N-hydroxy-4-((2-methyl-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indol-9-yl)methyl)benzamide trifluoroacetate | 1239034-62-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: N-hydroxy-4-((2-methyl-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indol-9-yl)methyl)benzamide trifluoroacetate
• 英文别名: N-hydroxy-4-(2-methyl-1,2,3,4-tetrahydro-β-carbolin-9-ylmethyl)benzamide trifluoroacetic acid salt；N-hydroxy-4-((2-methyl-3,4-dihydro-1H-pyrido[3,4-b]indol-9(2H)-yl)methyl)benzamide TFA；N-hydroxy-4-[(2-methyl-3,4-dihydro-1H-pyrido[3,4-b]indol-9-yl)methyl]benzamide;2,2,2-trifluoroacetic acid
• CAS: 1239034-62-8
• 化学式: C₂HF₃O₂*C₂₀H₂₁N₃O₂
• 分子量: 449.43
• InChiKey: OMLUTJHTWFLQLY-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.43
• 重原子数：
  32
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  94.8
• 氢给体数：
  3
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  1,2,3,4-四氢-9H-吡啶[3,4-B]并吲哚 在 盐酸羟胺 、 potassium tert-butylate 、 sodium methylate 、 三乙胺 、 三氟乙酸 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 32.25h， 生成 N-hydroxy-4-((2-methyl-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indol-9-yl)methyl)benzamide trifluoroacetate
  参考文献：
  名称：

  Second-Generation Histone Deacetylase 6 Inhibitors Enhance the Immunosuppressive Effects of Foxp3+ T-Regulatory Cells

  摘要：

  Second-generation Tubastatin A analogues were synthesized and evaluated for their ability to inhibit selectively histone deacetylase 6 (HDAC6). Substitutions to the carboline cap group were well-tolerated with substitution at the 2-position of both beta- and gamma-carbolines being optimal for HDAC6 activity and selectivity. Some compounds in this series were determined to have subnanomolar activity at HDAC6 with more than 7000 fold selectivity for HDAC6 versus HDAC1. Selected compounds were then evaluated for their ability to augment the immunosuppressive effect of Foxp3+ regulatory T cells. All compounds tested were found to enhance the ability of regulatory T cells to inhibit the mitotic division of effector T cells both in vitro and in vivo, suggesting that further investigation into the use of these compounds for the treatment of autoimmune disorders is warranted.

  DOI：

  10.1021/jm200773h

文献信息

• Rational Design and Simple Chemistry Yield a Superior, Neuroprotective HDAC6 Inhibitor, Tubastatin A
  作者：Kyle V. Butler、Jay Kalin、Camille Brochier、Guilio Vistoli、Brett Langley、Alan P. Kozikowski

  DOI：10.1021/ja102758v

  日期：2010.8.11

  Structure-based drug design combined with homology modeling techniques were used to develop potent inhibitors of HDAC6 that display superior selectivity for the HDAC6 isozyme compared to other inhibitors. These inhibitors can be assembled in a few synthetic steps, and thus are readily scaled up for in vivo studies. An optimized compound from this series, designated Tubastatin A, was tested in primary cortical neuron cultures in which it was found to induce elevated levels of acetylated a-tubulin, but not histone, consistent with its HDAC6 selectivity. Tubastatin A also conferred dose-dependent protection in primary cortical neuron cultures against glutathione depletion-induced oxidative stress. Importantly, when given alone at all concentrations tested, this hydroxamate-containing HDAC6-selective compound displayed no neuronal toxicity, thus, forecasting the potential application of this agent and its analogues to neurodegenerative conditions.
• [EN] HDAC INHIBITORS AND THERAPEUTIC METHODS USING THE SAME<br/>[FR] INHIBITEURS DE HDAC ET PROCÉDÉS THÉRAPEUTIQUES LES UTILISANT
  申请人：UNIV ILLINOIS

  公开号：WO2011011186A3

  公开（公告）日：2011-05-26
• Second-Generation Histone Deacetylase 6 Inhibitors Enhance the Immunosuppressive Effects of Foxp3+ T-Regulatory Cells
  作者：Jay H. Kalin、Kyle V. Butler、Tatiana Akimova、Wayne W. Hancock、Alan P. Kozikowski

  DOI：10.1021/jm200773h

  日期：2012.1.26

  Second-generation Tubastatin A analogues were synthesized and evaluated for their ability to inhibit selectively histone deacetylase 6 (HDAC6). Substitutions to the carboline cap group were well-tolerated with substitution at the 2-position of both beta- and gamma-carbolines being optimal for HDAC6 activity and selectivity. Some compounds in this series were determined to have subnanomolar activity at HDAC6 with more than 7000 fold selectivity for HDAC6 versus HDAC1. Selected compounds were then evaluated for their ability to augment the immunosuppressive effect of Foxp3+ regulatory T cells. All compounds tested were found to enhance the ability of regulatory T cells to inhibit the mitotic division of effector T cells both in vitro and in vivo, suggesting that further investigation into the use of these compounds for the treatment of autoimmune disorders is warranted.
• Selective Inhibition of Histone Deacetylase 10: Hydrogen Bonding to the Gatekeeper Residue is Implicated
  作者：Magalie Géraldy、Michael Morgen、Peter Sehr、Raphael R. Steimbach、Davide Moi、Johannes Ridinger、Ina Oehme、Olaf Witt、Mona Malz、Mauro S. Nogueira、Oliver Koch、Nikolas Gunkel、Aubry K. Miller

  DOI：10.1021/acs.jmedchem.8b01936

  日期：2019.5.9

  The discovery of isozyme-selective histone deacetylase (HDAC) inhibitors is critical for understanding the biological functions of individual HDACs and for validating HDACs as drug targets. The isozyme HDAC10 contributes to chemotherapy resistance and has recently been described to be a polyamine deacetylase, but no studies toward selective HDAC10 inhibitors have been published. Using two complementary assays, we found Tubastatin A, an HDAC6 inhibitor, to potently bind HDAC10. We synthesized Tubastatin A derivatives and found that a basic amine in the cap group was required for strong HDAC10 binding. HDAC10 inhibitors mimicked knockdown by causing dose-dependent accumulation of acidic vesicles in a neuroblastoma cell line. Furthermore, docking into human HDAC10 homology models indicated that a hydrogen bond between a cap group nitrogen and the gatekeeper residue Glu272 was responsible for potent HDAC10 binding. Taken together, our data provide an optimal platform for the development of HDAC10-selective inhibitors, as exemplified with the Tubastatin A scaffold.