Design and synthesis of novel substituted naphthyridines as potential c-Met kinase inhibitors based on MK-2461.
Design and synthesis of novel substituted naphthyridines as potential c-Met kinase inhibitors based on MK-2461.
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DOI：
10.1016/j.bmcl.2015.05.082
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发表时间：
2015-08
影响因子：
2.7
通讯作者：
Jing-Fang Wu;Mingming Liu;Shao-Xu Huang;Yang Wang
中科院分区：
文献类型：
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作者：
Jing-Fang Wu;Mingming Liu;Shao-Xu Huang;Yang Wang
以c-Met激酶抑制剂MK-2461为基础，在支架跳跃策略的指导下，设计合成了两个新的1,5-萘啶和1,6-萘啶衍生物系列。用c-Met激酶和体外抗肿瘤活性对Hela和A549细胞株进行检测。结果表明，与1,5-萘啶相比，1,6-萘啶是一个更有前途的c-Met抑制结构核心。其中26band26c表现出最好的酶活性和细胞毒活性。western blot实验表明，26c的细胞毒活性可能部分通过抑制c-Met激酶的磷酸化来实现。
Two series of novel 1,5-naphthyridine and 1,6-naphthyridine derivatives were designed and synthesized based on the c-Met kinase inhibitor MK-2461 under the guidance of scaffold hopping strategy. All were tested on c-Met kinase and in vitro anti-tumor activities against Hela and A549 cell lines. The results indicated that 1,6-naphthyridine was a more promising c-Met inhibitory structure core compared with 1,5-naphthyridine. Among them,26band26cshowed the best enzymic and cytotoxic activities. The western blot experiments implied that the cytotoxic activity of26cmight be partially through suppressing the phosphorylation of c-Met kinase.