Hybrids of MEK inhibitor and NO donor as multitarget antitumor drugs
Hybrids of MEK inhibitor and NO donor as multitarget antitumor drugs
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MEK抑制剂和NO供体的混合体作为多靶点抗肿瘤药物
DOI：
10.1016/j.ejmech.2020.112271
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发表时间：
2020
影响因子：
6.7
通讯作者：
Ping Xu
中科院分区：
文献类型：
--
作者：
Chao Wang;D;an Xi;Han Wang;Yan Niu;Lei Liang;Fengrong Xu;Yihong Peng;Ping Xu
设计合成了一系列MEK抑制剂与一氧化氮供体的杂化化合物。经证实，化合物(18h[4-(3-((3-(2-fluoro-3-((N-methylsulfamoyl)amino)benzyl)-4-methyl-2-oxo-2H-chromen-7-yl)oxy)丙氧基)-3-(苯磺酰基)-1，2，5-恶二唑-2-氧化物]比临床化合物RO5126766对MDAMB-231细胞有更强的抑制作用。化合物18h能显著降低pMEK和PERK的水平，诱导MDA-MB-231细胞凋亡，并在细胞内有效释放NO，表明这些杂交物在表现出MEK抑制剂和NO供体的特性的同时，具有不同于MEK抑制剂和NO供体的作用机制。因此，我们能够报道一系列具有比已知的MEK抑制剂和无供体更好的抗肿瘤效力的多靶点杂交物。
A series of hybrids of MEK inhibitor and nitric oxide donor have been designed and synthesized. Compound18h [4-(3-((3-(2-fluoro-3-((N-methylsulfamoyl)amino)benzyl)-4-methyl-2-oxo-2H-chromen-7-yl)oxy) propoxy)-3-(phenylsulfonyl)-1,2,5-oxadiazole 2-oxide] was proven to be more potent than the clinical compoundRO5126766in MDA-MB-231 cells. Compound18hcan significantly reduce the levels of pMEK and pERK, induce cell apoptosis in MDA-MB-231 cells, and release NO in cells efficiently, suggesting that these hybrids, while displaying the properties of both MEK inhibitors and NO donors have a mechanism of action different from that of MEK inhibitors and NO donors. Thus, we are able to report a series of multitarget hybrids with better antitumor potency than a known MEK inhibitor and NO donor.