3-benzyloxy-4-methoxybenzhydroxamic acid

• 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: 3-benzyloxy-4-methoxybenzhydroxamic acid
• 英文别名: 3-(benzyloxy)-N-hydroxy-4-methoxybenzamide；HDAC8-IN-20a；N-hydroxy-4-methoxy-3-phenylmethoxybenzamide
• 化学式: C₁₅H₁₅NO₄
• 分子量: 273.288
• InChiKey: IGVRDNCZCPXENL-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.4
• 重原子数：
  20
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.13
• 拓扑面积：
  67.8
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  3-苄氧基-4-甲氧基苯甲酸 在 盐酸 、 benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate 、 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 、 水 为溶剂， 生成 3-benzyloxy-4-methoxybenzhydroxamic acid
  参考文献：
  名称：

  具有抗神经母细胞瘤活性的选择性组蛋白脱乙酰基酶8（HDAC8）抑制剂的基于结构的设计和生物学特性

  摘要：

  组蛋白脱乙酰基酶（HDACs）是表观遗传基因调控的重要调节剂，还可以控制非组蛋白的蛋白质底物的活性。对于HDAC 1–3和6，已经获得了许多有效的选择性抑制剂，而对于其他亚型，对选择性抑制剂及其抑制作用的了解却很少。本报告描述了取代的苯氧肟酸作为有效的和选择性的HDAC8抑制剂的发展。使用可用晶体结构的对接研究已用于该系列化合物的基于结构的优化。在这项研究中，我们研究了HDAC8在癌细胞增殖中的作用，并优化了体外和细胞培养中命中率和选择性的命中。基于结构的设计，综合，

  DOI：

  10.1021/acs.jmedchem.7b01447

文献信息

• Structure-Based Design and Biological Characterization of Selective Histone Deacetylase 8 (HDAC8) Inhibitors with Anti-Neuroblastoma Activity
  作者：Tino Heimburg、Fiona R. Kolbinger、Patrik Zeyen、Ehab Ghazy、Daniel Herp、Karin Schmidtkunz、Jelena Melesina、Tajith Baba Shaik、Frank Erdmann、Matthias Schmidt、Christophe Romier、Dina Robaa、Olaf Witt、Ina Oehme、Manfred Jung、Wolfgang Sippl

  DOI：10.1021/acs.jmedchem.7b01447

  日期：2017.12.28

  Histone deacetylases (HDACs) are important modulators of epigenetic gene regulation and additionally control the activity of non-histone protein substrates. While for HDACs 1–3 and 6 many potent selective inhibitors have been obtained, for other subtypes much less is known on selective inhibitors and the consequences of their inhibition. The present report describes the development of substituted benzhydroxamic

  组蛋白脱乙酰基酶（HDACs）是表观遗传基因调控的重要调节剂，还可以控制非组蛋白的蛋白质底物的活性。对于HDAC 1–3和6，已经获得了许多有效的选择性抑制剂，而对于其他亚型，对选择性抑制剂及其抑制作用的了解却很少。本报告描述了取代的苯氧肟酸作为有效的和选择性的HDAC8抑制剂的发展。使用可用晶体结构的对接研究已用于该系列化合物的基于结构的优化。在这项研究中，我们研究了HDAC8在癌细胞增殖中的作用，并优化了体外和细胞培养中命中率和选择性的命中。基于结构的设计，综合，
• Structure-Based Design and Synthesis of Novel Inhibitors Targeting HDAC8 from <i>Schistosoma mansoni</i> for the Treatment of Schistosomiasis
  作者：Tino Heimburg、Alokta Chakrabarti、Julien Lancelot、Martin Marek、Jelena Melesina、Alexander-Thomas Hauser、Tajith B. Shaik、Sylvie Duclaud、Dina Robaa、Frank Erdmann、Matthias Schmidt、Christophe Romier、Raymond J. Pierce、Manfred Jung、Wolfgang Sippl

  DOI：10.1021/acs.jmedchem.5b01478

  日期：2016.3.24

  Schistosomiasis is a major neglected parasitic disease that affects more than 265 million people worldwide and for which the control strategy consists of mass treatment with the only available drug, praziquantel. In this study, a series of new benzohydroxamates were prepared as potent inhibitors of Schistosoma mansoni histone deacetylase 8 (smHDAC8). Crystallographic analysis provided insights into the: inhibition mode of smHDAC8 activity by these 3-amidobenzohydroxamates. The newly designed inhibitors were evaluated in screens for enzyme inhibitory activity against schistosome and human HDACs. Twenty-seven compounds were found to be active in the nanomolar range, and some of them showed selectivity toward smHDAC8 over the major human HDACs (I and 6). The active benzohydroxamates were additionally screened for lethality against the schistosome larval stage using a fluorescence-based assay. Four of these showed significant dose-dependent killing of the schistosome larvae and markedly impaired egg laying of adult worm pairs maintained in culture.
• Discovery of N-hydroxy-3-alkoxybenzamides as direct acid sphingomyelinase inhibitors using a ligand-based pharmacophore model
  作者：Kan Yang、Keyi Nong、Qinlan Gu、Jibin Dong、Jinxin Wang

  DOI：10.1016/j.ejmech.2018.03.065

  日期：2018.5

  Acid sphingomyelinase (ASM) has been shown to be involved in many physiological processes, emerging to be a promising drug target. In this study, we constructed a ligand-based pharmacophore model of ASM inhibitors and applied this model to optimize the lead compound alpha-mangostin, a known inhibitor of ASM. 23 compounds were designed and evaluated in vitro for ASM inhibition, of these, 10 compounds were found to be more potent than alpha-mangostin. This high hit ratio confirmed that the presented model is very effective and practical. The most potent hit, 1c, was found to selectively and competitively inhibit the enzyme and inhibit the generation of ceramide in a dose-dependent manner. Furthermore, 1c showed favorable anti-apoptosis and anti-inflammatory activity. Interactions with key residues and the Zn2+ cofactor of 1c were found by docking simulation. These results provide promising leads and important guidance for further development of efficient ASM inhibitors and drug candidates. (C) 2018 Elsevier Masson SAS. All rights reserved.