N⁴-(3-hydroxyphenyl)quinazoline-4,6-diamine | 1428063-79-9

• 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: N⁴-(3-hydroxyphenyl)quinazoline-4,6-diamine
• 英文别名: 3-((6-aminoquinazolin-4-yl)amino)phenol；3-((6-Aminoquinazolin-4-YL)amino)phenol；3-[(6-aminoquinazolin-4-yl)amino]phenol
• CAS: 1428063-79-9
• 化学式: C₁₄H₁₂N₄O
• 分子量: 252.275
• InChiKey: SAOOQKBWRMJPEW-UHFFFAOYSA-N

物化性质

• 沸点：
  497.1±35.0 °C(Predicted)
• 密度：
  1.427±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.4
• 重原子数：
  19
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  84.1
• 氢给体数：
  3
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  potassium cyanate 、 N⁴-(3-hydroxyphenyl)quinazoline-4,6-diamine 在 溶剂黄146 作用下， 反应 2.0h， 以86%的产率得到[4-(3-Hydroxyanilino)quinazolin-6-yl]urea
  参考文献：
  名称：

  Design, synthesis and in vitro anti-proliferative activity of 4,6-quinazolinediamines as potent EGFR-TK inhibitors

  摘要：

  4-Anilino-6-substituted-quinazolines were designed, synthesized and evaluated for EGFR-TK and tumor growth inhibitory activities. The target compounds were designed with enamine ester or urea moieties appended at the C-6 of quinazoline as additional hydrogen bond acceptor functions. Most of the synthesized compounds displayed potent EGFR-TK inhibitory activity at 10 mu M and the 6-ureido-anilinoquinazoline derivative 7a showed IC50 value of 0.061 mu M. Moreover, six compounds were tested by National Cancer Institute (NCI), USA for their anti-proliferative activity at 10 mu M in full NCI 60 cell panel. Compound 7a was further assayed for five dose molar ranges in full NCI 60 cell panel and exhibited remarkable growth inhibitory activity pattern against Non-Small Cell Lung Cancer EKVX (GI(50) = 037 mu M), NCI-H322M (GI(50) = 0.36 mu M), Renal Cancer A498 (GI(50) = 0.46 mu M), TK-10 (GI(50) = 0.99 mu M) and Breast Cancer MDA-MB-468 (GI(50) = 1.096 mu M) which are of high EGFR expression. Docking study was performed for the active compounds into ATP binding site of EGFR-TK which showed similar binding mode to gefitinib and additional binding with Cys-773 at the gatekeeper of EGFR-TK enzyme. (C) 2012 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2012.10.017
• 作为产物：
  描述：

  2-氰基-4-硝基苯胺 在 乙酸酐 、 tin(ll) chloride 作用下， 以 甲醇 、 溶剂黄146 为溶剂， 反应 26.0h， 生成 N⁴-(3-hydroxyphenyl)quinazoline-4,6-diamine
  参考文献：
  名称：

  表皮生长因子受体激酶和NF-κB活性的第一个双特异性抑制剂作为新型抗癌药。

  摘要：

  NF-κB转录因子的激活是用EGFR激酶抑制剂治疗后诱导的主要适应性反应，导致在非小细胞肺癌和其他肿瘤类型中出现耐药性。为了抑制这种存活机制，我们开发了新的硫脲喹唑啉衍生物，它们既是EGFR激酶又是NF-κB活性的双重抑制剂。在NF-κB报告基因分析中确定的最佳命中化合物可导致化合物9b表现出对IC的NF-κB抑制力为0.3μM的细胞IC 50，同时保留了有效的EGFR激酶抑制作用（IC 50= 60 nM）。在体外和体内异种移植模型中，双重抑制剂均显示出比吉非替尼更高的抑制EGFR过表达肿瘤细胞系细胞生长的效力，但未观察到毒性迹象。对NF-κB抑制的分子机制的研究表明，双重抑制剂耗尽了细胞核中NF-κB复合物的转录共激活因子CREB结合蛋白。

  DOI：

  10.1021/acs.jmedchem.6b01774

文献信息

• Design, synthesis and in vitro anti-proliferative activity of 4,6-quinazolinediamines as potent EGFR-TK inhibitors
  作者：Samar Mowafy、Nahla A. Farag、Khaled A.M. Abouzid

  DOI：10.1016/j.ejmech.2012.10.017

  日期：2013.3

  4-Anilino-6-substituted-quinazolines were designed, synthesized and evaluated for EGFR-TK and tumor growth inhibitory activities. The target compounds were designed with enamine ester or urea moieties appended at the C-6 of quinazoline as additional hydrogen bond acceptor functions. Most of the synthesized compounds displayed potent EGFR-TK inhibitory activity at 10 mu M and the 6-ureido-anilinoquinazoline derivative 7a showed IC50 value of 0.061 mu M. Moreover, six compounds were tested by National Cancer Institute (NCI), USA for their anti-proliferative activity at 10 mu M in full NCI 60 cell panel. Compound 7a was further assayed for five dose molar ranges in full NCI 60 cell panel and exhibited remarkable growth inhibitory activity pattern against Non-Small Cell Lung Cancer EKVX (GI(50) = 037 mu M), NCI-H322M (GI(50) = 0.36 mu M), Renal Cancer A498 (GI(50) = 0.46 mu M), TK-10 (GI(50) = 0.99 mu M) and Breast Cancer MDA-MB-468 (GI(50) = 1.096 mu M) which are of high EGFR expression. Docking study was performed for the active compounds into ATP binding site of EGFR-TK which showed similar binding mode to gefitinib and additional binding with Cys-773 at the gatekeeper of EGFR-TK enzyme. (C) 2012 Elsevier Masson SAS. All rights reserved.
• First Bispecific Inhibitors of the Epidermal Growth Factor Receptor Kinase and the NF-κB Activity As Novel Anticancer Agents
  作者：Mostafa M. Hamed、Sarah S. Darwish、Jennifer Herrmann、Ashraf H. Abadi、Matthias Engel

  DOI：10.1021/acs.jmedchem.6b01774

  日期：2017.4.13

  0.3 μM while retaining a potent EGFR kinase inhibition (IC50 = 60 nM). The dual inhibitors showed a higher potency than gefitinib to inhibit cell growth of EGFR-overexpressing tumor cell lines in vitro and in a xenograft model in vivo, while no signs of toxicity were observed. An investigation of the molecular mechanism of NF-κB suppression revealed that the dual inhibitors depleted the transcriptional

  NF-κB转录因子的激活是用EGFR激酶抑制剂治疗后诱导的主要适应性反应，导致在非小细胞肺癌和其他肿瘤类型中出现耐药性。为了抑制这种存活机制，我们开发了新的硫脲喹唑啉衍生物，它们既是EGFR激酶又是NF-κB活性的双重抑制剂。在NF-κB报告基因分析中确定的最佳命中化合物可导致化合物9b表现出对IC的NF-κB抑制力为0.3μM的细胞IC 50，同时保留了有效的EGFR激酶抑制作用（IC 50= 60 nM）。在体外和体内异种移植模型中，双重抑制剂均显示出比吉非替尼更高的抑制EGFR过表达肿瘤细胞系细胞生长的效力，但未观察到毒性迹象。对NF-κB抑制的分子机制的研究表明，双重抑制剂耗尽了细胞核中NF-κB复合物的转录共激活因子CREB结合蛋白。