tert-butyl 5-(4-(methoxycarbonyl)benzyl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate | 1354547-51-5

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: tert-butyl 5-(4-(methoxycarbonyl)benzyl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate
• 英文别名: tert-butyl 5-[(4-methoxycarbonylphenyl)methyl]-3,4-dihydro-1H-pyrido[4,3-b]indole-2-carboxylate
• CAS: 1354547-51-5
• 化学式: C₂₅H₂₈N₂O₄
• 分子量: 420.508
• InChiKey: RPWZYLPOJJUYMQ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.2
• 重原子数：
  31
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  60.8
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  tert-butyl 5-(4-(methoxycarbonyl)benzyl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate 在 盐酸 、 三乙胺 作用下， 以 乙醚 、 二氯甲烷 为溶剂， 反应 1.5h， 生成 methyl 4-((2-acetyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)methyl)benzoate
  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：

  2,3,4,5-四氢-1H-吡啶并[4,3-b]吲哚 在 potassium tert-butylate 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 为溶剂， 反应 10.25h， 生成 tert-butyl 5-(4-(methoxycarbonyl)benzyl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate
  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

• Mitochondrial NIR imaging probe mitigating oxidative damage by targeting HDAC6
  作者：Jungryun Kim、Paramesh Jangili、Jeongah Kim、Stephani Edwina Lucia、Jae Ryun Ryu、Renuka Prasad、Soyu Zi、Pilhan Kim、Woong Sun、Jong Seung Kim

  DOI：10.1039/d3cc03259k

  日期：——

  Despite the apparent copious fluorescent probes targeting mitochondria, the development of low cytotoxic probes is still needed for improving validation of mitochondrial function assessment. Herein, we report a novel cyanine-based NIR fluorescent probe, T2, which selectively targets mitochondria with significantly low toxicity by modulating the intracellular redox status. Additionally, T2 inhibits

  尽管有大量针对线粒体的荧光探针，但仍需要开发低细胞毒性探针来改进线粒体功能评估的验证。在此，我们报道了一种新型的基于花青的近红外荧光探针T2，它通过调节细胞内氧化还原状态选择性地靶向线粒体，且毒性显着降低。此外，T2还可抑制氧化应激诱导的皮质神经元细胞死亡。这项研究为通过调节氧化还原稳态来开发低毒线粒体成像剂提供了新的见解。
• 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.
• 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.