Boc-Lys(Tfa)-AMC | 97885-44-4

• 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-Lys(Tfa)-AMC
• 英文别名: Boc-Lys(trifluoroacetyl)-AMC；Boc-Lys(trifluoracetyl)-AMC；tert-butyl N-[(2S)-1-[(4-methyl-2-oxochromen-7-yl)amino]-1-oxo-6-[(2,2,2-trifluoroacetyl)amino]hexan-2-yl]carbamate
• CAS: 97885-44-4
• 化学式: C₂₃H₂₈F₃N₃O₆
• 分子量: 499.487
• InChiKey: UFFVNATYYXBMGO-INIZCTEOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  35
• 可旋转键数：
  10
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.48
• 拓扑面积：
  123
• 氢给体数：
  3
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  Boc-Lys(Tfa)-AMC 在 human recombinant histone deacetylase 7 作用下， 生成 7-氨基-4-甲基香豆素
  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

• Profiling of Substrates for Zinc-dependent Lysine Deacylase Enzymes: HDAC3 Exhibits Decrotonylase Activity In Vitro
  作者：Andreas S. Madsen、Christian A. Olsen

  DOI：10.1002/anie.201203754

  日期：2012.9.3

  of the activities of the eleven human zinc‐dependent lysine deacylases against a series of fluorogenic substrates (see scheme) as well as kinetic evaluation revealed substrates for screenings of histone deacetylases HDAC10 and HDAC11 at reasonably low enzyme concentrations. Furthermore, HDAC3 in complex with nuclear receptor corepressor 1 (HDAC3–NCoR1) was shown to harbor decrotonylase activity in vitro

  系统针对一系列荧光底物的11人的锌依赖性赖氨酸脱酰的活动的筛选（参见方案）以及动力学评价揭示基板组蛋白的脱乙酰放映和HDAC10 HDAC11在合理的低的酶浓度。此外，HDAC3在复合体与核受体辅抑制子1（HDAC3-NCoR1）显示窝藏在体外decrotonylase活性。
• 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.