(S)-2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)-5-(3-(6-(4-((((3-oxo-1-phenylpent-4-en-2-yl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-1-yl)hexyl)thioureido)benzoic acid

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并吡喃
• 英文名称: (S)-2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)-5-(3-(6-(4-((((3-oxo-1-phenylpent-4-en-2-yl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-1-yl)hexyl)thioureido)benzoic acid
• 英文别名: 2-(3-hydroxy-6-oxoxanthen-9-yl)-5-[6-[4-[[(2S)-3-oxo-1-phenylpent-4-en-2-yl]carbamoyloxymethyl]triazol-1-yl]hexylcarbamothioylamino]benzoic acid
• 化学式: C₄₂H₄₀N₆O₈S
• 分子量: 788.881
• InChiKey: AWNVKNUHUYCYOM-DHUJRADRSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.8
• 重原子数：
  57
• 可旋转键数：
  18
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.21
• 拓扑面积：
  226
• 氢给体数：
  5
• 氢受体数：
  11

反应信息

• 作为产物：
  描述：

  ((prop-2-yn-1-yloxy)carbonyl)-L-phenylalanine 在 1-羟基苯并三唑 、 copper(II) sulfate 、 sodium ascorbate 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 四氢呋喃 、 二氯甲烷 、 水 为溶剂， 反应 21.0h， 生成 (S)-2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)-5-(3-(6-(4-((((3-oxo-1-phenylpent-4-en-2-yl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-1-yl)hexyl)thioureido)benzoic acid
  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