2-Methoxydiol derivatives as new tubulin and HDAC dual-targeting inhibitors, displaying antitumor and antiangiogenic response
2-Methoxydiol derivatives as new tubulin and HDAC dual-targeting inhibitors, displaying antitumor and antiangiogenic response
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2-甲氧基二醇衍生物作为新型微管蛋白和 HDAC 双靶向抑制剂，具有抗肿瘤和抗血管生成反应
DOI：
10.1016/j.bioorg.2022.105625
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发表时间：
2022-01-22
影响因子：
5.1
通讯作者：
Yao, Yongfang
中科院分区：
文献类型：
--
作者：
Sun, Moran;Qin, Jinling;Yao, Yongfang
多靶点药物设计因其在肿瘤治疗中的优势而成为一个活跃的研究领域。本研究首次将HDAC抑制剂药效团与2-甲氧基乙烯（2 ME 2）结合成一个新的杂合分子。合成了47个2 ME 2衍生物，并评价了其抗增殖活性。特别地，化合物4s表现出微管蛋白聚合和HDAC活性的双重抑制（对HDAC 2的IC 50 = 0.06 μ M），以及对六种癌细胞系的最有效的细胞毒性IC 50值0.37-4.84 μ M。化合物4s可显著破坏A549细胞的微管网络，使细胞周期阻滞于G2/M期，诱导线粒体膜电位下降，最终导致细胞凋亡。值得注意的是，4s被发现有效地阻碍HUVEC的管形成，并抑制HUVEC以及A549细胞的增殖、迁移和侵袭。此外，通过斑马鱼模型试验证明了抗血管生成和抗转移活性。所有这些有益的抗癌活性以及对非癌细胞的高选择性，表明4s可能值得考虑用于癌症治疗。
Multi-target drugs design has become an active research field because of their advantages in cancer treatment. In present study, HDAC inhibitors pharmacophore and 2-methoxyestradiol(2ME2) were combined into a new hybrid molecule for the first time. Forty-seven 2ME2 derivatives were synthesized and evaluated for anti proliferative activity. In particular, compound 4s exhibited a dual inhibition of tubulin polymerization and HDAC (IC50 = 0.06 mu M toward HDAC2) activity, as well as the most potent cytotoxicity IC50 values of 0.37-4.84 mu M against six cancer cell lines. Compound 4s remarkably disrupted microtubule networks, arrested cell cycle at G2/M phase, induced mitochondrial membrane potential collapse and eventually apoptosis in A549 cells. Notably, 4s was discovered to potently imped the tube-formation of HUVECs and prohibited the proliferation, migration, and invasion of HUVECs, as well as A549 cells. In addition, the anti-angiogenic and anti-metastasis activities were demonstrated via a zebrafish model test. All these beneficial anticancer activities together with its high selectivity toward noncancer cells, suggested 4s may deserves consideration for cancer therapy.