Design, synthesis and biological evaluation of novel N-(3-amino-4-methoxyphenyl)acrylamide derivatives as selective EGFR(L858R/T790M) kinase inhibitors

doi:10.1016/j.bioorg.2021.105471

	Design, synthesis and biological evaluation of novel N-(3-amino-4-methoxyphenyl)acrylamide derivatives as selective EGFR(L858R/T790M) kinase inhibitors
	Ding, Shi 1,2,3; Dong, Xiaoyong 1; Gao, Ziye 1; Zheng, Xiangshan 1; Ji, Jingchao 1; Zhang, Mingjuan 1; Liu, Fang 1; Wu, Shuang 1; Li, Min 1; Song, Wenshan 1; Shen, Jiwei 1,2,3; Duan, Wenwen4 ; Liu, Ju 1,2,3; Chen, Ye 1,2,3
	2022-01
发表期刊	BIOORGANIC CHEMISTRY (IF:4.5[JCR-2023],4.7[5-Year])
ISSN	0045-2068
EISSN	1090-2120
卷号	118
发表状态	已发表
DOI	10.1016/j.bioorg.2021.105471
摘要	On the basis of N-(3-amino-4-methoxyphenyl)acrylamide scaffold, a series of novel compounds containing 3-substitutional-1-methyl-1H-indole, 2-substitutional pyrrole or thiophene moieties were synthesized and their in vitro antiproliferation activities against A549 and H1975 cell lines were evaluated. The results indicated that most of the compounds showed moderate to excellent antitumor activities. Especially, compounds 9a (A549 IC50 = 1.96 mu M, H1975 IC50 = 0.095 mu M), 17i (A549 IC50 = 4.17 mu M, H1975 IC50 = 0.052 mu M), 17j (A549 IC50 = 1.67 mu M, H1975 IC50 = 0.061 mu M) exhibited comparable antitumor activities and selectivity ratios compared to the positive control osimertinib (A549 IC50 = 2.91 mu M, H1975 IC50 = 0.064 mu M). In vitro inhibitory activities against EGFR kinases containing different mutations were also tested. Compound 17i showed remarkable inhibitory activity (with IC50 value of 1.7 nM) to EGFR(L858R/T790M) kinase and selectivity (22-folds compared to EGFRWT kinase). Furthermore, acridine orange/ethidium bromide (AO/EB) staining assay, cell apoptosis assay, cell cycle distribution assay and wound-healing assay of the compounds 9a and 17i were performed on H1975 cell line. The results showed dose-dependent activities of the induction of apoptosis, G0/G1-phase arrestation and inhibition of migration, which were similar to the positive control osimertinib. Additionally, molecular docking analysis was performed to seek the possible binding mode between the selected compounds (9a, 17i-17j) and EGFR(L858R/T790M) kinase. The results demonstrated that compound 17i is a promising candidate and worth further study.
关键词	N-(3-amino-4-methoxyphenyl)acrylamide derivatives EGFR-TKIs Kinase selectivity Antitumor activity Docking study
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收录类别	SCI ; SCIE ; IC
语种	英语
资助项目	National Natural Science Foundation of China[21807055] ; Pre-declaration Foundation of Liaoning University[LDGY2019002] ; National College Students Innovation and Entrepreneurship Training Program[D202011262238223108] ; Natural Science Foundation of Liaoning Provincial Department of Science and Technology[2019-ZD-0191] ; General Project of Education Department of Liaoning Province[LJC201907]
WOS研究方向	Biochemistry & Molecular Biology ; Chemistry
WOS类目	Biochemistry & Molecular Biology ; Chemistry, Organic
WOS记录号	WOS:000823056200005
出版者	ACADEMIC PRESS INC ELSEVIER SCIENCE
引用统计	正在获取...
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/214743
专题	iHuman研究所_公共科研平台_IT平台
通讯作者	Liu, Ju; Chen, Ye
作者单位	1.Liaoning Univ, Coll Pharm, 66 Chongshan Rd, Shenyang 110036, Peoples R China 2.API Engn Technol Res Ctr Liaoning Prov, 66 Chongshan Rd, Shenyang 110036, Peoples R China 3.Small Mol Targeted Drug R&D Engn Res Ctr Liaoning, 66 Chongshan Rd, Shenyang 110036, Peoples R China 4.ShanghaiTech Univ, iHuman Inst, 393 Middle Huaxia Rd, Shanghai 201210, Peoples R China
推荐引用方式 GB/T 7714	Ding, Shi,Dong, Xiaoyong,Gao, Ziye,et al. Design, synthesis and biological evaluation of novel N-(3-amino-4-methoxyphenyl)acrylamide derivatives as selective EGFR(L858R/T790M) kinase inhibitors[J]. BIOORGANIC CHEMISTRY,2022,118.
APA	Ding, Shi.,Dong, Xiaoyong.,Gao, Ziye.,Zheng, Xiangshan.,Ji, Jingchao.,...&Chen, Ye.(2022).Design, synthesis and biological evaluation of novel N-(3-amino-4-methoxyphenyl)acrylamide derivatives as selective EGFR(L858R/T790M) kinase inhibitors.BIOORGANIC CHEMISTRY,118.
MLA	Ding, Shi,et al."Design, synthesis and biological evaluation of novel N-(3-amino-4-methoxyphenyl)acrylamide derivatives as selective EGFR(L858R/T790M) kinase inhibitors".BIOORGANIC CHEMISTRY 118(2022).