Synthesis and antitumor evaluation of novel 5-substituted-4-hydroxy-8-nitroquinazolines as EGFR signaling-targeted inhibitors
文献类型：期刊论文
| 作者 | Jin, Y ; Li, HY; Lin, LP; Tan, JZ; Ding, J; Luo, XM; Long, YQ
|
| 刊名 | BIOORGANIC & MEDICINAL CHEMISTRY
 |
| 出版日期 | 2005-10-01 |
| 卷号 | 13期号:19页码:5613-5622 |
| 关键词 | EGFR inhibitor quinazolines ErbB-2 breast cancer cellular signaling |
| ISSN号 | 0968-0896 |
| DOI | 10.1016/j.bmc.2005.05.045 |
| 文献子类 | Article |
| 英文摘要 | The synthesis and biological activity of a series of novel 5-substituted-4-hydroxy-8-nitroquinazolines that may function as inhibitors of EGFR- and/or ErbB-2-related oncogenic signaling are described. These compounds were prepared by SNAr reaction of 5-chloro-4-hydroxy-8-nitroquinazo line with alkyl or aryl amines, or alkyl alcohol as nucleophiles. Although the enzyme assay showed a weak inhibition effect against both EGFR and ErbB-2 tyrosine kinases, the cell-based antitumor activity turned out promising. Compounds having 5-anilino substituent exhibit high potency with 5-(4-methoxy)anilino-4-hydroxy-8-nitroquinazoline (1h) being the best dual EGFR/ErbB-2 inhibitors, which effectively inhibited the growth of both EGFR (MDA-MB-468, IC50 < 0-01 mu M) and ErbB-2 (SK-BR-3, IC50 = 13 mu M) overexpressing human tumor cell lines in vitro. More interestingly, the variation of the substituent(s) at the 3- and/or 4-position of the 5-anilino portion was found to modulate the selectivity and potency dramatically. However, compounds having an alkylamino or alkyloxy group at the 5-position of 4-hydroxy-8-nitroquinazolines are essentially inactive. These results are consistent with molecular modeling observations. This study was the first attempt to identify new structural types of dual EGFR/ErbB-2-related signaling inhibitors by incorporation of the anilino group at the 5-position of 4-hydroxy-8-nitroquinazolines' core structure, providing promising new templates for further development of potent inhibitors targeting both EGFR and ErbB-2 tyrosine kinases. (c) 2005 Elsevier Ltd. All rights reserved. |
| WOS关键词 | GROWTH-FACTOR RECEPTOR ; TYROSINE KINASE INHIBITORS ; CANCER |
| WOS研究方向 | Biochemistry & Molecular Biology ; Pharmacology & Pharmacy ; Chemistry |
| 语种 | 英语 |
| WOS记录号 | WOS:000231663300010 |
| 出版者 | PERGAMON-ELSEVIER SCIENCE LTD |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/273793]  |
| 专题 | 药物化学研究室 中科院受体结构与功能重点实验室 新药研究国家重点实验室 |
| 通讯作者 | Long, YQ |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai Inst Biol Sci, Drug Discovery & Design Ctr,Grad Sch, Shanghai 201203, Peoples R China 2.Chinese Acad Sci, Grad Sch, Shanghai Inst Biol Sci, Shanghai Inst Mat Med,State Key Lab Drug Res, Shanghai 201203, Peoples R China 3.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai Inst Biol Sci, Div Antitumor Pharmacol, Shanghai 201203, Peoples R China |
| 推荐引用方式 GB/T 7714 | Jin, Y,Li, HY,Lin, LP,et al. Synthesis and antitumor evaluation of novel 5-substituted-4-hydroxy-8-nitroquinazolines as EGFR signaling-targeted inhibitors[J]. BIOORGANIC & MEDICINAL CHEMISTRY,2005,13(19):5613-5622. |
| APA | Jin, Y.,Li, HY.,Lin, LP.,Tan, JZ.,Ding, J.,...&Long, YQ.(2005).Synthesis and antitumor evaluation of novel 5-substituted-4-hydroxy-8-nitroquinazolines as EGFR signaling-targeted inhibitors.BIOORGANIC & MEDICINAL CHEMISTRY,13(19),5613-5622. |
| MLA | Jin, Y,et al."Synthesis and antitumor evaluation of novel 5-substituted-4-hydroxy-8-nitroquinazolines as EGFR signaling-targeted inhibitors".BIOORGANIC & MEDICINAL CHEMISTRY 13.19(2005):5613-5622. |
入库方式： OAI收割
来源：上海药物研究所
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