1-(4-((3-chloro-4-((3-fluorobenzyl)oxy)phenyl)amino)quinazolin-6-yl)urea

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 英文名称: 1-(4-((3-chloro-4-((3-fluorobenzyl)oxy)phenyl)amino)quinazolin-6-yl)urea
• 英文别名: [4-[3-Chloro-4-[(3-fluorophenyl)methoxy]anilino]quinazolin-6-yl]urea；[4-[3-chloro-4-[(3-fluorophenyl)methoxy]anilino]quinazolin-6-yl]urea
• 化学式: C₂₂H₁₇ClFN₅O₂
• 分子量: 437.861
• InChiKey: HUROJPARIBKVDY-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.2
• 重原子数：
  31
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.05
• 拓扑面积：
  102
• 氢给体数：
  3
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  2-氰基-4-硝基苯胺 在 铁粉 、 溶剂黄146 作用下， 以 乙醇 、 水 为溶剂， 反应 8.5h， 生成 1-(4-((3-chloro-4-((3-fluorobenzyl)oxy)phenyl)amino)quinazolin-6-yl)urea
  参考文献：
  名称：

  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

  摘要：

  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.

  DOI：

  10.1016/j.bmcl.2015.10.003

文献信息

• Toward discovery of mutant EGFR inhibitors; Design, synthesis and in vitro biological evaluation of potent 4-arylamino-6-ureido and thioureido-quinazoline derivatives
  作者：Samar Mowafy、A. Galanis、Zainab M. Doctor、Raymond M. Paranal、Deena S. Lasheen、Nahla A. Farag、Pasi A. Jänne、Khaled A.M. Abouzid

  DOI：10.1016/j.bmc.2016.05.063

  日期：2016.8

  evaluated as wild type (WT) and mutant EGFR inhibitors. Most of the compounds inhibited EGFR kinase wild type (EGFR WT) with IC50 values in the low nanomolar range (<0.495–9.05 nM) and displayed more potent cytotoxic effect in BaF/3 expressing EGFR WT than reference compound gefitinib. The anti-proliferative effect of all synthesized compounds against gefitinib insensitive double mutant cell lines Ba/F3

  设计，合成和评价了具有C-6脲基和硫脲基侧链以及在C-4苯胺基部分具有各种取代基的一系列新的4-苯胺基喹唑啉，并将其评估为野生型（WT）和突变型EGFR抑制剂。大多数化合物抑制EGFR激酶野生型（EGFR WT）的IC 50值都在低纳摩尔范围（<0.495–9.05 nM），并且比参考化合物吉非替尼在表达BaF / 3的EGFR WT中显示出更强的细胞毒性作用。测定了所有合成化合物对吉非替尼不敏感的双突变体表达Del19 / T790M的Ba / F3和表达Ba / F3的L858R / T790M的抗增殖作用。化合物4d，6f，7e表现出显着的抑制作用（IC 50 与拉帕替尼（60.1 nM）相比 ，这些突变株中的Hs2 = 1.76–2.38μM，并且具有显着的Her2酶抑制（IC 50 = 19.2–40.6 nM）。证明了化合物6d，6f，7a，7b和8b的结合模式。此外，测试了对
• 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.