吉非替尼
A431电池
阿法替尼
埃罗替尼
化学
表皮生长因子受体
自磷酸化
喹唑啉
酪氨酸激酶
MTT法
药理学
噻吩
细胞培养
癌症研究
A549电池
细胞生长
生物化学
激酶
体外
立体化学
细胞
细胞周期
受体
医学
生物
蛋白激酶A
有机化学
癌基因
遗传学
作者
Min Zou,Jin Bo,Yanrong Liu,Huiping Chen,Zhang Zhuang-li,Changzheng Zhang,Zhihong Zhao,Liyun Zheng
出处
期刊:Letters in Drug Design & Discovery
[Bentham Science]
日期:2018-11-29
卷期号:16 (2): 102-110
被引量:8
标识
DOI:10.2174/1570180815666180803125935
摘要
Background: With the approval of gefitinib, erlotinib, afatinib, and osimertinib for clinical use, targeting Epidermal Growth Factor Receptor (EGFR) has been intensively pursued. Similar to most therapies, challenges related to the treatment resistance against these drugs have emerged over time, so new EGFR Tyrosine Kinase Inhibitors (TKIs) need to be developed. This study aimed to investigate the potential use of a series of thiophene-bearing quinazoline derivatives as EGFR inhibitors. We designed and synthesized nine quinazolin derivatives, among which five compounds (5e, 5f, 5g, 5h, and 5i) were reported for the first time. </P><P> Methods: Two cancer cell lines, A431 (overexpressing EGFR) and A549 (EGFR wild-type and Kras mutation), were treated by these compounds and subjected to MTT assay. The A431 cells were selected for further treatment (5e) and Western blot analysis. Results: Although the compounds exerted no obvious effects on the proliferation of A549 cells, seven out of the nine compounds significantly inhibited the growth of A431 cells. In particular, the IC50 values of 5e and erlotinib were nearly equal. Western blot results showed that 5e significantly inhibited EGFR autophosphorylation in A431 cells. Structure-activity relationships indicated that quinazolines bearing 6,7-side chains were more potent than those unsubstituted at the 6,7-positions. Moreover, electron-withdrawing hydrophobic groups on the 5-position of the thiophene were preferred, such as chlorine or bromine atom. Conclusion: Nine 4-aminoquinazolin derivatives were designed, synthesized, and evaluated against A431 and A549 cell lines. Seven compounds significantly inhibited the growth of A431 cells. In particular, 5e possessed similar antitumor potency to that of erlotinib.
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