N-羟基-4-[(2-苯基乙酰基)氨基]苯甲酰胺 | 656261-23-3

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 中文名称: N-羟基-4-[(2-苯基乙酰基)氨基]苯甲酰胺
• 英文名称: N-hydroxy-4-(2-phenylacetamido)benzamide
• 英文别名: N-hydroxy-4-phenylacetylamino-benzamide；N-hydroxy-4-[(2-phenylacetyl)amino]benzamide
• CAS: 656261-23-3
• 化学式: C₁₅H₁₄N₂O₃
• 分子量: 270.288
• InChiKey: VQGKLYBEQDAOSV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.9
• 重原子数：
  20
• 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：
  78.4
• 氢给体数：
  3
• 氢受体数：
  3

反应信息

• 作为产物：
  描述：

  methyl 4-(2-phenylacetamido)benzoate 在 palladium on activated charcoal 氢氧化钾 、 TEA 、 氢气 、 双(2-氧代-3-恶唑烷基)次磷酰氯 作用下， 以 四氢呋喃 、 甲醇 为溶剂， 反应 3.0h， 生成 N-羟基-4-[(2-苯基乙酰基)氨基]苯甲酰胺
  参考文献：
  名称：

  Zn²⁺-Chelating Motif-Tethered Short-Chain Fatty Acids as a Novel Class of Histone Deacetylase Inhibitors

  摘要：

  Among various classes of histone deacetylase (HDAC) inhibitors, short-chain fatty acids exhibit the least potency, with IC50 in the millimolar range. We rationalized that this weak potency was, in part, attributable to their inability to access the zinc cation in the HDAC active-site pocket, which is pivotal to the deacetylation catalysis. We thus explored the structural optimization of valproate, butyrate, phenylacetate, and phenylbutyrate by coupling them with Zn2+-chelating motifs (hydroxamic acid and o-phenylenediamine) through aromatic W-amino acid linkers. This strategy has led to a novel class of Zn2+ -chelating, motif-tethered, short-chain fatty acids that exhibited varying degrees of HDAC inhibitory potency. One hydroxamate-tethered phenylbutyrate compound, N-hydroxy-4-(4-phenylbutyrylamino)benzamide (HTPB), displayed nanomolar potency in inhibiting HDAC activity. Exposure of several cancer cell lines to HTPB at the submicromolar level showed reduced cell proliferation accompanied by histone hyperacetylation and elevated p21(WAF/CIPI) expression, which are hallmark features associated with intracellular HDAC inhibition.

  DOI：

  10.1021/jm0303655

文献信息

• Achiral Derivatives of Hydroxamate AR-42 Potently Inhibit Class I HDAC Enzymes and Cancer Cell Proliferation
  作者：Jiahui Tng、Junxian Lim、Kai-Chen Wu、Andrew J. Lucke、Weijun Xu、Robert C. Reid、David P. Fairlie

  DOI：10.1021/acs.jmedchem.0c00230

  日期：2020.6.11

  active inhibitor of histone deacetylases (HDACs) in clinical trials for multiple myeloma, leukemia, and lymphoma. It has few hydrogen bond donors and acceptors but is a chiral 2-arylbutyrate and potentially prone to racemization. We report achiral AR-42 analogues incorporating a cycloalkyl group linked via a quaternary carbon atom, with up to 40-fold increased potency against human class I HDACs (e

  在多发性骨髓瘤，白血病和淋巴瘤的临床试验中，AR-42是组蛋白脱乙酰基酶（HDAC）的口服活性抑制剂。它几乎没有氢键供体和受体，但是是手性的2-芳基丁酸酯，可能易于消旋。我们报道了非手性AR-42类似物，其包含通过季碳原子连接的环烷基，对人类I类HDAC的效力提高了40倍（例如，JT86，IC 500.7 nM，HDAC1），对五种人类癌细胞系的细胞毒性增加了25倍，而对正常人类细胞的毒性降低了多达70倍。JT86在促进MM96L黑色素瘤细胞中乙酰化组蛋白H4积累方面比racAR-42强9倍。分子模型和结构-活性之间的关系支持四氢吡喃与HDAC1的结合，而四氢吡喃则是对酶表面水的疏水屏蔽。这种有效的I类HDAC抑制剂可在AR-42活跃的疾病（癌症，寄生虫感染，炎性疾病）中显示出益处。
• Zn2Motif-Tethered Short-Chain Fatty Acids as a Novel Class of Histone Deacetylase
  申请人：Chen Ching-Shih

  公开号：US20070225373A1

  公开（公告）日：2007-09-27

  Zn 2+ -chelating motif-tethered fatty acids as histone deacetylase (HDAC) inhibitors. One hydroxamate-tethered phenylbutyrate compound, N-hydroxy-4-(4-phenylbutyrylamino)-benzamide (HTPB), displayed nM potency in inhibiting HDAC activity. Exposure of several cancer cell lines to HTPB at sub-μM concentrations showed reduced cell proliferation accompanied by histone hyperacetylation and elevated p21 WAF/CIP1 expression, hallmark features associated with intracellular HDAC inhibition.

  Zn2+螯合基固定的脂肪酸作为组蛋白去乙酰化酶（HDAC）抑制剂。一种羟酰胺基固定的苯丁酸化合物，N-羟基-4-(4-苯丁酰氨基)-苯甲酰胺（HTPB），在抑制HDAC活性方面表现出纳摩尔级别的效力。将几种癌细胞系暴露于亚微米浓度的HTPB中，显示出细胞增殖减少，伴随着组蛋白高乙酰化和升高的p21WAF/CIP1表达，这是与细胞内HDAC抑制相关的标志性特征。
• ZN2+Chelating Motif-Tethered Short-Chain Fatty Acids as a Novel Class of Histone Deacetylase Inhibitors
  申请人：Chen Ching-Shih

  公开号：US20090137679A1

  公开（公告）日：2009-05-28

  Zn 2+ -chelating motif-tethered fatty acids as histone deacetylase (HDAC) inhibitors. Compounds performed well in in vitro and in vivo tests.

  以Zn2+螯合基固定的脂肪酸作为组蛋白去乙酰化酶（HDAC）抑制剂。该化合物在体外和体内测试中表现良好。
• Structure-Based Optimization of Phenylbutyrate-Derived Histone Deacetylase Inhibitors
  作者：Qiang Lu、Da-Sheng Wang、Chang-Shi Chen、Yuan-Dong Hu、Ching-Shih Chen

  DOI：10.1021/jm0503749

  日期：2005.8.1

  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.
• ZN 24 -CHELATING MOTIF-TETHERED SHORT-CHAIN FATTY ACIDS AS A NOVEL CLASS OF HISTONE DEACETYLASE INHIBITORS
  申请人：THE OHIO STATE UNIVERSITY RESEARCH FOUNDATION

  公开号：EP1696898A2

  公开（公告）日：2006-09-06