S-(p-chlorophenyl-N-hydroxycarbamoyl)glutathione dicyclopentyl ester

• 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: S-(p-chlorophenyl-N-hydroxycarbamoyl)glutathione dicyclopentyl ester
• 英文别名: cyclopentyl (2S)-2-amino-5-[[(2R)-3-[(4-chlorophenyl)-hydroxycarbamoyl]sulfanyl-1-[(2-cyclopentyloxy-2-oxoethyl)amino]-1-oxopropan-2-yl]amino]-5-oxopentanoate
• 化学式: C₂₇H₃₇ClN₄O₈S
• 分子量: 613.132
• InChiKey: AANYKQZXVMXUEA-VXKWHMMOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  41
• 可旋转键数：
  16
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.59
• 拓扑面积：
  203
• 氢给体数：
  4
• 氢受体数：
  10

反应信息

• 作为产物：
  描述：

  环戊醇 、 S-(N-4-chlorophenyl-N-hydroxycarbamoyl)glutathione 在 盐酸 作用下， 反应 48.0h， 以90%的产率得到S-(p-chlorophenyl-N-hydroxycarbamoyl)glutathione dicyclopentyl ester
  参考文献：
  名称：

  A New Method for Rapidly Generating Inhibitors of Glyoxalase I inside Tumor Cells Using S-(N-Aryl-N-hydroxycarbamoyl)ethylsulfoxides

  摘要：

  The enediol analogue S-(N-p-chlorophenyl-N-hydroxycarbamoyl)glutathione is a powerful mechanism-based competitive inhibitor of the anticancer target enzyme glyoxalase I. Nevertheless, this compound exhibits limited toxicity toward tumor cells in vitro because it does not readily diffuse across cell membranes. We describe an efficient method for indirectly delivering the enzyme inhibitor into murine leukemia L1210 cells via acyl interchange between intracellular glutathione and the cell-permeable prodrug S-(N-p-chlorophenyl-N-hydroxycarbamoyl)ethylsulfoxide. The second-order rate constant for the acyl-interchange reaction in a cell-free system is 1.84 mM(-1) min(-1) (100 mM potassium phosphate buffer, 5% ethanol, pH 7.5, 25 degrees C). Incubation of L1210 cells with the sulfoxide in vitro results in a rapid increase in the intracellular concentration of the glyoxalase I inhibitor (k(app) = 1.41 +/- 0.03 min(-1) (37 degrees C)) and inhibition of cell growth (GI(50) = 0.5 +/- 0.1 mu M). This represents an improvement in both efficiency and potency over the dialkyl ester prodrug strategy in which the inhibitor is indirectly delivered into tumor cells as the [glycyl,glutamyl] diethyl or dicyclopentyl esters. The fact that pi-glutathione transferase catalyzes the acyl-interchange reaction between GSH and the sulfoxide suggests that the sulfoxide, or related compounds, might exhibit greater selective toxicity toward tumor cells that overexpress the transferase.

  DOI：

  10.1021/jm980712o

文献信息

• A New Method for Rapidly Generating Inhibitors of Glyoxalase I inside Tumor Cells Using <i>S</i>-(<i>N</i>-Aryl-<i>N</i>-hydroxycarbamoyl)ethylsulfoxides
  作者：Diana S. Hamilton、Malcolm J. Kavarana、Ellyn M. Sharkey、Julie L. Eiseman、Donald J. Creighton

  DOI：10.1021/jm980712o

  日期：1999.5.1

  The enediol analogue S-(N-p-chlorophenyl-N-hydroxycarbamoyl)glutathione is a powerful mechanism-based competitive inhibitor of the anticancer target enzyme glyoxalase I. Nevertheless, this compound exhibits limited toxicity toward tumor cells in vitro because it does not readily diffuse across cell membranes. We describe an efficient method for indirectly delivering the enzyme inhibitor into murine leukemia L1210 cells via acyl interchange between intracellular glutathione and the cell-permeable prodrug S-(N-p-chlorophenyl-N-hydroxycarbamoyl)ethylsulfoxide. The second-order rate constant for the acyl-interchange reaction in a cell-free system is 1.84 mM(-1) min(-1) (100 mM potassium phosphate buffer, 5% ethanol, pH 7.5, 25 degrees C). Incubation of L1210 cells with the sulfoxide in vitro results in a rapid increase in the intracellular concentration of the glyoxalase I inhibitor (k(app) = 1.41 +/- 0.03 min(-1) (37 degrees C)) and inhibition of cell growth (GI(50) = 0.5 +/- 0.1 mu M). This represents an improvement in both efficiency and potency over the dialkyl ester prodrug strategy in which the inhibitor is indirectly delivered into tumor cells as the [glycyl,glutamyl] diethyl or dicyclopentyl esters. The fact that pi-glutathione transferase catalyzes the acyl-interchange reaction between GSH and the sulfoxide suggests that the sulfoxide, or related compounds, might exhibit greater selective toxicity toward tumor cells that overexpress the transferase.