Design, synthesis and biological evaluation of novel 6-alkenylamides substituted of 4-anilinothieno[2,3-d]pyrimidines as irreversible epidermal growth factor receptor inhibitors
Design, synthesis and biological evaluation of novel 6-alkenylamides substituted of 4-anilinothieno[2,3-d]pyrimidines as irreversible epidermal growth factor receptor inhibitors
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替代4-苯胺噻吩并[2,3-d]嘧啶的新型6-烯基酰胺作为不可逆表皮生长因子受体抑制剂的设计、合成和生物学评价
DOI：
10.1016/j.bmc.2014.01.035
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发表时间：
2014-04-01
影响因子：
3.5
通讯作者：
Liu, Hong
中科院分区：
文献类型：
--
作者：
Ji, Xun;Peng, Ting;Liu, Hong
设计、合成了一系列6-烯基酰胺类4-苯胺基噻吩并[2，3-d]嘧啶衍生物，并对其作为表皮生长因子受体（EGFR）的不可逆抑制剂进行了评价。大多数化合物对EGFR野生型（EGFR wt）和EGFR T790 M/L 858 R表现出良好的效力。其中，17种化合物对EGFR wt的半数最大抑制浓度（IC 50）值小于0.020 μ M，12种化合物的IC 50值小于0.010 μ M。10个化合物对EGFR T790 M/L 858 R的IC 50值小于0.005 μ M。化合物8l、9 n、9 o、9 q和9v在1 μ M时几乎完全阻断A431细胞系中EGFR的磷酸化。化合物8l、9 n、9 o、9 q和9v在高浓度（1 μ M）下阻断NCI-H1975细胞中EGFR的自磷酸化，并且通过稀释法证实化合物8l是不可逆的抑制剂。(c)2014由Elsevier Ltd.出版
A novel series of 6-alkenylamides of 4-anilinothieno[2,3-d]pyrimidine derivatives was designed, synthesized and evaluated as irreversible inhibitors of the epidermal growth factor receptor (EGFR). Most of the compounds exhibited good potency against EGFR wild type (EGFR wt) and EGFR T790M/L858R. Among these, the half-maximal inhibitory concentration (IC50) values of 17 compounds against EGFR wt were less than 0.020 mu M, and those of 12 compounds were less than 0.010 mu M. The IC50 values of 10 compounds against EGFR T790M/L858R were less than 0.005 mu M. Compounds 8l, 9n, 9o, 9q and 9v almost completely blocked the phosphorylation of EGFR in the A431 cell line at 1 mu M. Compounds 8l, 9n, 9o, 9q and 9v blocked the autophosphorylation of EGFR in NCI-H1975 cells at high concentration (1 mu M), and compound 8l was confirmed to be an irreversible inhibitor through the dilution method. (c) 2014 Published by Elsevier Ltd.