N-(4-hydroxycarbamoylbenzyl)-1,2,4,9-tetrahydro-3-thia-9-azafluorene | 1431080-93-1

• 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-(4-hydroxycarbamoylbenzyl)-1,2,4,9-tetrahydro-3-thia-9-azafluorene
• 英文别名: 4-(3,4-dihydro-1H-thiopyrano[4,3-b]indol-5-ylmethyl)-N-hydroxybenzamide
• CAS: 1431080-93-1
• 化学式: C₁₉H₁₈N₂O₂S
• 分子量: 338.43
• InChiKey: NAHIKSGGBQEYMV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.9
• 重原子数：
  24
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.21
• 拓扑面积：
  79.6
• 氢给体数：
  2
• 氢受体数：
  3

反应信息

• 作为产物：
  描述：

  1,3,4,5-四氢噻喃并[4,3-b]吲哚 在 potassium cyanide 、 羟胺 、 sodium hydride 作用下， 以 1,4-二氧六环 、 水 、 N,N-二甲基甲酰胺 、 mineral oil 为溶剂， 反应 16.75h， 生成 N-(4-hydroxycarbamoylbenzyl)-1,2,4,9-tetrahydro-3-thia-9-azafluorene
  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

• Potent and selective HDAC6 inhibitory activity of N-(4-hydroxycarbamoylbenzyl)-1,2,4,9-tetrahydro-3-thia-9-azafluorenes as novel sulfur analogues of Tubastatin A
  作者：Rob De Vreese、Tom Verhaeghe、Tom Desmet、Matthias D'hooghe

  DOI：10.1039/c3cc41422a

  日期：——

  Eight N-(4-hydroxycarbamoylbenzyl)-1,2,4,9-tetrahydro-3-thia-9-azafluorenes were efficiently prepared as sulfur analogues of Tubastatin A and thus evaluated as new HDAC6 inhibitors. All compounds exhibited potency against HDAC6, and four of them were active in the nanomolar range (IC50 = 1.9–22 nM). Further analysis revealed that the sulfone derivatives (designated as Tubathians) are superior to their non-oxidized sulfide analogues, and the two most active sulfones showed good to excellent HDAC6 selectivity compared to all other HDAC isoform classes.

  八种 N-(4-羟基氨基甲酰基苄基)-1,2,4,9-四氢-3-硫杂-9-氮杂芴被有效地制备成 Tubastatin A 的硫类似物，并因此被评估为新的 HDAC6 抑制剂。所有化合物都对 HDAC6 具有抑制作用，其中四个化合物的活性在纳摩尔范围内（IC50 = 1.9-22 nM）。进一步的分析表明，砜类衍生物（被命名为 Tubathians）优于其非氧化的硫化物类似物，与所有其他 HDAC 同工酶类别相比，两种活性最强的砜类化合物显示出良好至卓越的 HDAC6 选择性。
• [EN] HDAC6 INHIBITORS AND USES THEREOF<br/>[FR] INHIBITEURS DE HDAC6 ET LEURS UTILISATIONS
  申请人：UNIV GENT

  公开号：WO2014147178A1

  公开（公告）日：2014-09-25

  The present invention relates to Histone deacetylases 6 (HDAC6) inhibitors and compositions containing the same. Methods of treating diseases and conditions wherein inhibition of HDAC6 provides a benefit, like a cell proliferative disease, an autoimmune or inflammatory disorder, a neurodegenerative disease, a viral disease, malaria, or a combination thereof, also are disclosed.

  本发明涉及组蛋白去乙酰化酶6（HDAC6）抑制剂及含有该抑制剂的组合物。还公开了通过抑制HDAC6提供益处的治疗疾病和病况的方法，如细胞增殖性疾病、自身免疫或炎症性疾病、神经退行性疾病、病毒性疾病、疟疾或其组合。
• HDAC6 INHIBITORS AND USES THEREOF
  申请人：Bracke Marc

  公开号：US20160009730A1

  公开（公告）日：2016-01-14

  Histone deacetylases 6 (HDAC6) inhibitors and compositions containing the same. Methods of treating diseases and conditions wherein inhibition of HDAC6 provides a benefit, like a cell proliferative disease, an autoimmune or inflammatory disorder, a neurodegenerative disease, a viral disease, malaria, or a combination thereof.

  组蛋白去乙酰化酶6（HDAC6）抑制剂和含有它们的组合物。治疗通过抑制HDAC6获得益处的疾病和病情的方法，如细胞增殖性疾病，自身免疫或炎症性疾病，神经退行性疾病，病毒性疾病，疟疾或其组合。
• US9586973B2
  申请人：——

  公开号：US9586973B2

  公开（公告）日：2017-03-07