N-phenyl-N'-(3-(((6,7-dimethoxyquinazolin-4-yl)amino)methyl)phenyl)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: N-phenyl-N'-(3-(((6,7-dimethoxyquinazolin-4-yl)amino)methyl)phenyl)urea
• 英文别名: N-phenyl-N'-{3-[(6,7-dimethoxyquinazoline-4-amino)methyl]phenyl}urea；1-[3-[[(6,7-Dimethoxyquinazolin-4-yl)amino]methyl]phenyl]-3-phenylurea；1-[3-[[(6,7-dimethoxyquinazolin-4-yl)amino]methyl]phenyl]-3-phenylurea
• 化学式: C₂₄H₂₃N₅O₃
• 分子量: 429.478
• InChiKey: ZRGVPLFEUUDIDA-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.9
• 重原子数：
  32
• 可旋转键数：
  7
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.12
• 拓扑面积：
  97.4
• 氢给体数：
  3
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  4-氯-6,7-二甲氧基喹唑啉 在 三乙胺 作用下， 以 二氯甲烷 、 1,2-二氯乙烷 为溶剂， 生成 N-phenyl-N'-(3-(((6,7-dimethoxyquinazolin-4-yl)amino)methyl)phenyl)urea
  参考文献：
  名称：

  Synthesis and in vitro anti-bladder cancer activity evaluation of quinazolinyl-arylurea derivatives

  摘要：

  Based on the structural modification of molecular-targeted agent sorafenib, a series of quinazolinylarylurea derivatives were synthesized and evaluated for their anti-proliferative activities against six human cancer cell lines. Compared with other cell lines tested, T24 was more sensitive to most compounds. Compound 7j exhibited the best profile with lower IC50 value and favorable selectivity. In this study, we focused on 7j-induced death forms of T24 cells and tried to elucidate the reason for its potent proliferative inhibitory activity. Compound 7j treatment could trigger three different cell death forms including apoptosis, ferroptosis, and autophagy; which form would occur depended on the concentrations and incubation time of 7j: (1) Lower concentrations within the initial 8 h of 7j treatment led to apoptosis-dependent death. (2) Ferroptosis and autophagy occurred in the case of higher concentrations combining with extended incubation time through effectively regulating the Sxc(-)/GPx4/ROS and PI3K/ Akt/mTOR/ULK1 pathways, respectively. (3) The above death forms were closely associated with intracellular ROS generation and decreased mitochondrial membrane potential induced by 7j. In molecular docking and structure-activity relationship analyses, 7j could bind well to the active site of the corresponding receptor glutathione peroxidase 4 (GPx4). Compound 7j could be a promising lead for molecular-targeted anti-bladder cancer agents' discovery. (C) 2020 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2020.112661

文献信息

• 具有抗肿瘤作用的喹唑啉-芳基脲衍生物及其应 用
  申请人：广西师范大学

  公开号：CN104292170B

  公开（公告）日：2016-06-29

  本发明涉及具有抗肿瘤作用的通式（Ⅱ）表示的喹唑啉-芳基脲衍生物及其应用。通式（Ⅱ）中取代基的定义见说明书。本发明以索拉非尼和吉非替尼为先导化合物，保留索拉非尼的药效团——脲基；同时，保留吉非替尼等EGFR-TKIs中的喹唑啉环，合成并得到一系列喹唑啉-芳基脲衍生物，经体外活性测试，部分化合物表现出优异的抗肿瘤活性，此类衍生物具有较高的研究与实用价值。（Ⅱ）。
• Design, synthesis, and biological evaluation of novel quinazolinyl-diaryl urea derivatives as potential anticancer agents
  作者：Jia-Nian Chen、Xian-Fu Wang、Ting Li、De-Wen Wu、Xiao-Bo Fu、Guang-Ji Zhang、Xing-Can Shen、Heng-Shan Wang

  DOI：10.1016/j.ejmech.2015.10.045

  日期：2016.1

  Through a structure-based molecular hybridization approach, a series of novel quinazolinyl-diaryl urea derivatives were designed, synthesized, and screened for their in vitro antiproliferative activities against three cancer cell lines (HepG2, MGC-803, and A549). Six compounds (7g, 7m, 7o, 8e, 8g, and 8m) showed stronger activity against a certain cell line compared with the positive reference drugs sorafenib and gefitinib. Among the six compounds, 8g exhibited the strongest activity. In particular, compound 8g induced A549 apoptosis, arrested cell cycle at the G0/G1 phase, elevated intracellular reactive oxygen species level, and decreased mitochondrial membrane potential. This compound can also effectively regulate the expression of apoptosis- and cell cycle-related proteins, and influence the Raf/MEK/ERK pathway. Molecular docking and structure activity relationship analyses revealed that it can bind well to the active site of the receptor c-Raf, which was consistent with the biological data. Therefore, compound 8g may be a potent antitumor agent, representing a promising lead for further optimization. (C) 2015 Elsevier Masson SAS. All rights reserved.
• Synthesis and in vitro anti-bladder cancer activity evaluation of quinazolinyl-arylurea derivatives
  作者：Jia-Nian Chen、Ting Li、Li Cheng、Tai-Sheng Qin、Ye-Xiang Sun、Chu-Ting Chen、Yue-Zhen He、Guang Liu、Di Yao、Ying Wei、Qiu-Yin Li、Guang-Ji Zhang

  DOI：10.1016/j.ejmech.2020.112661

  日期：2020.11

  Based on the structural modification of molecular-targeted agent sorafenib, a series of quinazolinylarylurea derivatives were synthesized and evaluated for their anti-proliferative activities against six human cancer cell lines. Compared with other cell lines tested, T24 was more sensitive to most compounds. Compound 7j exhibited the best profile with lower IC50 value and favorable selectivity. In this study, we focused on 7j-induced death forms of T24 cells and tried to elucidate the reason for its potent proliferative inhibitory activity. Compound 7j treatment could trigger three different cell death forms including apoptosis, ferroptosis, and autophagy; which form would occur depended on the concentrations and incubation time of 7j: (1) Lower concentrations within the initial 8 h of 7j treatment led to apoptosis-dependent death. (2) Ferroptosis and autophagy occurred in the case of higher concentrations combining with extended incubation time through effectively regulating the Sxc(-)/GPx4/ROS and PI3K/ Akt/mTOR/ULK1 pathways, respectively. (3) The above death forms were closely associated with intracellular ROS generation and decreased mitochondrial membrane potential induced by 7j. In molecular docking and structure-activity relationship analyses, 7j could bind well to the active site of the corresponding receptor glutathione peroxidase 4 (GPx4). Compound 7j could be a promising lead for molecular-targeted anti-bladder cancer agents' discovery. (C) 2020 Elsevier Masson SAS. All rights reserved.