(2R)-2-乙酰氨基-3-[2-(4-氯苯氧基)-2-甲基-丙酰]巯基丙酸 | 84489-15-6

• 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
• 中文名称: (2R)-2-乙酰氨基-3-[2-(4-氯苯氧基)-2-甲基-丙酰]巯基丙酸
• 中文别名: 2H-吡喃,6-[(1E)-1-乙氧基-1,3-丁二烯-1-基]-3,4-二氢-4,4-二甲基-
• 英文名称: clofibryl-S-acyl-N-acetylcysteine
• 英文别名: Clofibrate mercapturate；(2R)-2-acetamido-3-[2-(4-chlorophenoxy)-2-methylpropanoyl]sulfanylpropanoic acid
• CAS: 84489-15-6
• 化学式: C₁₅H₁₈ClNO₅S
• 分子量: 359.831
• InChiKey: CIZGEASWPCDLRX-LBPRGKRZSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  23
• 可旋转键数：
  8
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  118
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  N-乙酰-L-半胱氨酸 、 clofibryl-S-acyl-glutathione 在 buffer 作用下， 以75%的产率得到(2R)-2-乙酰氨基-3-[2-(4-氯苯氧基)-2-甲基-丙酰]巯基丙酸
  参考文献：
  名称：

  Interaction of γ-Glutamyltranspeptidase with Clofibryl-S-acyl-glutathione in Vitro and in Vivo in Rat

  摘要：

  Clofibric acid (CA) is metabolized to chemically reactive acylating products that can transacylate glutathione to form clofibryl-S-acyl-glutathione (CA-SG) in vitro and in vivo. We investigated the first step in the degradation of CA-SG to the mercapturic acid conjugate, clofibryl-S-acyl-N-acetylcysteine (CA-SNAC), which is catalyzed by gamma -glutamyltranspeptidase (gamma -GT). After gamma -GT mediated cleavage of glutamate from CA-SG, the product clofibryl-S-acylcysteinylglycine (CA-S-CG) should undergo an intramolecular rearrangement reaction [Tate, S. S. (1975) FEBS Lett. 54, 319-322] to form clofibryl-N-acyl-cysteinylglycine (CA-N-CG). We performed in vitro studies incubating CA-SG with gamma -GT to determine the products formed, and in vivo studies examining the products excreted in urine after dosing rats with CA-SG or CA. Thus, CA-SG (0.1 mM) was incubated with gamma -GT (0.1 unit/mL) in buffer (pH 7.4, 25 degreesC) and analyzed for products formed by reversed-phase HPLC and electrospray mass spectrometry (ESI/MS). Results showed that CA-SG is degraded completely after 6 h of incubation leading to the formation of two products, CA-N-CG and its disulfide, with no detection of CA-S-CG thioester. After 36 h of incubation, only the disulfide remained in the incubation. Treatment of the disulfide with dithiothreitol led to the reappearance of CA-N-CG. ESI/LC/MS analysis of urine (16 h) extracts of CA-SG-dosed rats (200 mg/kg, iv) showed that CA-SG is degraded to CA-N-CG, CA-N-acyl-cysteine (CA-N-C) and their respective S-methylated products. The mercapturic acid conjugate (CA-SNAC) was found as a minor product. Analysis of urine extracts from CA-dosed rats (200 mg/kg, ip) resulted in the detection of clofibryl-N-acyl-cysteine (CAN-C), but no evidence for the formation of CA-SNAC was obtained. These in vitro and in vivo experiments indicate that gamma -GT mediated degradation of clofibryl-S-acyl-glutathione leads primarily to the formation and excretion of clofibryl-N-acyl-eysteine products rather than the S-acyl-NAC conjugate.

  DOI：

  10.1021/tx010039x

文献信息

• Interaction of γ-Glutamyltranspeptidase with Clofibryl-<i>S</i>-acyl-glutathione in Vitro and in Vivo in Rat
  作者：Mark P. Grillo、Leslie Z. Benet

  DOI：10.1021/tx010039x

  日期：2001.8.1

  Clofibric acid (CA) is metabolized to chemically reactive acylating products that can transacylate glutathione to form clofibryl-S-acyl-glutathione (CA-SG) in vitro and in vivo. We investigated the first step in the degradation of CA-SG to the mercapturic acid conjugate, clofibryl-S-acyl-N-acetylcysteine (CA-SNAC), which is catalyzed by gamma -glutamyltranspeptidase (gamma -GT). After gamma -GT mediated cleavage of glutamate from CA-SG, the product clofibryl-S-acylcysteinylglycine (CA-S-CG) should undergo an intramolecular rearrangement reaction [Tate, S. S. (1975) FEBS Lett. 54, 319-322] to form clofibryl-N-acyl-cysteinylglycine (CA-N-CG). We performed in vitro studies incubating CA-SG with gamma -GT to determine the products formed, and in vivo studies examining the products excreted in urine after dosing rats with CA-SG or CA. Thus, CA-SG (0.1 mM) was incubated with gamma -GT (0.1 unit/mL) in buffer (pH 7.4, 25 degreesC) and analyzed for products formed by reversed-phase HPLC and electrospray mass spectrometry (ESI/MS). Results showed that CA-SG is degraded completely after 6 h of incubation leading to the formation of two products, CA-N-CG and its disulfide, with no detection of CA-S-CG thioester. After 36 h of incubation, only the disulfide remained in the incubation. Treatment of the disulfide with dithiothreitol led to the reappearance of CA-N-CG. ESI/LC/MS analysis of urine (16 h) extracts of CA-SG-dosed rats (200 mg/kg, iv) showed that CA-SG is degraded to CA-N-CG, CA-N-acyl-cysteine (CA-N-C) and their respective S-methylated products. The mercapturic acid conjugate (CA-SNAC) was found as a minor product. Analysis of urine extracts from CA-dosed rats (200 mg/kg, ip) resulted in the detection of clofibryl-N-acyl-cysteine (CAN-C), but no evidence for the formation of CA-SNAC was obtained. These in vitro and in vivo experiments indicate that gamma -GT mediated degradation of clofibryl-S-acyl-glutathione leads primarily to the formation and excretion of clofibryl-N-acyl-eysteine products rather than the S-acyl-NAC conjugate.