新型二芳基β-内酰胺类微管蛋白聚集抑制剂的设计、合成及抗肿瘤活性研究

Tubulin dynamics is among the most successful targets for anticancer therapy. The colchicine binding site is one of the most important pockets for potential tubulin polymerization inhibitors, which exert their biological effects by inhibiting tubulin assembly, suppressing microtubule formation and mostly acting as vascular-targeting agents, rapidly destroying newly formed vasculature to shut down the blood supply to tumors. In our previous work, the asymmetric synthesis of a series of diaryl β-lactam derivatives was achieved in high enantioselectivity. Further pharmacological studies revealed that these compounds provided a privileged scaffold to possess potent antiproliferative activity in vitro and in vivo with low toxicity and display significant inhibition of tubulin polymerization. Based on these promising results, a large number of target molecules with comprehensive structural diversity have been designed in this project according to bioisosterism principle and will be synthesized via our methodology to evaluate for their antiproliferative activities in vitro and in vivo, as well as the mechanism of action will be studied with the aim of finding highly potent, low toxicity novel candidate drugs for treatment of cancers.

微管是最成功的抗肿瘤药物靶点之一。秋水仙碱结合位点是微管蛋白聚集抑制剂重要的结合区域，该类药物通过抑制微管蛋白的组装，从而阻滞微管的形成；并且大多可作为血管靶向试剂，快速破坏肿瘤新生血管、停止肿瘤的血液供给。在我们的前期工作中，一系列二芳基β-内酰胺类化合物可以通过高对映选择性的不对称合成方法获得。进一步药理研究表明，该类化合物具有显著的体外和体内抗肿瘤活性以及微管蛋白聚集抑制活性且毒性小。基于这些研究结果，根据生物电子等排原理，本课题设计了具有结构多样性的目标化合物，通过已有方法合成获得，并测定其体内外抗肿瘤活性，研究其作用机制，有望发现高效、低毒新型微管蛋白聚集抑制剂类抗肿瘤候选药物。

微管是最成功的抗肿瘤药物靶点之一。秋水仙碱结合位点是微管蛋白聚集抑制剂重要的结合区域，该类药物通过抑制微管蛋白的组装，从而阻滞微管的形成；并且大多可作为血管靶向试剂，快速破坏肿瘤新生血管、停止肿瘤的血液供给。本项目通过高对映选择性的不对称合成方法获得了一系列手性二芳基-β-内酰胺类目标化合物。药理活性研究表明，该类化合物具有显著的体外和体内抗肿瘤活性以及微管蛋白聚集抑制活性且毒性小，对该类化合物的构效关系规律进行了总结，还获得了3个目标化合物与微管蛋白的X-射线衍射共晶结构，直观阐明了其与微管蛋白的作用模式，有望成为高效、低毒新型微管蛋白聚集抑制剂类抗肿瘤候选药物。

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