4-amino-N-(benzyloxy)benzamide | 863666-15-3

• 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: 4-amino-N-(benzyloxy)benzamide
• 英文别名: 4-amino-N-phenylmethoxybenzamide
• CAS: 863666-15-3
• 化学式: C₁₄H₁₄N₂O₂
• 分子量: 242.277
• InChiKey: XUOWMAHUTJJSLH-UHFFFAOYSA-N

物化性质

• 密度：
  1.216±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.1
• 重原子数：
  18
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.07
• 拓扑面积：
  64.4
• 氢给体数：
  2
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  4-amino-N-(benzyloxy)benzamide 在 palladium on activated charcoal 氢气 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 四氢呋喃 、 甲醇 为溶剂， 反应 2.0h， 生成 4-(5-phenylpentanamido)benzohydroxamic acid
  参考文献：
  名称：

  Structure-Based Optimization of Phenylbutyrate-Derived Histone Deacetylase Inhibitors

  摘要：

  Previously, we developed a strategy to develop a novel class of histone deacetylase (HDAC) inhibitors by tethering short-chain fatty acids with Zn2+-chelating motifs, which led to N-hydroxy-4-(4-phenylbutyryl-amino)benzamide (HTPB), a hydroxamate-tethered phenylbutyrate derivative with sub-micromolar potency in inhibiting HDAC activity and cancer cell proliferation. In this study, we carried out structure-based optimization of HTPB by using the framework generated by the structure of histone deacetylase-like protein (HDLP)-trichostatin A (TSA) complexes. Docking of HTPB into the HDLP binding domain suggested that the hydrophobic microenvironment encompassed by Phe-198 and Phe-200 could be exploited for structural optimization. This premise was corroborated by the greater potency of (S)-(+)-N-hydroxy-4-(3-methyl-2-phenylbutyrylamino)-benzamide [(S)-11] (IC50 in HDAC inhibition, 16 nM), of which the isopropyl moiety was favorable in interacting with this hydrophobic motif. (S)-11 at concentrations as low as 0.1 mu M was effective in causing histone hyperacetylation and p21(WAF/CIP1) overexpression and suppressing proliferation in cancer cells.

  DOI：

  10.1021/jm0503749
• 作为产物：
  描述：

  N-BOC-4-氨基苯甲酸 在 N,N-bis(2-oxo-3-oxazolidinyl)phosphoramidic chloride 、 三乙胺 、 三氟乙酸 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 2.0h， 生成 4-amino-N-(benzyloxy)benzamide
  参考文献：
  名称：

  Structure-Based Optimization of Phenylbutyrate-Derived Histone Deacetylase Inhibitors

  摘要：

  Previously, we developed a strategy to develop a novel class of histone deacetylase (HDAC) inhibitors by tethering short-chain fatty acids with Zn2+-chelating motifs, which led to N-hydroxy-4-(4-phenylbutyryl-amino)benzamide (HTPB), a hydroxamate-tethered phenylbutyrate derivative with sub-micromolar potency in inhibiting HDAC activity and cancer cell proliferation. In this study, we carried out structure-based optimization of HTPB by using the framework generated by the structure of histone deacetylase-like protein (HDLP)-trichostatin A (TSA) complexes. Docking of HTPB into the HDLP binding domain suggested that the hydrophobic microenvironment encompassed by Phe-198 and Phe-200 could be exploited for structural optimization. This premise was corroborated by the greater potency of (S)-(+)-N-hydroxy-4-(3-methyl-2-phenylbutyrylamino)-benzamide [(S)-11] (IC50 in HDAC inhibition, 16 nM), of which the isopropyl moiety was favorable in interacting with this hydrophobic motif. (S)-11 at concentrations as low as 0.1 mu M was effective in causing histone hyperacetylation and p21(WAF/CIP1) overexpression and suppressing proliferation in cancer cells.

  DOI：

  10.1021/jm0503749

文献信息

• Structure–Activity and Structure–Toxicity Relationships of Peptoid‐Based Histone Deacetylase Inhibitors with Dual‐Stage Antiplasmodial Activity
  作者：Marcel K. W. Mackwitz、Eva Hesping、Yevgeniya Antonova‐Koch、Daniela Diedrich、Tamirat Gebru Woldearegai、Tina Skinner‐Adams、Mary Clarke、Andrea Schöler、Laura Limbach、Thomas Kurz、Elizabeth A. Winzeler、Jana Held、Katherine T. Andrews、Finn K. Hansen

  DOI：10.1002/cmdc.201800808

  日期：2019.5.6

  development of drug resistance in malaria-endemic countries. In this regard, histone deacetylases (HDACs) have emerged as new and promising malaria drug targets. In this work, we present the design, synthesis, and biological evaluation of 20 novel HDAC inhibitors with antiplasmodial activity. Based on a previously discovered peptoid-based hit compound, we modified all regions of the peptoid scaffold by using

  鉴于疟疾流行国家耐药性的发展，新的疟疾干预策略非常重要。在这方面，组蛋白脱乙酰酶（HDAC）已成为新的、有前途的疟疾药物靶点。在这项工作中，我们介绍了 20 种具有抗疟原虫活性的新型 HDAC 抑制剂的设计、合成和生物学评价。基于之前发现的基于类肽的命中化合物，我们通过使用一锅多组分途径和亚单体途径修饰了类肽支架的所有区域，以更深入地了解结构-活性和结构-毒性关系。大多数化合物对无性血液期恶性疟原虫寄生虫表现出有效的活性，IC50值在0.0052-0.25μm范围内，并且对哺乳动物细胞具有良好的选择性（SIPf3D7/HepG2：170-1483）。此外，几种化合物对伯氏疟原虫外红细胞形式（PbEEF）表现出令人鼓舞的亚微摩尔活性。我们的研究发现了热门化合物 N-(2-(苄氨基)-2-氧代乙基)-N-(4-(羟基氨基甲酰基)苄基)-4-异丙基苯甲酰胺 (2 h) 作为一种有效的寄生虫特异性
• Inhibitors of Histone Deacetylase
  申请人：Chakravarty K. Prasun

  公开号：US20080015190A1

  公开（公告）日：2008-01-17

  The present invention relates to hydroxamic acid derivatives that are inhibitors of histone deacetylase (HDAC). The compounds of the present invention are useful for treating cellular proliferative diseases, including cancer. Further, the compounds of the present invention are useful for treating neurodegenerative diseases, schizophrenia and stroke among other diseases. Further, the compounds of the present invention have antiprotozoal properties.

  本发明涉及羟羧酰胺酸衍生物，这些衍生物是组蛋白去乙酰化酶（HDAC）的抑制剂。本发明的化合物可用于治疗细胞增殖性疾病，包括癌症。此外，本发明的化合物可用于治疗神经退行性疾病、精神分裂症和中风等其他疾病。此外，本发明的化合物具有抗原虫特性。
• 具有HDAC抑制活性的化合物、制备方法、组合物及用途
  申请人：北京鑫开元医药科技有限公司

  公开号：CN112225737A

  公开（公告）日：2021-01-15

  本发明属于药物技术领域，尤其涉及具有HDAC抑制活性的化合物、制备方法、组合物及用途，所述化合物是具有式I结构的化合物或其药学上可接受的盐：，式中，R1代表取代的苯基、不取代的苯基、取代的芳杂环基或不取代的芳杂环基，X代表CH或N，本发明提供的化合物特异性高，副作用低，具有良好的HDAC抑制活性，通过抑制HDAC的活性达到治疗肿瘤的目的，可应用于对于肿瘤药物的开发，对于肿瘤的预防和治疗具有重要意义。
• Histone deacetylase (HDAC) inhibitor specificity determinants are preserved in a class of dual HDAC/non-covalent proteasome inhibitors
  作者：Alexandria M. Chan、Ashley Mitchell、Lena Grogan、Paul Shapiro、Steven Fletcher

  DOI：10.1016/j.bmc.2024.117680

  日期：2024.4

  HDAC6 inhibitor ricolinostat and the proteasome inhibitor bortezomib, we herein describe a focused family of dual HDAC/non-covalent proteasome inhibitors, and explore the impact of linker and zinc-binding group identities on HDAC1/6 isozyme selectivity. In general, previously reported specificity determinants of monovalent HDAC1/6 inhibitors were preserved in our dual HDAC/proteasome inhibitors.

  许多疾病状态需要多种药物来抑制多个靶点以进行有效的治疗/管理，即药物鸡尾酒疗法或“多药治疗”。相比之下，多药理学是开发可以抑制多个靶点的单一药物。每个策略都与优点和缺点相关。受 HDAC6 抑制剂利可林司他和蛋白酶体抑制剂硼替佐米联合治疗多发性骨髓瘤的有希望的临床试验数据的启发，我们在此描述了双 HDAC/非共价蛋白酶体抑制剂的重点家族，并探讨了接头和锌的影响- HDAC1/6 同工酶选择性的结合基团身份。一般来说，先前报道的单价 HDAC1/6 抑制剂的特异性决定因素保留在我们的双 HDAC/蛋白酶体抑制剂中。
• From C ₁ to C ₃ : Copper‐Catalyzed <i>gem</i> ‐Bis(trifluoromethyl)olefination of α‐Diazo Esters with TMSCF ₃
  作者：Qian Wang、Chuanfa Ni、Mingyou Hu、Qiqiang Xie、Qinghe Liu、Shitao Pan、Jinbo Hu

  DOI：10.1002/anie.202002409

  日期：2020.5.25

  AbstractA Cu‐catalyzed gem‐bis(trifluoromethyl)olefination of α‐diazo esters, using TMSCF3 as the only fluorocarbon source, has been developed and provides an exquisite method to access gem‐bis(trifluoromethyl)alkenes. This unprecedented olefination process involves a carbene migratory insertion into “CuCF3” to generate the α‐CF3‐substituted organocopper species, which then undergoes β‐fluoride elimination and two consecutive addition‐elimination processes to give the desired products. The key to this efficient one‐pot C1‐to‐C3 synthetic protocol lies in the controllable double (over single and triple) trifluoromethylations of the gem‐difluoroalkene intermediates.