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Synthesis and biological evaluation of a series of podophyllotoxins derivatives as a class of potent antitubulin agents

机译:一系列鬼臼毒素衍生物作为一种有效的抗微管蛋白药物的合成及生物学评价

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摘要

A series of eight novel podophyllotoxin derivatives were designed, synthesized and evaluated for biological activities. The antiproliferative activities were tested against a panel of human cancer cell lines (K562, SGC, Hela and HepG) and the inhibition of tubulin polymerization was also evaluated. Compound 8e displayed significant antiproliferative activities for all four cell lines and strong levels of tubulin polymerization inhibition effect. Combined with cell apoptosis and cell cycle analysis, it demonstrated that compound 3e that effectively interfere with tubulin dynamics prevent mitosis in cancer cells, leading to cell cycle arrest and, eventually dose dependent apoptosis. All experimental measurements were also supported by molecular docking simulations of colchicine binding site, which revealed the governing forces for the binding behavior and a good relationship with anti-tubulin activity and antiproliferative activities. The synthesis and biological studies provided an interesting new class of antitubulin agents for development of lead compounds and also a direction for further structure modification to obtain more potent anti-cancer drugs.
机译:设计,合成和评估了一系列八种新颖的鬼臼毒素衍生物。测试了针对一组人类癌细胞系(K562,SGC,Hela和HepG)的抗增殖活性,并评估了微管蛋白聚合的抑制作用。化合物8e对所有四个细胞系均显示出显着的抗增殖活性,并且具有显着水平的微管蛋白聚合抑制作用。结合细胞凋亡和细胞周期分析,证明有效干扰微管蛋白动力学的化合物3e可阻止癌细胞中的有丝分裂,从而导致细胞周期停滞并最终导致剂量依赖性凋亡。秋水仙碱结合位点的分子对接模拟也支持所有实验测量,该模拟揭示了结合行为的控制力,并且与抗微管蛋白活性和抗增殖活性有良好的关系。合成和生物学研究为开发先导化合物提供了有趣的一类新的抗微管蛋白药物,也为进一步结构修饰以获得更有效的抗癌药物提供了方向。

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