γGlu-N-methyl-Cys(ethacrynic acid)-Gly | 350033-79-3

• 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: γGlu-N-methyl-Cys(ethacrynic acid)-Gly
• 英文别名: γ-Glu[MeCys(EA)-Gly-OH]-OH；(2S)-2-amino-5-[[(2R)-3-[2-[4-(carboxymethoxy)-2,3-dichlorobenzoyl]butylsulfanyl]-1-(carboxymethylamino)-1-oxopropan-2-yl]-methylamino]-5-oxopentanoic acid
• CAS: 350033-79-3
• 化学式: C₂₄H₃₁Cl₂N₃O₁₀S
• 分子量: 624.496
• InChiKey: SMBQTGXSQQYLHM-ZRNAQANOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.9
• 重原子数：
  40
• 可旋转键数：
  18
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  239
• 氢给体数：
  5
• 氢受体数：
  12

反应信息

• 作为产物：
  描述：

  oNs-Cys(Acm)-Gly-OtBu 在 ammonium hydroxide 、 三丁基膦 、 偶氮二甲酸二异丙酯 、 碘 、 1-羟基苯并三唑 、 苯硫酚 、 达卡巴嗪 、 N,N-二异丙基乙胺 、 三苯基膦 、 三氟乙酸 作用下， 以 四氢呋喃 、 甲醇 、 丙醇 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 75.17h， 生成 γGlu-N-methyl-Cys(ethacrynic acid)-Gly
  参考文献：
  名称：

  Peptidomimetic Glutathione Analogues as Novel γGT Stable GST Inhibitors

  摘要：

  Elevated levels of glutathione-S-transferase (GST) isoenzymes are found in many tumor cells and are thought to play a role in the onset of multidrug resistance (MDR). To evaluate the contribution of GST to this process, inhibitors are needed. Glutathione (GSH) conjugates, although good GST inhibitors, cannot be used in vivo, because they are eliminated rapidly. In this paper., we describe the synthesis of a series of novel peptidomimetic glutathione analogues that are stabilized against peptidase mediated breakdown. The peptide bonds in GSH were replaced by isosteres, such as the 'reduced' amide (which was prepared using a novel method), N-methylamide, urethane, and methylene linkages. The in vitro evaluation of the compounds focuses on GST inhibition and stability towards gamma -glutamyl-transpeptidase (gamma GT), the main enzyme involved in GSH breakdown. The compounds were conjugated to the model electrophile ethacrynic acid (EA) to resemble GS-EA, an efficient GST inhibitor. All novel GSH-analogues were shown to inhibit rat liver cytosolic GSTs. Furthermore, peptidomimetic changes of the gamma -glutamyl-cysteine amide bond greatly improved stability towards GT. These compounds may therefore be useful in the design of novel in vivo applicable GST inhibitors. (C) 2001 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0968-0896(01)00269-3

文献信息

• Peptidomimetic Glutathione Analogues as Novel γGT Stable GST Inhibitors
  作者：Danny Burg、Dmitri V Filippov、Ralph Hermanns、Gijs A van der Marel、Jacques H van Boom、Gerard J Mulder

  DOI：10.1016/s0968-0896(01)00269-3

  日期：2002.1

  Elevated levels of glutathione-S-transferase (GST) isoenzymes are found in many tumor cells and are thought to play a role in the onset of multidrug resistance (MDR). To evaluate the contribution of GST to this process, inhibitors are needed. Glutathione (GSH) conjugates, although good GST inhibitors, cannot be used in vivo, because they are eliminated rapidly. In this paper., we describe the synthesis of a series of novel peptidomimetic glutathione analogues that are stabilized against peptidase mediated breakdown. The peptide bonds in GSH were replaced by isosteres, such as the 'reduced' amide (which was prepared using a novel method), N-methylamide, urethane, and methylene linkages. The in vitro evaluation of the compounds focuses on GST inhibition and stability towards gamma -glutamyl-transpeptidase (gamma GT), the main enzyme involved in GSH breakdown. The compounds were conjugated to the model electrophile ethacrynic acid (EA) to resemble GS-EA, an efficient GST inhibitor. All novel GSH-analogues were shown to inhibit rat liver cytosolic GSTs. Furthermore, peptidomimetic changes of the gamma -glutamyl-cysteine amide bond greatly improved stability towards GT. These compounds may therefore be useful in the design of novel in vivo applicable GST inhibitors. (C) 2001 Elsevier Science Ltd. All rights reserved.