2,2,3,3,4,4,5,5,6,6,7,7-dodecafluorooctanedioic acid hydroxyamide (4-[1-phenyl-1H-[1,2,3]triazol-4-yl]phenyl)amide | 1308677-64-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 2,2,3,3,4,4,5,5,6,6,7,7-dodecafluorooctanedioic acid hydroxyamide (4-[1-phenyl-1H-[1,2,3]triazol-4-yl]phenyl)amide
• 英文别名: N-Hydroxy-N'-[4-(1-phenyltriazol-4-yl)phenyl]perfluorooctanediamide；2,2,3,3,4,4,5,5,6,6,7,7-dodecafluoro-N-hydroxy-N'-[4-(1-phenyltriazol-4-yl)phenyl]octanediamide
• CAS: 1308677-64-6
• 化学式: C₂₂H₁₃F₁₂N₅O₃
• 分子量: 623.358
• InChiKey: DEECQNVLWFLNTJ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5
• 重原子数：
  42
• 可旋转键数：
  10
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  109
• 氢给体数：
  3
• 氢受体数：
  17

反应信息

• 作为产物：
  描述：

  4-乙炔基苯胺 在 copper(ll) sulfate pentahydrate 、 羟胺 、 sodium ascorbate 、 三乙胺 作用下， 以 四氢呋喃 、 水 、 叔丁醇 为溶剂， 反应 22.0h， 生成 2,2,3,3,4,4,5,5,6,6,7,7-dodecafluorooctanedioic acid hydroxyamide (4-[1-phenyl-1H-[1,2,3]triazol-4-yl]phenyl)amide
  参考文献：
  名称：

  Synthesis and biochemical analysis of 2,2,3,3,4,4,5,5,6,6,7,7-dodecafluoro-N-hydroxy-octanediamides as inhibitors of human histone deacetylases

  摘要：

  Inhibition of human histone deacetylases (HDACs) has emerged as a novel concept in the chemotherapeutic treatment of cancer. Two chemical entities, SAHA (ZOLINZA, Merck) and romidepsin (Istodax, Celgene) have been recently approved by the FDA as first-in-class drugs against cutaneous T-cell lymphoma. Clinical use of these drugs revealed several side effects including gastro-intestinal symptoms, fatigue, thrombocytopenia, thrombosis. Romidepsin is associated with an yet unresolved cardiotoxicity issue. A general hypothesis for the diminishment of unwanted adverse effects and an improved therapeutical window suggests the development of more isotype selective inhibitors. In this study the first time HDAC inhibitors with perfluorinated spacers between the zinc chelating moiety and the aromatic capping group were synthesized and tested against representatives of HDAC classes I, IIa and IIb. Competitive binding assays and a combined approach by using blind docking and molecular dynamics support binding of the perfluorinated analogs of SAHA to the active site of the HDAC-like amidohydrolase from Bordetella/Alcaligenes and presumably also to human HDACs. In contrast to the alkyl spacer of SAHA and derivatives, the perfluorinated alkyl spacer seems to contribute to or facilitate the induction of selectivity for class 11, particularly class IIa, HDACs even though the overall potency of the perfluorinated SAHA analogs in this study against human HDACs remained still rather moderate in the micromolar range. (C) 2011 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2011.11.041

文献信息

• Synthesis and biochemical analysis of 2,2,3,3,4,4,5,5,6,6,7,7-dodecafluoro-N-hydroxy-octanediamides as inhibitors of human histone deacetylases
  作者：Leonhard M. Henkes、Patricia Haus、Felix Jäger、Joachim Ludwig、Franz-Josef Meyer-Almes

  DOI：10.1016/j.bmc.2011.11.041

  日期：2012.1

  Inhibition of human histone deacetylases (HDACs) has emerged as a novel concept in the chemotherapeutic treatment of cancer. Two chemical entities, SAHA (ZOLINZA, Merck) and romidepsin (Istodax, Celgene) have been recently approved by the FDA as first-in-class drugs against cutaneous T-cell lymphoma. Clinical use of these drugs revealed several side effects including gastro-intestinal symptoms, fatigue, thrombocytopenia, thrombosis. Romidepsin is associated with an yet unresolved cardiotoxicity issue. A general hypothesis for the diminishment of unwanted adverse effects and an improved therapeutical window suggests the development of more isotype selective inhibitors. In this study the first time HDAC inhibitors with perfluorinated spacers between the zinc chelating moiety and the aromatic capping group were synthesized and tested against representatives of HDAC classes I, IIa and IIb. Competitive binding assays and a combined approach by using blind docking and molecular dynamics support binding of the perfluorinated analogs of SAHA to the active site of the HDAC-like amidohydrolase from Bordetella/Alcaligenes and presumably also to human HDACs. In contrast to the alkyl spacer of SAHA and derivatives, the perfluorinated alkyl spacer seems to contribute to or facilitate the induction of selectivity for class 11, particularly class IIa, HDACs even though the overall potency of the perfluorinated SAHA analogs in this study against human HDACs remained still rather moderate in the micromolar range. (C) 2011 Elsevier Ltd. All rights reserved.