tert-butyl 2-benzyl-2-(2-bromoacetyl)hydrazinecarboxylate | 500022-32-2

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: tert-butyl 2-benzyl-2-(2-bromoacetyl)hydrazinecarboxylate
• 英文别名: N'-Benzyl-N'-(2-bromoacetyl)-hydrazinecarboxylic acid tert-butyl ester；tert-butyl N-[benzyl-(2-bromoacetyl)amino]carbamate
• CAS: 500022-32-2
• 化学式: C₁₄H₁₉BrN₂O₃
• 分子量: 343.22
• InChiKey: ZESJMRMPDHYYNY-UHFFFAOYSA-N

物化性质

• 熔点：
  76 °C
• 密度：
  1.366±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.9
• 重原子数：
  20
• 可旋转键数：
  5
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  58.6
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  tert-butyl 2-benzyl-2-(2-bromoacetyl)hydrazinecarboxylate 在 盐酸 作用下， 以 乙醚 、 氯仿 为溶剂， 反应 24.0h， 生成 N'-(N-Benzyl-hydrazinocarbonylmethyl)-N'-isobutyl-hydrazinecarboxylic acid benzyl ester
  参考文献：
  名称：

  Hydrazino-aza and N -azapeptoids with therapeutic potential as anticancer agents

  摘要：

  The ubiquitin-proteasome-mediated degradation pathway plays an important role in regulating protein turnover in eucaryotic cells and, consequently, regulates both cell proliferation and cell death. The proteasome influences many cellular regulatory signals and is thus a potential target for pharmacological agents. The study of proteasome function has led to the identification of several natural and synthetic compounds that can act as tumor cell growth inhibitors. In this study, we have developed a series of hydrazino-aza and N-azapeptoids, analogues of Ac-Leucyl-Leucyl-Norleucinal (ALLN) a non-specific peptidyl aldehyde inhibitor of the proteasome. These peptide analogues share a common backbone and bear different C- and N-terminal functions. Their antiproliferative activity on murine leukemia L1210 cells is reported here. (C) 2003 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2003.09.018
• 作为产物：
  描述：

  肼基甲酸叔丁酯 在 sodium cyanoborohydride 、 溶剂黄146 、 三乙胺 作用下， 以 四氢呋喃 为溶剂， 反应 38.0h， 生成 tert-butyl 2-benzyl-2-(2-bromoacetyl)hydrazinecarboxylate
  参考文献：
  名称：

  Phenylalanine-Based Inactivator of AKT Kinase: Design, Synthesis, and Biological Evaluation

  摘要：

  Strategies to inhibit kinases by targeting the substrate binding site offer many advantages, including naturally evolved selectivity filters, but normally suffer from poor potency. In this work we propose a strategy to design and prepare covalent substrate-competitive kinase inhibitors as a method to improve potency. We have chosen Ala as the model kinase for this work. Using the AKT-GSK3 beta cocrystal structure and a reactive cysteine near the substrate binding site, we have identified phenylalanine (Phe) as an appropriate scaffold for the covalent inactivator portion of these inhibitors. By synthesizing compounds that incorporate cysteine-reactive electrophiles into phenylalanine and testing these compounds as AKT inhibitors, we have identified Boc-Phe-vinyl ketone as a submicromolar inactivator of AKT. We also show that Boc-Phe-vinyl ketone (1) potently inhibits AKT1 and inhibits cell growth in HCT116 and H460 cells nearly as well as AKT inhibitors GSK690693 and MK-2206, (2) is selective for kinases that possess an activation loop cysteine such as AKT, (3) requires the vinyl ketone for inactivation, (4) has inactivation that is time-dependent, and (5) alkylates Cys310 of AKT as shown by mass spectrometry. Identification of Boc-Phe-vinyl ketone as a covalent inactivator of AKT will allow the development of peptide and small-molecule substrate-competitive covalent kinase inhibitors that incorporate additional substrate binding elements to increase selectivity and potency. This proof-of-principle study also provides a basis to apply this strategy to other kinases of the AGC and CAMK families.

  DOI：

  10.1021/ml500088x

文献信息

• Phenylalanine-Based Inactivator of AKT Kinase: Design, Synthesis, and Biological Evaluation
  作者：Thuy Nguyen、Robert A. Coover、Jenson Verghese、Richard G. Moran、Keith C. Ellis

  DOI：10.1021/ml500088x

  日期：2014.5.8

  Strategies to inhibit kinases by targeting the substrate binding site offer many advantages, including naturally evolved selectivity filters, but normally suffer from poor potency. In this work we propose a strategy to design and prepare covalent substrate-competitive kinase inhibitors as a method to improve potency. We have chosen Ala as the model kinase for this work. Using the AKT-GSK3 beta cocrystal structure and a reactive cysteine near the substrate binding site, we have identified phenylalanine (Phe) as an appropriate scaffold for the covalent inactivator portion of these inhibitors. By synthesizing compounds that incorporate cysteine-reactive electrophiles into phenylalanine and testing these compounds as AKT inhibitors, we have identified Boc-Phe-vinyl ketone as a submicromolar inactivator of AKT. We also show that Boc-Phe-vinyl ketone (1) potently inhibits AKT1 and inhibits cell growth in HCT116 and H460 cells nearly as well as AKT inhibitors GSK690693 and MK-2206, (2) is selective for kinases that possess an activation loop cysteine such as AKT, (3) requires the vinyl ketone for inactivation, (4) has inactivation that is time-dependent, and (5) alkylates Cys310 of AKT as shown by mass spectrometry. Identification of Boc-Phe-vinyl ketone as a covalent inactivator of AKT will allow the development of peptide and small-molecule substrate-competitive covalent kinase inhibitors that incorporate additional substrate binding elements to increase selectivity and potency. This proof-of-principle study also provides a basis to apply this strategy to other kinases of the AGC and CAMK families.
• Hydrazino-aza and N -azapeptoids with therapeutic potential as anticancer agents
  作者：Karine Bouget、Sandrine Aubin、Jean-Guy Delcros、Yannick Arlot-Bonnemains、Michèle Baudy-Floc'h

  DOI：10.1016/j.bmc.2003.09.018

  日期：2003.11

  The ubiquitin-proteasome-mediated degradation pathway plays an important role in regulating protein turnover in eucaryotic cells and, consequently, regulates both cell proliferation and cell death. The proteasome influences many cellular regulatory signals and is thus a potential target for pharmacological agents. The study of proteasome function has led to the identification of several natural and synthetic compounds that can act as tumor cell growth inhibitors. In this study, we have developed a series of hydrazino-aza and N-azapeptoids, analogues of Ac-Leucyl-Leucyl-Norleucinal (ALLN) a non-specific peptidyl aldehyde inhibitor of the proteasome. These peptide analogues share a common backbone and bear different C- and N-terminal functions. Their antiproliferative activity on murine leukemia L1210 cells is reported here. (C) 2003 Elsevier Ltd. All rights reserved.