吉非替尼
喹唑啉
化学
硫脲
细胞培养
芳基
铅化合物
突变体
亚胺
T790米
结构-活动关系
表皮生长因子受体抑制剂
生长抑制
硫代酰胺
立体化学
细胞生长
体外
表皮生长因子受体
生物化学
受体
生物
遗传学
有机化学
催化作用
烷基
基因
作者
Mostafa M. Hamed,Dalal A. Abou El Ella,Adam B. Keeton,Gary A. Piazza,Ashraf H. Abadi,Rolf W. Hartmann,Matthias Engel
出处
期刊:ChemMedChem
[Wiley]
日期:2013-07-11
卷期号:8 (9): 1495-1504
被引量:15
标识
DOI:10.1002/cmdc.201300147
摘要
Abstract A group of novel anilinoquinazoline derivatives with variable aryl and heterocyclic substituents at position 6 were synthesized and tested for their EGFR‐inhibitory activity. Aryl and heterocyclic rings were attached to the quinazoline scaffold through different linkages such as imine, amide, and thiourea. Most of the aryl and heterocyclic derivatives showed potent inhibition of wild‐type EGFR with IC 50 values in the low nanomolar range. Among these, thiourea derivatives 6 a , 6 b and compound 10 b also retained significant activity toward the gefitinib‐insensitive EGFR T790M/L858R mutant, displaying up to 24‐fold greater potency than gefitinib. In addition, cell growth inhibitory activity was tested against cancer cell lines with wild‐type (KB cells) and mutant EGFR (H1975 cells). Several compounds including 6 a were found to be more potent than the reference compound gefitinib toward both cell lines, as was the case for compound 10 b against H1975 cells. Therefore, compounds 6 a and 10 b in particular may serve as new leads for the development of inhibitors effective against wild‐type EGFR as well as gefitinib‐resistant mutants.
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