Design and synthesis of novel 6-hydroxy-4-methoxy-3- methylbenzofuran-7-carboxamide derivatives as potent Mnks inhibitors by fragment-based drug design
Design and synthesis of novel 6-hydroxy-4-methoxy-3- methylbenzofuran-7-carboxamide derivatives as potent Mnks inhibitors by fragment-based drug design
复制标题
通过基于片段的药物设计设计和合成新型 6-羟基-4-甲氧基-3-甲基苯并呋喃-7-甲酰胺衍生物作为有效的 Mnks 抑制剂
DOI：
10.1016/j.bmc.2018.05.004
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发表时间：
2018
影响因子：
3.5
通讯作者：
Linxiang Zhao
中科院分区：
文献类型：
--
作者：
Shuxiang Wang;Bo Li;Bo Liu;Min Huang;Deyi Li;Lihong Guan;Jie Zang;Dan Liu;Linxiang Zhao
采用片段药物设计法，设计合成了一系列具有不同碳二取代基的6-羟基-4-甲氧基-3-甲基苯并呋喃-7-甲酰胺类Mnks抑制剂。其中，5 b、5i、5 o和8 k对Mnk 2的抑制活性最强，IC_（50）分别为1.45、1.16、3.55和0.27 μ M。这些化合物对Mnk 1的活性均有抑制作用。此外，化合物5 o和8 k对人白血病细胞株THP-1和MOLM-13以及结肠癌细胞株HCT-116具有抗增殖作用。Western blot结果显示，8 k可剂量依赖性地降低HCT-116细胞p-eIF 4 E的表达。对接研究表明8 k和Mnk 2之间存在强相互作用。因此，这种独特的苯并呋喃支架显示出作为具有改善的效力的有效Mnks抑制剂进一步开发的巨大潜力。
A novel series of 6-hydroxy-4-methoxy-3-methylbenzofuran-7-carboxamide derivatives featured with.various C-2 substituents were designed and synthesized as Mnks inhibitors through fragment-based drug.design. Among them, 5b, 5i, 5o and 8k showed the best Mnk2 inhibitory activity with IC50 values of 1.45,.1.16, 3.55 and 0.27 lM, respectively. And these compounds inhibited the activity of Mnk1 at the same.time. Furthermore, compounds 5o and 8k exhibited anti-proliferative effects to human leukemia cancer.THP-1 and MOLM-13 cell lines and colon cancer HCT-116 cell line. Moreover, Western blot assay.suggested that 8k could decrease the levels of p-eIF4E in a dose-dependent manner in HCT-116.cells. Docking studies demonstrated strong interactions between 8k and Mnk2. Therefore, this unique.benzofuran scaffold demonstrated great potential to be further explored as potent Mnks inhibitors with.improved potency.