Synthesis, characterization, screening and docking analysis of 4-anilinoquinazoline derivatives as tyrosine kinase inhibitors
文献类型：期刊论文
| 作者 | Lu, Shuang; Zheng, Wei; Ji, Liyun; Luo, Qun; Hao, Xiang; Li, Xianchan; Wang, Fuyi |
| 刊名 | EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
 |
| 出版日期 | 2013-03-01 |
| 卷号 | 61页码:84-94 |
| 关键词 | Receptor Tyrosine Kinase Epidermal Growth Factor Receptor (Egfr) Anilinoquinazoline Inhibitor Docking Analysis |
| ISSN号 | 0223-5234 |
| DOI | 10.1016/j.ejmech.2012.07.036 |
| 英文摘要 | We report here the design and synthesis of a series of 4-anilinoquinazoline derivatives, of which 7 compounds were crystallographically characterized, as epidermal growth factor receptor (EGFR) inhibitors by modifications on the aniline ring or at the 6-alkoxy site of the 6,7-dimethoxy-4-anilinoquinazoline pharmacophore. The relative inhibition efficiency on EGFR of all as-prepared compounds were measured and ordered, and the IC50 values of nine highly active compounds were determined by ELISA. Docking studies indicated that all 4-anilinoquinazoline derivatives could be inserted into the ATP-binding pocket of the EGFR via indirect docking, and that the modifications at the 3'-position of the anilino group and 6-alkoxy site of the quinazoline ring have little interference with the formation of the two essential H-bonds between the N3 of the quinazoline ring and Thr766 through a water molecule, and the N1 of the quinazoline ring and N-H of Met769. The displacing of the phenyl at 4-position with pyridinyl dramatically reduces the activity of the quinazoline pharmacophore, the resulting derivative (10) being the least active compound. The docking results also showed that the formation of new H-bonds between the N-H of the ethylenediamine group linked to the 6-alkoxy site and Asp776/Cys773 in the binding pocket of EGFR makes compounds 19 (IC50= 12.1 +/- 1.6 nM) and 20 (IC50 = 13.6 +/- 0.8 nM) the most potent EGFR inhibitors in this class and worthy of further modification to obtain more potent anticancer compounds. (C) 2012 Elsevier Masson SAS. All rights reserved. |
| 语种 | 英语 |
| WOS记录号 | WOS:000316537200008 |
| 出版者 | ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER |
| 源URL | [http://ir.iccas.ac.cn/handle/121111/54839]  |
| 专题 | 中国科学院化学研究所 |
| 通讯作者 | Luo, Qun |
| 作者单位 | Chinese Acad Sci, Inst Chem, Beijing Natl Lab Mol Sci, CAS Key Lab Analyt Chem Living Biosyst, Beijing 100190, Peoples R China |
| 推荐引用方式 GB/T 7714 | Lu, Shuang,Zheng, Wei,Ji, Liyun,et al. Synthesis, characterization, screening and docking analysis of 4-anilinoquinazoline derivatives as tyrosine kinase inhibitors[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2013,61:84-94. |
| APA | Lu, Shuang.,Zheng, Wei.,Ji, Liyun.,Luo, Qun.,Hao, Xiang.,...&Wang, Fuyi.(2013).Synthesis, characterization, screening and docking analysis of 4-anilinoquinazoline derivatives as tyrosine kinase inhibitors.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,61,84-94. |
| MLA | Lu, Shuang,et al."Synthesis, characterization, screening and docking analysis of 4-anilinoquinazoline derivatives as tyrosine kinase inhibitors".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 61(2013):84-94. |
入库方式： OAI收割
来源：化学研究所
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