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论文类型：期刊论文

发表时间：2018-12-01

发表刊物：CHEMICAL BIOLOGY & DRUG DESIGN

收录刊物：PubMed、SCIE、Scopus

卷号：92

期号：6

页面范围：1972-1980

ISSN号：1747-0277

关键字：ALK; anti-cancer; Crizotinib; glycol diaryl ether; NSCLC

摘要：Crizotinib, a drug for anaplastic lymphoma kinase (ALK) positive and c-ros oncogene 1 receptor tyrosine kinase (ROS1) positive non-small cell lung cancer (NSCLC), was structurally optimized via a strategy of structure-based fragment replacing. Computational study showed it was beneficial for interaction of crizotinib and ALK to increase the distance between pyridyl ring and phenyl ring in crizotinib, and thus, a series of novel glycol diaryl ethers were synthesized. The in vitro anti-tumor activity of synthesized compounds was studied in NSCLC cell line H2228 and neurobalstoma cell line SH-SY5Y. Among the synthesized compounds, 9e exhibits stronger anti-cancer activity than crizotinib toward H2228 cell line with an IC50 value of 0.22 mu M. Molecular docking indicated that a longer chain between pyridyl ring and phenyl ring enabled molecule to have new interaction with a neighboring small hydrophobic pocket.