1-(2-((4-((3-chloro-4-fluorophenyl)amino)-7-ethoxyquinazolin-6-yl)amino)ethyl)-1,3-dimethylthiourea

• 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-(2-((4-((3-chloro-4-fluorophenyl)amino)-7-ethoxyquinazolin-6-yl)amino)ethyl)-1,3-dimethylthiourea
• 英文别名: 1-[2-[[4-(3-Chloro-4-fluoroanilino)-7-ethoxyquinazolin-6-yl]amino]ethyl]-1,3-dimethylthiourea；1-[2-[[4-(3-chloro-4-fluoroanilino)-7-ethoxyquinazolin-6-yl]amino]ethyl]-1,3-dimethylthiourea
• 化学式: C₂₁H₂₄ClFN₆OS
• 分子量: 462.979
• InChiKey: FWEOLULOLSUCTN-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.4
• 重原子数：
  31
• 可旋转键数：
  8
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  106
• 氢给体数：
  3
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  氯(三乙基膦)金(I) 、 1-(2-((4-((3-chloro-4-fluorophenyl)amino)-7-ethoxyquinazolin-6-yl)amino)ethyl)-1,3-dimethylthiourea 在 silver nitrate 作用下， 以 四氢呋喃 、 甲醇 为溶剂， 以46%的产率得到[Au(1-(2-((4-((3-chloro-4-fluorophenyl)amino)-7-ethoxyquinazolin-6-yl)amino)ethyl)-1,3-dimethylthiourea)PEt3](NO3)
  参考文献：
  名称：

  Synthesis, Reactivity, and Biological Activity of Gold(I) Complexes Modified with Thiourea-Functionalized Tyrosine Kinase Inhibitors

  摘要：

  Thiourea-modified 3-chloro-4-fluoroanilino-quinazoline derivatives have been studied as potential receptor-targeted carrier ligands in linear gold(I) complexes. The molecules mimic the epidermal growth factor receptor (EGFR) tyrosine kinase-targeted inhibitor gefitinib. Thiourea groups were either directly attached to quinazoline-C6 (compounds 4, 5, and 7) or linked to this position via a flexible ethylamino chain (compound 9). Compound 7 acts as a thiourea-S/quinazoline-N1 mixed-donor ligand, giving the unexpected dinuclear complex [{Au(mu-7-S,N)}(2)]X-2 (X = Cl-, SCN-) (12a,b) (X-ray crystallography, electrospray mass spectrometry). Derivative 9 forms a stable linear complex, [Au(PEt3)(9-S)](NO3) (13). The biological activity of the carrier ligands and corresponding gold(I) complexes was studied in NCI-H460 and NCI-H1975 lung cancer cells. Compound 9 partially overcomes resistance to gefitinib in NCI-H1975, a lung cancer cell line characterized by a L858R/T790M mutation in EGFR (IC50 values of 1.7 and 30 mu M, respectively). The corresponding gold complex (13) maintains activity in the low-micromolar concentration range similar to the metal-free carrier. Compound 9 and the corresponding [Au(PEt3)] complex, 13, inhibit EGFR kinase-mediated phosphorylation with sub-micromolar IC50 values similar to those observed for gefitinib under the same assay conditions. Potential mechanisms of action and reactions in biological media of this new type of hybrid agent, as well as shortcomings of the current design are discussed.

  DOI：

  10.1021/ic502998a
• 作为产物：
  描述：

  N⁴-(3-chloro-4-fluorophenyl)-7-ethoxyquinazoline-4,6-diamine 在 盐酸 、 水 、 sodium cyanoborohydride 、 溶剂黄146 作用下， 以 甲醇 、 乙醇 为溶剂， 反应 15.0h， 生成 1-(2-((4-((3-chloro-4-fluorophenyl)amino)-7-ethoxyquinazolin-6-yl)amino)ethyl)-1,3-dimethylthiourea
  参考文献：
  名称：

  [EN] FUNCTIONALIZED TYROSINE KINASE INHIBITORS MODIFIED WITH PRECIOUS METAL ELECTROPHILES AND METHODS ASSOCIATED THEREWITH
  [FR] INHIBITEURS FONCTIONNALISÉS DE LA TYROSINE KINASE MODIFIÉS AVEC DES AGENTS ÉLECTROPHILES DE MÉTAL PRÉCIEUX ET LEURS PROCÉDÉS ASSOCIÉS

  摘要：

  新合成的硫脲修饰的3-氯-4-氟苯胺喹唑啉衍生物已被研究，作为线性金(I)配合物中的末端载体配体。这些分子通过计算对接实验模拟了酪氨酸激酶抑制剂吉非替尼。硫脲基团直接连接到喹唑啉-C6上，或通过柔性的乙基氨链连接到该位置。其中一个化合物作为硫脲-S/喹唑啉-Nl混合供体配体，通过X射线晶体学和/或电喷雾质谱确定为非寻常的二核复合物。一个化合物形成所需的稳定线性配合物。在NCI-H460和NCI-H1975肺癌细胞中研究了载体配体和相应的金(I)配合物的生物活性。其中一个被测试的化合物在NCI-H1975中部分克服了对吉非替尼的抵抗（分别具有1.7和30μΜ的IC50值），相应的金配合物（13）在低微摩尔浓度范围内保持活性。

  公开号：

  WO2015142683A1

文献信息

• [EN] FUNCTIONALIZED TYROSINE KINASE INHIBITORS MODIFIED WITH PRECIOUS METAL ELECTROPHILES AND METHODS ASSOCIATED THEREWITH<br/>[FR] INHIBITEURS FONCTIONNALISÉS DE LA TYROSINE KINASE MODIFIÉS AVEC DES AGENTS ÉLECTROPHILES DE MÉTAL PRÉCIEUX ET LEURS PROCÉDÉS ASSOCIÉS
  申请人：UNIV WAKE FOREST

  公开号：WO2015142683A1

  公开（公告）日：2015-09-24

  Newly synthesized thiourea-modified 3-chloro-4-fluoroanilio-quinazoline derivatives have been studied, as terminal carrier ligands in linear gold(I) complexes. The molecules mimic the tyrosine kinase inhibitor gefitinib (by computational docking experiments). Thiourea groups were either directly attached to quinazoline-C6 or linked to this position via a flexible ethylarmino chain. One compound tested acts as a thiourea-S/quinazoline-Nl mixed-donor ligand, giving an unusual dinuclear complex as determined by X-ray crystallography and/or electrospray mass spectrometry. One compound formed the desired stable linear complex. The biological activity of the carrier ligands and corresponding gold(I) complexes was studied in NCI-H460 and NCI-H1975 lung cancer cells. One compound that was tested partially overcomes resistance to gefitmib in NCI-H1975 (with IC50 values of 1.7 and 30 μΜ, respectively), and the corresponding gold complex (13) maintains activity in the low-micromolar concentration range.

  新合成的硫脲修饰的3-氯-4-氟苯胺喹唑啉衍生物已被研究，作为线性金(I)配合物中的末端载体配体。这些分子通过计算对接实验模拟了酪氨酸激酶抑制剂吉非替尼。硫脲基团直接连接到喹唑啉-C6上，或通过柔性的乙基氨链连接到该位置。其中一个化合物作为硫脲-S/喹唑啉-Nl混合供体配体，通过X射线晶体学和/或电喷雾质谱确定为非寻常的二核复合物。一个化合物形成所需的稳定线性配合物。在NCI-H460和NCI-H1975肺癌细胞中研究了载体配体和相应的金(I)配合物的生物活性。其中一个被测试的化合物在NCI-H1975中部分克服了对吉非替尼的抵抗（分别具有1.7和30μΜ的IC50值），相应的金配合物（13）在低微摩尔浓度范围内保持活性。
• FUNCTIONALIZED TYROSINE KINASE INHIBITORS MODIFIED WITH PRECIOUS METAL ELECTROPHILES AND METHODS ASSOCIATED THEREWITH
  申请人：Wake Forest University

  公开号：EP3105240B1

  公开（公告）日：2018-10-17
• Functionalized Tyrosine Kinase Inhibitors Modified with Precious Metal Electrophiles and Methods Associated Therewith
  申请人：WAKE FOREST UNIVERSITY

  公开号：US20170081293A1

  公开（公告）日：2017-03-23

  Newly synthesized thiourea-modified 3-chloro-4-fluoroanilino-quinazoline derivatives have been studied as terminal carrier ligands in linear gold(I) complexes. The molecules mimic the tyrosine kinase inhibitor gefitinib (by computational docking experiments). Thiourea groups were either directly attached to quinazoline-C6 or linked to this position via a flexible ethylamino chain. One compound tested acts as a thiourea-S/quinazoline-N1 mixed-donor ligand, giving an unusual dinuclear complex as determined by X-ray crystallography and/or electrospray mass spectrometry. One compound formed the desired stable linear complex. The biological activity of the carrier ligands and corresponding gold(I) complexes was studied in NCI-H460 and NCI-H1975 lung cancer cells. One compound that was tested partially overcomes resistance to gefitinib in NCI-H1975 (with IC 50 values of 1.7 and 30 μM, respectively), and the corresponding gold complex (13) maintains activity in the low-micromolar concentration range.
• Synthesis, Reactivity, and Biological Activity of Gold(I) Complexes Modified with Thiourea-Functionalized Tyrosine Kinase Inhibitors
  作者：Mu Yang、Amanda J. Pickard、Xin Qiao、Matthew J. Gueble、Cynthia S. Day、Gregory L. Kucera、Ulrich Bierbach

  DOI：10.1021/ic502998a

  日期：2015.4.6

  Thiourea-modified 3-chloro-4-fluoroanilino-quinazoline derivatives have been studied as potential receptor-targeted carrier ligands in linear gold(I) complexes. The molecules mimic the epidermal growth factor receptor (EGFR) tyrosine kinase-targeted inhibitor gefitinib. Thiourea groups were either directly attached to quinazoline-C6 (compounds 4, 5, and 7) or linked to this position via a flexible ethylamino chain (compound 9). Compound 7 acts as a thiourea-S/quinazoline-N1 mixed-donor ligand, giving the unexpected dinuclear complex [Au(mu-7-S,N)}(2)]X-2 (X = Cl-, SCN-) (12a,b) (X-ray crystallography, electrospray mass spectrometry). Derivative 9 forms a stable linear complex, [Au(PEt3)(9-S)](NO3) (13). The biological activity of the carrier ligands and corresponding gold(I) complexes was studied in NCI-H460 and NCI-H1975 lung cancer cells. Compound 9 partially overcomes resistance to gefitinib in NCI-H1975, a lung cancer cell line characterized by a L858R/T790M mutation in EGFR (IC50 values of 1.7 and 30 mu M, respectively). The corresponding gold complex (13) maintains activity in the low-micromolar concentration range similar to the metal-free carrier. Compound 9 and the corresponding [Au(PEt3)] complex, 13, inhibit EGFR kinase-mediated phosphorylation with sub-micromolar IC50 values similar to those observed for gefitinib under the same assay conditions. Potential mechanisms of action and reactions in biological media of this new type of hybrid agent, as well as shortcomings of the current design are discussed.