Discovery of novel ( )-Usnic acid derivatives as potential anti-leukemia agents with pan-Pim kinases inhibitory activity
Discovery of novel ( )-Usnic acid derivatives as potential anti-leukemia agents with pan-Pim kinases inhibitory activity
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发现新型 ( )-松萝酸衍生物作为具有泛 Pim 激酶抑制活性的潜在抗白血病药物
DOI：
10.1016/j.bioorg.2019.102971
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发表时间：
2019
影响因子：
5.1
通讯作者：
Zhao Linxiang
中科院分区：
文献类型：
--
作者：
Wang Shuxiang;Zang Jie;Huang Min;Guan Lihong;Xing Kun;Zhang Jian;Liu Dan;Zhao Linxiang
松萝酸（UA）是地衣中的主要次级代谢产物，具有中等的抗癌活性。设计并合成了一小部分以黄烷酮为特征的（+）-UA衍生物，并对它们的白血病细胞进行了抗肿瘤活性评价。结果表明，（+）-UA衍生物6a-6 g对白血病细胞HL-60和K562具有较低的微摩尔IC_（50）。研究了6 g诱导HL-60和K562细胞凋亡的作用机制，并对MNK/eIF 4 E轴相关蛋白Mcl-1、p-eIF 4 E、p-4 E-BP 1的表达产生影响。激酶抑制实验表明6 g是一种潜在的泛Pim激酶抑制剂。同时，6 g对BAD和4 E-BP 1磷酸化的阻断作用以及6 g与Pim-1的结合模式进一步证实了其Pim抑制作用。我们的发现为（+）-UA衍生物6气体抗白血病药物的潜在机制提供了视野。
Usnic acid (UA) is the main secondary metabolite isolated from lichens, with moderate anticancer activity. A small group of (+)-UA derivatives characterized with flavanone moiety was designed and synthesized, and their anticancer activities were evaluated in leukemia cells. It was demonstrated that (+)-UA derivatives6a–6ginhibited the proliferation of leukemia cells HL-60 and K562 with low micromolar IC50values. Mechanisms of action were investigated to find that6ginduced apoptosis in HL-60 and K562 cell lines, and affected the expression of MNK/eIF4E axis-related proteins, such as Mcl-1, p-eIF4E, p-4E-BP1. Finally, kinase inhibition assay suggested6gwas a potential inhibitor of pan-Pim kinases. Meanwhile, the blocking of phosphorylation of BAD and 4E-BP1 by6g, together with the proposed binding mode of6gwith Pim-1 further confirmed its Pim inhibition effects. Our finding provides the sight towards the potential mechanism of (+)-UA derivatives6gas anti-leukemia agents.