N-hydroxy-4-((1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indol-9-yl)methyl)benzamide trifluoroacetate | 1354547-65-1

• 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-((1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indol-9-yl)methyl)benzamide trifluoroacetate
• 英文别名: 4-((3,4-dihydro-1H-pyrido[3,4-b]indol-9(2H)-yl)methyl)-N-hydroxybenzamide TFA；N-hydroxy-4-(1,2,3,4-tetrahydropyrido[3,4-b]indol-9-ylmethyl)benzamide;2,2,2-trifluoroacetic acid
• CAS: 1354547-65-1
• 化学式: C₂HF₃O₂*C₁₉H₁₉N₃O₂
• 分子量: 435.403
• InChiKey: XPYGKFBOUQGICH-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.09
• 重原子数：
  31
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.24
• 拓扑面积：
  104
• 氢给体数：
  4
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  N-hydroxy-4-((1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indol-9-yl)methyl)benzamide trifluoroacetate 、 三氟乙酸 、 碘甲烷 在 三乙胺 作用下， 以 乙腈 为溶剂， 反应 16.0h， 以2.7 mg的产率得到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：

  Selective Inhibition of Histone Deacetylase 10: Hydrogen Bonding to the Gatekeeper Residue is Implicated

  摘要：

  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.

  DOI：

  10.1021/acs.jmedchem.8b01936
• 作为产物：
  描述：

  1,2,3,4-四氢-9H-吡啶[3,4-B]并吲哚 在 盐酸 、 potassium cyanide 、 羟胺 、 sodium hydride 、 三乙胺 作用下， 以 1,4-二氧六环 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 、 mineral oil 为溶剂， 反应 37.75h， 生成 N-hydroxy-4-((1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indol-9-yl)methyl)benzamide trifluoroacetate
  参考文献：
  名称：

  Selective Inhibition of Histone Deacetylase 10: Hydrogen Bonding to the Gatekeeper Residue is Implicated

  摘要：

  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.

  DOI：

  10.1021/acs.jmedchem.8b01936

文献信息

• 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.