1,2-difluoro-4-(isocyanatomethyl)benzene | 866538-73-0

• 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: 1,2-difluoro-4-(isocyanatomethyl)benzene
• CAS: 866538-73-0
• 化学式: C₈H₅F₂NO
• 分子量: 169.131
• InChiKey: DIZUMMHPEYKKJL-UHFFFAOYSA-N

物化性质

• 沸点：
  204.6±30.0 °C(Predicted)
• 密度：
  1.20±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.9
• 重原子数：
  12
• 可旋转键数：
  2
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.12
• 拓扑面积：
  29.4
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  1,2-difluoro-4-(isocyanatomethyl)benzene 在 硫酸 、 1,8-二氮杂双环[5.4.0]十一碳-7-烯 作用下， 以 乙腈 为溶剂， 反应 6.0h， 生成 5-[(3,4-Difluorophenyl)methyl]-11-[(4-methoxyphenyl)methyl]-3,5,7,9,11,13-hexazatricyclo[8.3.0.02,6]trideca-1(10),2,6,8,12-pentaen-4-one
  参考文献：
  名称：

  Structure-based drug design and potent anti-cancer activity of tricyclic 5:7:5-fused diimidazo[4,5-d:4′,5′-f][1,3]diazepines

  摘要：

  Judicial structural modifications of 5: 7-fused ring-expanded nucleosides (RENs), based on molecular modeling studies with one of its known targets, human RNA helicase (hDDX3), led to the lead, novel, 5:7-5-fused tricyclic heterocycle (1). The latter exhibited promising broad-spectrum in vitro anti-cancer activity against a number of cancer cell lines screened. This paper describes our systematic, albeit limited, structure-activity relationship (SAR) studies on this lead compound, which produced a number of analogs with broad-spectrum in vitro anti-cancer activities against lung, breast, prostate, and ovarian cancer cell lines, in particular compounds 15i, 15j, 15m and 15n which showed IC50 values in submicromolar to micromolar range, and are worthy of further explorations. The SAR data also enabled us to propose a tentative SAR model for future SAR efforts for ultimate realization of optimally active and minimally toxic anti-cancer compounds based on the diimidazo[4,5-d:4',5'-f][1,3]diazepine structural skeleton of the lead compound 1. (C) 2012 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2012.11.050
• 作为产物：
  描述：

  3,4-二氟苯乙酸 在 叠氮磷酸二苯酯 、 三乙胺 作用下， 以 甲苯 为溶剂， 反应 1.25h， 生成 1,2-difluoro-4-(isocyanatomethyl)benzene
  参考文献：
  名称：

  Structure-based drug design and potent anti-cancer activity of tricyclic 5:7:5-fused diimidazo[4,5-d:4′,5′-f][1,3]diazepines

  摘要：

  Judicial structural modifications of 5: 7-fused ring-expanded nucleosides (RENs), based on molecular modeling studies with one of its known targets, human RNA helicase (hDDX3), led to the lead, novel, 5:7-5-fused tricyclic heterocycle (1). The latter exhibited promising broad-spectrum in vitro anti-cancer activity against a number of cancer cell lines screened. This paper describes our systematic, albeit limited, structure-activity relationship (SAR) studies on this lead compound, which produced a number of analogs with broad-spectrum in vitro anti-cancer activities against lung, breast, prostate, and ovarian cancer cell lines, in particular compounds 15i, 15j, 15m and 15n which showed IC50 values in submicromolar to micromolar range, and are worthy of further explorations. The SAR data also enabled us to propose a tentative SAR model for future SAR efforts for ultimate realization of optimally active and minimally toxic anti-cancer compounds based on the diimidazo[4,5-d:4',5'-f][1,3]diazepine structural skeleton of the lead compound 1. (C) 2012 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2012.11.050

文献信息

• [EN] 4-HYDROXYPIPERIDINE DERIVATIVES AND THEIR USE AS INHIBITORS OF UBIQUITIN SPECIFIC PROTEASE 19 (USP19)<br/>[FR] DÉRIVÉS DE 4-HYDROXYPIPÉRIDINE ET LEUR UTILISATION EN TANT QU'INHIBITEURS DE LA PROTÉASE 19 SPÉCIFIQUE DE L'UBIQUITINE
  申请人：ALMAC DISCOVERY LTD

  公开号：WO2019150119A1

  公开（公告）日：2019-08-08

  Inhibitors of ubiquitin specific protease 19 (USP19) of Formula (I) are provided, together with pharmaceutical compositions comprising said inhibitors, and methods of use thereof. The compounds can be used in in the treatment of muscular atrophy, obesity, insulin resistance or type II diabetes or in reducing the loss of muscle mass.

  提供了公式（I）的泛素特异性蛋白酶19（USP19）的抑制剂，以及包含该抑制剂的药物组合物，以及其使用方法。这些化合物可用于治疗肌肉萎缩、肥胖、胰岛素抵抗或2型糖尿病，或减少肌肉质量的流失。
• Synthesis and biological evaluation of glycogen synthase kinase 3 (GSK-3) inhibitors: An fast and atom efficient access to 1-aryl-3-benzylureas
  作者：Fabio Lo Monte、Thomas Kramer、Alexander Boländer、Batya Plotkin、Hagit Eldar-Finkelman、Ana Fuertes、Juan Dominguez、Boris Schmidt

  DOI：10.1016/j.bmcl.2011.06.131

  日期：2011.9

  approach utilizing readily accessible building blocks and (b) a divergent approach based on a microwave heating assisted Suzuki coupling. We established a chromatography-free purification method to generate products with sufficient purity for the biological assays. The structure–activity relationship of the library provided the rationale for the synthesis of the benzothiazolylurea 66 (IC50 = 140 nM) and the

  糖原合酶激酶3（GSK-3）参与多个细胞过程，并已与阿尔茨海默氏病（AD）的发病机理有关。在我们的研究主题过程中，我们合成了有效的GSK-3抑制剂库。我们利用了有效且高度选择性的GSK-3抑制剂AR-A014418（AstraZeneca）中存在的尿素支架。该部分既适合（a）利用易于获得的构件的收敛方法，又适合（b）基于微波加热辅助的Suzuki耦合的发散方法。我们建立了无色谱纯化方法，以产生具有足够纯度的生物测定产物。文库的构效关系为合成苯并噻唑基脲66（IC 50 在我们的测定中 ，其活性为 140 nM）和吡啶基脲62（IC 50 = 98 nM），与参考化合物18（AR-A014418：IC 50 = 330 nM）相比，其活性提高了2到3倍。
• 3-Hydroxypyrimidine-2,4-dione-5-<i>N</i>-benzylcarboxamides Potently Inhibit HIV-1 Integrase and RNase H
  作者：Bulan Wu、Jing Tang、Daniel J. Wilson、Andrew D. Huber、Mary C. Casey、Juan Ji、Jayakanth Kankanala、Jiashu Xie、Stefan G. Sarafianos、Zhengqiang Wang

  DOI：10.1021/acs.jmedchem.6b00040

  日期：2016.7.14

  of INST as the antiviral mechanism of action, selected antiviral analogues also potently inhibited reverse transcriptase (RT) associated RNase H, implying potential dual target inhibition. In vitro ADME assays demonstrated that this novel chemotype possesses largely favorable physicochemical properties suitable for further development.

  人类免疫缺陷病毒（HIV）对已知药物方案的耐药性选择需要发现具有独特耐药性的结构新颖的抗病毒药物。基于我们先前报道的3-hydroxypyrimidine-2,4-dione（HPD）核心，我们设计并合成了一种新型的整合酶链转移（INST）抑制剂类型，其特征是5- N-苄基羧酰胺部分。重要的是，这种新化学型的6-烷基氨基变体始终赋予针对HIV-1的低纳摩尔抑制活性。针对一些对拉格列韦耐药的HIV-1克隆进行的扩展抗病毒测试显示，其耐药性与第二代INST抑制剂（INSTI）dolutegravir相似。尽管生化测试和分子模型也强烈证实了INST作为抗病毒作用机制的抑制作用，但所选的抗病毒类似物也有效抑制了逆转录酶（RT）相关的RNase H，暗示了潜在的双重靶标抑制作用。体外ADME分析表明，这种新的化学型具有非常有利的理化性质，适合进一步开发。
• Assessment of the structure-activity relationship and antileukemic activity of diacylpyramide compounds as human ClpP agonists
  作者：Ranran Zhang、Pengyu Wang、Bingyan Wei、Liang Chen、Xiaomin Song、Yihui Pan、Jiahui Li、Jianhua Gan、Tao Zhang、Cai-Guang Yang

  DOI：10.1016/j.ejmech.2023.115577

  日期：2023.10

  (ClpP) is required for the regulatory hydrolysis of mitochondrial proteins. Allosteric ClpP agonists dysfunctionally activate mitochondrial ClpP in antileukemic therapies. We previously developed ZG111, a potent ClpP agonist derived from ICG-001, inhibits the proliferation of pancreatic ductal adenocarcinoma cell lines in vitro and in vivo by degrading respiratory chain complex proteins. Herein, we studied

  线粒体蛋白的调节性水解需要人酪蛋白分解酶 P (ClpP) 。在抗白血病治疗中，变构 ClpP 激动剂会功能失调地激活线粒体 ClpP 。我们之前开发了ZG111 ，一种源自ICG-001的有效 ClpP 激动剂，通过降解呼吸链复合蛋白在体外和体内抑制胰腺导管腺癌细胞系的增殖。在此，我们研究了ICG-001类似物作为抗白血病药物的构效关系。与ZG111的稳定作用相比，化合物ZG36对急性髓系白血病（AML）细胞系中ClpP的热稳定性表现出改善的稳定作用，表明ZG36和ClpP之间的直接结合。事实上，解析的ZG36 /ClpP 结构复合物揭示了ZG36在 ClpP 结合过程中的作用模式。化合物ZG36非选择性降解呼吸链复合物并减少线粒体 DNA，最终导致线粒体功能崩溃和白血病细胞死亡。最后， ZG36治疗可抑制体外3-D 细胞生长，并抑制异种移植小鼠模型中 AML 细胞的肿瘤发生。 总的来说，我们开发了一种新型人类
• WO2020115501A5
  申请人：——

  公开号：WO2020115501A5

  公开（公告）日：2022-12-13