基于微管靶点新结构双吲哚马来酰亚胺生物碱HD-ZWM288抗肿瘤作用及其机制的研究

Microtubules are long-standing targets in cancer chemotherapy. Microtubules constitute the mitotic spindle apparatus during cell division, which is critical for cellular proliferation. This vital role of microtubules has made them a general target of numerous antitumor drugs. Currently, microtubule-targeted drugs comprise some of the most effective and potent agents in cancer chemotherapy. However, many side effects of these drugs such as non-specific cytotoxicity , the drug resistance, toxicity etc. in clinic has required the continued investigation and characterization of potent and tumor-specific compounds. Thus, finding the novel structure type of anticancer drugs targeting microtuble is still a hot topic of research. ..HD-ZWM288, a new bisindole maleimide alkaloids, synthetized by Prof. Zhu group in China Ocean University. We have found that HD-ZWM288 is a microtubule inhibitor with the new-skeleton. The mice are normal after they are intraperitoneal injected of this compound more than 80mg/kg, which exhibit promising antitumor therapeutic potential with low toxicity. The pre-experiments showed that HD-ZWM288 induced cell cycle arrest at G2/M phase, apoptosis in tumor cell lines and anti-angiogenesis in HUVEC cells, which is related closely to its effects of microtubule depolymerization. In this study, we will demonstrate the site that HD-ZWM288 binding to in tubulin. We will characterize the interaction of HD-ZWM288 with tubulin protein and microtubule associated proteins(MAP). Since microtubule play an important role in cell cycle, apoptosis in tumor cell lines and anti-angiogenesis. Further investigation will study underlying the mechanism of this compound in these microtubule-mediated effects and further animal experiments will be performed. ..Taken together, this study will supply the data and idea both in vitro and in vivo for the discovery of the anticancer drug and lead compounds targeting microtubule with the new skeleton ,which is the benefit for the new anti-cancer drugs development and clinical applications.

微管为靶点的抗肿瘤药物是临床最有效的药物，但普遍存在耐药、毒副作用大等问题，极大限制了疗效和应用。寻找和发现以微管为靶点的新结构类型抗肿瘤药物是研究的热点。HD-ZWM288是中国海洋大学朱伟明课题组以天然产物为先导物优化修饰得到的新双吲哚马来酰亚胺类生物碱，我们课题组发现其是具有抗肿瘤作用的新骨架微管抑制剂。急毒预试验结果表明小鼠腹腔注射超过80mg/kg，未见动物异常。本课题拟在前期发现HD-ZWM288具有抑制微管聚合的基础上, 进一步确证和揭示其靶向微管、破坏微管动态不平衡性、破坏纺锤体、阻滞细胞有丝分裂、引起细胞凋亡的通路和机制；探讨其微管介导的抗新生血管作用的机制；并进一步展开动物抗肿瘤试验工作。为发现抗肿瘤药物作用靶点、新骨架抗微管作用的先导物和发展新型抗肿瘤药物及临床应用奠定试验基础；为新靶点和新骨架抗肿瘤药物的发现提供生物信息学和生物学的试验数据。

微管为靶点的抗肿瘤药物是临床最有效的药物，但普遍存在耐药、毒副作用大等问题，极大的限制了疗效和应用。寻找和发现以微管为靶点的新结构类型抗肿瘤药物是研究的热点。HD-ZWM-X是中国海洋大学朱伟明课题组以天然产物为先导物优化修饰得到的新双吲哚马来酰亚胺及吲哚咔唑类生物碱，我们课题组发现HD-ZWM288是具有抗肿瘤作用的新骨架微管抑制剂。研究表明HD-ZWM288靶向微管、具有抑制微管聚合、破坏微管动态不平衡性、破坏纺锤体、阻滞细胞有丝分裂、引起细胞凋亡、抗新生血管作用的作用，体内实验表明，HD-ZWM288及其衍生物成盐的HD-ZWM155CL(BMA-155CL)对荷瘤动物具有明显的肿瘤抑制作用，并有抗新生血管及抗侵袭转移作用；毒性较低，成药前景良好，课题的结果为新骨架抗肿瘤微管抑制作用的先导物和发展新型抗肿瘤药物及临床应用奠定试验基础；为微管抑制药物结构优化、减毒增效提供实验依据；为新靶点和新骨架抗肿瘤药物的发现提供生物信息学和生物学的实验数据。