微管蛋白和微管剪切蛋白双靶点抗肿瘤化合物的设计、合成、活性及作用机制研究

Tubulin is one of the most successful anti-tumor targets. In our previous work, a series of novel chiral diaryl-β-lactams have been disclosed to have potent tubulin polymerization inhibitory activity and anti-proliferative activity against several human cancer cell lines, causing the cell cycle arrest, inducing cellular apoptosis and significantly inhibiting xenograft tumor growth in nude mice. The cocrystal structures with tubulin demonstrated that these compounds disrupt tubulin polymerization through interacting at the colchicine-binding site, and suppress angiogenesis in vitro and in vivo. It has been reported that katanin, one of the microtubule severing proteins, can disrupt microtubule into small fragments by hydrolyzing ATP, cause G2/M cell cycle arrest and trigger apoptosis. Our preliminary study showed that a class of novel diaryl substituted heterocyclic compounds designed by merging strategy demonstrated dual actions by targeting tubulin and katanin, and possessed anti-proliferative activity against several human cancer cell lines. Based on these promising results, a large number of target molecules with comprehensive structural diversity will be designed and synthesized in this project in view of synergistic effect and will be evaluated for their antiproliferative activities in vitro and in vivo. The mechanism of action will be studied as well with the aim of finding highly potent and low toxic novel dual-target drug candidates for treatment of cancers.

微管蛋白（Tubulin）是最成功的抗肿瘤药物作用靶点之一。在前期工作中我们获得了一系列新型手性二芳基-β-内酰胺化合物，具有优秀的微管蛋白聚集抑制活性，并能抑制多种肿瘤细胞增殖，阻滞细胞周期，诱导细胞凋亡。体内活性结果表明它们可显著抑制裸鼠皮下移植瘤的生长。晶体结构解析证明该类化合物结合于微管蛋白秋水仙碱位点，抑制微管蛋白组装，且显著抑制肿瘤血管生成。微管剪切蛋白（Katanin）可通过水解ATP剪切微管、使微管解聚，导致细胞周期阻滞和细胞凋亡。通过结构融合策略，我们设计合成了一类新型二芳基取代杂环化合物，初步活性结果表明其具有良好的微管蛋白和微管剪切蛋白双靶点作用以及多种肿瘤细胞增殖抑制活性。在此基础上，本项目拟设计合成具有结构多样性的目标化合物，并测定其体内外抗肿瘤活性，研究其作用机制，以期通过协同作用获得高效、低毒、具有微管蛋白和微管剪切蛋白双靶点作用的新型抗肿瘤候选药物。

微管蛋白（Tubulin）是最成功的抗肿瘤药物作用靶点之一。在前期工作中我们获得了一系列新型手性二芳基-β-内酰胺化合物，具有优秀的微管蛋白聚集抑制活性，并能抑制多种肿瘤细胞增殖，阻滞细胞周期，诱导细胞凋亡。体内活性结果表明它们可显著抑制裸鼠皮下移植瘤的生长。晶体结构解析证明该类化合物结合于微管蛋白秋水仙碱位点，抑制微管蛋白组装，且显著抑制肿瘤血管生成。微管剪切蛋白（Katanin）可通过水解ATP剪切微管、使微管解聚，导致细胞周期阻滞和细胞凋亡。通过结构融合策略，我们设计合成了一系列结构多样性的新型二芳基取代杂环化合物，活性结果表明其具有良好的Tubulin/Katanin、Tubulin/DNA、Tubulin/HDAC双靶点作用以及多种肿瘤细胞增殖抑制活性，并具有良好的体内抗肿瘤活性，有望发展成为高效、低毒、具有微管蛋白和微管剪切蛋白等双靶点作用的新型抗肿瘤候选药物。

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