from our laboratory has proposed 2-phenylpropenal as the reactive metabolite in felbamate bioactivation and identified its mercapturates in the urine of rats and patients undergoing felbamate therapy. While the reaction between 2-phenylpropenal and GSH has been shown to occur spontaneously under physiological conditions, the potential catalysis by glutathione transferases (GST) has remained unknown. The work presented here demonstrates a role for GST in the detoxification of 2-phenylpropenal. The kinetic data show that 2-phenylpropenal is a substrate for all three isoforms tested, with a k(cat)/K-m of 0.275 + 0.035 muM(-1) s(-1) for GSTM1-1, 0.164 +/- 0.005 muM(-1) s(-1) for GSTP1-1, and 0.042 +/- 0.005 muM(-1) s(-1) for GSTA1-1. Given that electrophilic substrates such as 2-propenal have been shown to inhibit GSTs, we also examined the inhibition of GSTM1-1, GSTP1-1 and GSTA1-1 by 2-phenylpropenal. The enzyme inhibition studies demonstrate that 2-phenylpropenal inhibits GSTP1-1 and GSTM1-1. The inhibition of GSTP1-1 was completely reversible upon filtration and reconstitution in buffer containing 10 mM GSH. However, 2-phenylpropenal inhibition of GSTM1-1 was irreversible under the same conditions. The irreversible inhibition of GSTM1-1 may be important in understanding the toxicities associated with felbamate. Given that 2-phenylpropenal is both a substrate and irreversible inhibitor for GSTM1-1, GSTM1-1 represents a potential target for 2-phenylpropenal haptenization in vivo, which may in turn mediate the observed idiosyncratic reactions.

  DOI：

  10.1021/tx000141e
• 作为产物：
  描述：

  N-乙酰-L-半胱氨酸 在 potassium phosphate buffer sodium tetrahydroborate 作用下， 以 甲醇 为溶剂， 反应 2.0h， 生成 N-acetyl-S-(2-phenylpropan-3-ol)-L-cysteine
  参考文献：
  名称：

  Identification of Modified Atropaldehyde Mercapturic Acids in Rat and Human Urine after Felbamate Administration

  摘要：

  3-Carbamoyl-2-phenylpropionaldehyde has recently been proposed [Thompson et al. (1996) Chem. Res. Toxicol. 9, 1225-1229] as a potential reactive metabolite of the anti-epileptic drug felbamate. This aldehyde was found to undergo rapid elimination to generate 2-phenylpropenal and reversible cyclization to generate 4-hydroxy-5-phenyltetrahydro-1,3-oxazin-2-one at physiological pH. 2-Phenylpropenal, an alpha,beta-unsaturated aldehyde commonly termed atropaldehyde, is a potent electrophile and undergoes rapid conjugation with glutathione. We sought to demonstrate the formation of atropaldehyde in vivo through the identification of mercapturic acids in rat and human urine after felbamate administration. In this paper, we describe the identification of both the reduced (N-acetyl-S-(2-phenylpropan-3-ol)-L-cysteine) and oxidized (N-acetyl-S-(2-phenyl-3-propanoic acid)-L-cysteine) mercapturic acids of atropaldehyde in rat and human urine. The reduced species was the more abundant in human (similar to 2:1) and rat (similar to 6: 1) urine. These findings establish the possibility that atropaldehyde is formed from felbamate in vivo, undergoes glutathione conjugation, and is ultimately excreted in urine in the form of mercapturic acids. Thus, the proposed pathway of felbamate biotransformation, if confirmed in patients, could contribute to our understanding of the toxicities observed during felbamate treatment.

  DOI：

  10.1021/tx960205e