2-氯-4-硝基-1-[3-(三氟甲基)苯氧基]-苯 | 40718-13-6

• 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: 2-氯-4-硝基-1-[3-(三氟甲基)苯氧基]-苯
• 英文名称: 2-chloro-4-nitro-1-(3-(trifluoromethyl)phenoxy)benzene
• 英文别名: 2-chloro-4-nitro-1-[3-(trifluoromethyl)phenoxy]benzene
• CAS: 40718-13-6
• 化学式: C₁₃H₇ClF₃NO₃
• 分子量: 317.652
• InChiKey: CKJFVJCOFJYOOX-UHFFFAOYSA-N

物化性质

• 沸点：
  328.1±42.0 °C(Predicted)
• 密度：
  1.461±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.8
• 重原子数：
  21
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.08
• 拓扑面积：
  55
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  2-氯-4-硝基-1-[3-(三氟甲基)苯氧基]-苯 在 盐酸 、 铁粉 作用下， 以 乙醇 、 水 为溶剂， 反应 6.0h， 以82%的产率得到3-氯-4-(3-三氟甲基-苯氧基)-苯胺
  参考文献：
  名称：

  N-（4-苯氧基苯基）苯甲酰胺衍生物作为新型SPAK抑制剂的结构发展，可阻断WNK激酶信号传导。

  摘要：

  我们在这里报告的N-（4-苯氧基苯基）苯甲酰胺衍生物作为新型SPAK（STE20 / SPS1相关脯氨酸/富含丙氨酸的激酶）抑制剂的结构发展。具有OSR1（氧化应激反应激酶1）/ SPAK和NCC（NaCl协同转运蛋白）的无赖氨酸激酶（WNK）信号级联的异常激活会导致特征性的盐敏感性高血压，因此是WNK-OSR1的抑制剂/ SPAK-NCC级联是抗高血压药物的候选药物。根据前导化合物2的结构，我们研究了N-（4-苯氧基苯基）苯甲酰胺衍生物的SAR ，并开发了作为有效SPAK抑制剂的化合物20l。化合物20l是新型抗高血压药的有希望的候选物。

  DOI：

  10.1016/j.bmcl.2020.127408
• 作为产物：
  描述：

  3-氯-4-氟硝基苯 、 间三氟甲基苯酚 在 potassium carbonate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 2.0h， 生成 2-氯-4-硝基-1-[3-(三氟甲基)苯氧基]-苯
  参考文献：
  名称：

  新型人表皮生长因子受体2（HER2）/表皮生长因子受体（EGFR）双重抑制剂带有吡咯并[3,2- d ]嘧啶骨架的设计与合成

  摘要：

  已经研究了人类表皮生长因子受体2（HER2）和表皮生长因子受体（EGFR）的双重抑制剂可治疗乳腺癌，肺癌，胃癌，前列腺癌和其他癌症。一种是拉帕替尼，目前已获准用于乳腺癌。为了开发新型的HER2 / EGFR双激酶抑制剂，我们设计并合成了能够适合受体ATP结合位点的吡咯并[3,2- d ]嘧啶衍生物。在制备的化合物中，34e显示出有效的HER2和EGFR（HER1）抑制活性以及肿瘤生长抑制活性。34e与HER2和EGFR的X射线共晶体结构表明34e与它们各自的ATP口袋中的预期残基相互作用。此外，由于34e具有良好的口服生物利用度，因此在过表达HER2的肿瘤异种移植模型中显示出强大的体内功效。基于这些发现，我们报道34e（TAK-285）作为一种新型HER2 / EGFR双激酶抑制剂在临床开发中很有希望。

  DOI：

  10.1021/jm2008634

文献信息

• Design and Synthesis of Novel Human Epidermal Growth Factor Receptor 2 (HER2)/Epidermal Growth Factor Receptor (EGFR) Dual Inhibitors Bearing a Pyrrolo[3,2-<i>d</i>]pyrimidine Scaffold
  作者：Tomoyasu Ishikawa、Masaki Seto、Hiroshi Banno、Youichi Kawakita、Mami Oorui、Takahiko Taniguchi、Yoshikazu Ohta、Toshiya Tamura、Akiko Nakayama、Hiroshi Miki、Hidenori Kamiguchi、Toshimasa Tanaka、Noriyuki Habuka、Satoshi Sogabe、Jason Yano、Kathleen Aertgeerts、Keiji Kamiyama

  DOI：10.1021/jm2008634

  日期：2011.12.8

  Dual inhibitors of human epidermal growth factor receptor 2 (HER2) and epidermal growth factor receptor (EGFR) have been investigated for breast, lung, gastric, prostate, and other cancers; one, lapatinib, is currently approved for breast cancer. To develop novel HER2/EGFR dual kinase inhibitors, we designed and synthesized pyrrolo[3,2-d]pyrimidine derivatives capable of fitting into the receptors’

  已经研究了人类表皮生长因子受体2（HER2）和表皮生长因子受体（EGFR）的双重抑制剂可治疗乳腺癌，肺癌，胃癌，前列腺癌和其他癌症。一种是拉帕替尼，目前已获准用于乳腺癌。为了开发新型的HER2 / EGFR双激酶抑制剂，我们设计并合成了能够适合受体ATP结合位点的吡咯并[3,2- d ]嘧啶衍生物。在制备的化合物中，34e显示出有效的HER2和EGFR（HER1）抑制活性以及肿瘤生长抑制活性。34e与HER2和EGFR的X射线共晶体结构表明34e与它们各自的ATP口袋中的预期残基相互作用。此外，由于34e具有良好的口服生物利用度，因此在过表达HER2的肿瘤异种移植模型中显示出强大的体内功效。基于这些发现，我们报道34e（TAK-285）作为一种新型HER2 / EGFR双激酶抑制剂在临床开发中很有希望。
• Navigating into the binding pockets of the HER family protein kinases: discovery of novel EGFR inhibitor as antitumor agent
  作者：Li Cai、Wei Liu、Jin-Feng Ning、Wei-Qing Meng、Jing Hu、Yan-Bin Zhao、Chao Liu

  DOI：10.2147/dddt.s85357

  日期：——

  The epidermal growth factor receptor (EGFR) family has been validated as a successful antitumor drug target for decades. Known EGFR inhibitors were exposed to distinct drug resistance against the various EGFR mutants within non-small-cell lung cancer (NSCLC), particularly the T790M mutation. Although so far a number of studies have been reported on the development of third-generation EGFR inhibitors for overcoming the resistance issue, the design procedure largely depends on the intuition of medicinal chemists. Here we retrospectively make a detailed analysis of the 42 EGFR family protein crystal complexes deposited in the Protein Data Bank (PDB). Based on the analysis of inhibitor binding modes in the kinase catalytic cleft, we identified a potent EGFR inhibitor (compound A-10) against drug-resistant EGFR through fragment-based drug design. This compound showed at least 30-fold more potency against EGFR T790M than the two control molecules erlotinib and gefitinib in vitro. Moreover, it could exhibit potent HER2 inhibitory activities as well as tumor growth inhibitory activity. Molecular docking studies revealed a structural basis for the increased potency and mutant selectivity of this compound. Compound A-10 may be selected as a promising candidate in further preclinical studies. In addition, our findings could provide a powerful strategy to identify novel selective kinase inhibitors on the basis of detailed kinase-ligand interaction space in the PDB.
• Surmounting the resistance against EGFR inhibitors through the development of thieno[2,3-d]pyrimidine-based dual EGFR/HER2 inhibitors
  作者：Sandra N. Milik、Amal Kamal Abdel-Aziz、Deena S. Lasheen、Rabah A.T. Serya、Saverio Minucci、Khaled A.M. Abouzid

  DOI：10.1016/j.ejmech.2018.06.011

  日期：2018.7

  In light of the emergence of resistance against the currently available EGFR inhibitors, our study focuses on tackling this problem through the development of dual EGFR/HER2 inhibitors with improved enzymatic affinities. Guided by the binding mode of the marketed dual EGFR/HER2 inhibitor, Lapatinib, we proposed the design of dual EGFR/HER2 inhibitors based on the 6-phenylthieno[2,3-d]pyrimidine as a core scaffold and hinge binder. After two cycles of screening aiming to identify the optimum aniline headgroup and solubilizing group, we eventually identified 27b as a dual EGFR/HER2 inhibitor with IC50 values of 91.7 nM and 1.2 mu M, respectively. Notably, 27b dramatically reduced the viability of various patient-derived cancer cells preferentially overexpressing EGFR/HER2 (A431, MDA-MBA-361 and SKBr3 with IC50 values of 1.45, 3.5 and 4.83 mu M, respectively). Additionally, 27b efficiently thwarted the proliferation of lapatinib-resistant human non-small lung carcinoma (NCI-H1975) cells, harboring T790 M mutation, with IC50 of 4.2 mu M. Consistently, 27b significantly blocked EGF-induced EGFR activation and inactivated its downstream AKT/mTOR/S6 signalling pathway triggering apoptotic cell death in NCI-H1975 cells. The present study presents a promising candidate for further design and development of novel EGFR/HER2 inhibitors capable of overcoming EGFR TKIs resistance. (C) 2018 Elsevier Masson SAS. All rights reserved.
• Targeting EGFR/HER2 tyrosine kinases with a new potent series of 6-substituted 4-anilinoquinazoline hybrids: Design, synthesis, kinase assay, cell-based assay, and molecular docking
  作者：Ahmed Elkamhawy、Ahmed Karam Farag、Ambily Nath Indu Viswanath、Tarek M. Bedair、Dong Gyu Leem、Kyung-Tae Lee、Ae Nim Pae、Eun Joo Roh

  DOI：10.1016/j.bmcl.2015.10.003

  日期：2015.11

  Coexpression of EGFR and HER2 has been found in many tumors such as breast, ovarian, colon and prostate cancers, with poor prognosis of the patients. Herein, our team has designed and synthesized new eighteen compounds with 6-substituted 4-anilinoquinazoline core to selectively inhibit EGFR/HER2 tyrosine kinases. Twelve compounds (8a-8d, 9a, 9c, 9d, 10a, 10c, 11b, 14, and 15) showed nanomolar range of IC50 values on EGFR and/or HER2 kinases. Accordingly, a detailed structure activity relationship (SAR) was established. A molecular docking study demonstrated the favorable binding modes of 8d, 9b, 9d and 10d at the ATP active site of both kinases. A kinase selectivity profile performed for compound 8d showed great selectivity for EGFR and HER2. In addition, 8d, 9c, and 9d exerted selective promising cytotoxic activity over BT-474 cell line with IC50 values of 2.70, 1.82 and 1.95 mu M, respectively. From these results, we report analogs 8d, 9c, and 9d as promising candidates for the discovery of well-balanced compounds in terms of the kinase inhibitory potency and antiproliferative activity. (C) 2015 Elsevier Ltd. All rights reserved.
• J. Med. Chem. 2011, 54, 8030-8050
  作者：

  DOI：——

  日期：——