Boc-Glo(ONp)-(OtBu) | 186097-60-9

• 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: Boc-Glo(ONp)-(OtBu)
• 英文别名: N-[(1,1-Dimethylethoxy)carbonyl]-O-[(4-nitrophenoxy)carbonyl]-L-serine 1,1-dimethylethyl ester；tert-butyl (2S)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-(4-nitrophenoxy)carbonyloxypropanoate
• CAS: 186097-60-9
• 化学式: C₁₉H₂₆N₂O₉
• 分子量: 426.423
• InChiKey: QEDFXMXMTKKRMF-AWEZNQCLSA-N

物化性质

• 沸点：
  555.3±50.0 °C(Predicted)
• 密度：
  1.242±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.35
• 重原子数：
  30.0
• 可旋转键数：
  6.0
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.53
• 拓扑面积：
  143.3
• 氢给体数：
  1.0
• 氢受体数：
  9.0

反应信息

• 作为反应物：
  描述：

  Boc-Glo(ONp)-(OtBu) 在 碘 作用下， 以 1,4-二氧六环 、 甲醇 为溶剂， 生成
  参考文献：
  名称：

  Peptide-bond modified glutathione conjugate analogs modulate GSTπ function in GSH-conjugation, drug sensitivity and JNK signaling

  摘要：

  Glutathione S-transferase pi (CST, E.C.2.5.1.18) overexpression contributes to resistance of cancer cells towards cytostatic drugs. Furthermore, GST pi is involved in the cellular stress response through inhibition of Jun N-terminal-kinase (JNK), a process that can be modulated by CST inhibitors. GSH conjugates are potent CST inhibitors, but are sensitive towards gamma-glutamyltranspeptidase (gamma GT)-mediated breakdown. In search for new peptidase stable CST inhibitors we employed the following strategy: (1) selection of a suitable (GST inhibiting) peptide-bond isostere from a series of previously synthesized gamma GT stabilized GSH-analogs. (2) The use of this peptidomimetic strategy to prepare a GSTT, selective inhibitor. Two gamma GT stable GSH conjugate analogs inhibited human GSTs, although non-selectively. One of these, a urethane-type peptide-bond is well accepted by GSTs and we selected this modification for the development of a gamma GT stable, GST pi selective inhibitor, UrPhg-Et-2. This compound displayed selectivity for GST pi compared to alpha and mu class enzymes. Furthermore, the inhibitor reversed GST pi-mediated drug resistance (MDR) in breast tumor cells. In addition, short-term exposure of cells to UrPhg-Et-2 led to GST pi oligornerization and JNK activation, suggesting that it activates the JNK-cJun signaling module through GST pi dissociation. Altogether, we show the successful use of peptidomimetic glutathione conjugate analogs as CST inhibitors and MDR-modifiers. As many MDR related enzymes, such as MRP1, glyoxalase 1 and DNA-pk are also inhibited by GSH conjugates, these peptidomimetic compounds can be used as scaffolds for the development of multi-target MDR drugs. (c) 2005 Elsevier Inc. All rights reserved.

  DOI：

  10.1016/j.bcp.2005.11.003
• 作为产物：
  描述：

  N-叔丁氧羰基丝氨酸叔丁酯 、 对硝基苯基氯甲酸酯 以 吡啶 为溶剂， 反应 24.0h， 以79%的产率得到Boc-Glo(ONp)-(OtBu)
  参考文献：
  名称：

  谷胱甘肽类似物γ-(L-γ-Oxaglutamyl)-L-半胱氨酰-甘氨酸的合成和活性

  摘要：

  骨架修饰的谷胱甘肽类似物 γ- (L - γ - oxaglutamyl) -L - 半胱氨酰 - 甘氨酸 (7) 的有效合成，其特征在于存在氨基甲酸酯 O - CO - NH 键取代 γ - 谷氨酰 CH2CO - NH 片段被描述。新的类似物已通过 1H- 和 13C-NMR 以及 FAB-MS 进行了全面表征。测试了化合物 7 对 γ-谷氨酰转移酶活性的抑制作用，发现它是猪肾 γ-谷氨酰转移酶 (EC 2.3.2.2) 的非竞争性抑制剂。

  DOI：

  10.1002/ardp.19963291105

文献信息

• Synthesis and activity of novel glutathione analogues containing an urethane backbone linkage
  作者：I Cacciatore、A.M Caccuri、A Di Stefano、G Luisi、M Nalli、F Pinnen、G Ricci、P Sozio

  DOI：10.1016/s0014-827x(03)00135-6

  日期：2003.9

  The new GSH analogues H-Glo(-Ser-Gly-OH)-OH (5), its O-benzyl derivative 4, and H-Glo(-Asp-Gly-OH)-OH (9), characterized by the replacement of central cysteine with either serine or aspartic acid, and containing an urethanic fragment as isosteric substitution of the scissile gamma-glutamylic junction, have been synthesized and characterized. Their ability to inhibit human GST P1-1 (hGST P1-1) in comparison

  新的GSH类似物H-Glo（-Ser-Gly-OH）-OH（5），其O-苄基衍生物4和H-Glo（-Asp-Gly-OH）-OH（9）已经合成并表征了含有丝氨酸或天冬氨酸的半胱氨酸中央半胱氨酸，并含有尿嘧啶片段作为可裂变的γ-谷氨酸连接的等位取代。与H-Glu（-Ser-Gly-OH）-OH和H-Glu（-Asp-Gly-OH）-OH相比，它们抑制人GST P1-1（hGST P1-1）的能力已经评估了大鼠GST 3-3和4-4的抑制剂。为了进一步研究等位取代对新的GSH类似物4、5和9的结合能力的影响，还对先前报道的含半胱氨酰的类似物H-Glo（-Cys-Gly-OH）-OH进行了评估。作为hGSTP1-1的共同底物。
• 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.
• Nitrobenzoxadiazole-based GSTP1-1 inhibitors containing the full peptidyl moiety of (pseudo)glutathione
  作者：Grazia Luisi、Adriano Mollica、Simone Carradori、Alessia Lenoci、Anastasia De Luca、Anna Maria Caccuri

  DOI：10.3109/14756366.2015.1070845

  日期：2016.11.1

  Context: The inhibition of glutathione S-transferase P1-1 (GSTP1-1) is a sound strategy to overcome drug resistance in oncology practice.Objective: The nitrobenzoxadiazolyl (NBD) S-conjugate of glutathione and the corresponding g-oxa-glutamyl isostere (compounds 1 and 5, respectively) have been disclosed as GST inhibitors. The rationale of their design is discussed in juxtaposition to non-peptide NBD thioethers. Materials and methods: Synthesis of derivatives 1 and 5 and in vitro evaluation on human GSTP1-1 and M2-2 are reported.Results: Conjugates 1 and 5 were found to be low micromolar inhibitors of both isoforms. Furthermore, they display a threefold reduction in selectivity for GSTM2-2 over the P1-1 isozyme in comparison with the potent non-peptide inhibitor nitrobenzoxadiazolyl-thiohexanol (NBDHEX).Discussion and conclusions: Spectroscopic data are congruent with the formation of a stable sigma-complex between GSH and the inhibitors in the protein active site. Conjugate 5 is suitable for in vivo modulation of GST activity in cancer treatment.