选择性靶向拓扑异构酶IIa的ATPase位点抑制剂：新型曼宋酮类化合物设计、合成和机制研究

项目名称： 选择性靶向拓扑异构酶IIa的ATPase位点抑制剂：新型曼宋酮类化合物设计、合成和机制研究

项目编号： No.21272288

项目类型： 面上项目

立项/批准年度： 2013

项目学科： 数理科学和化学

项目作者： 黄世亮

作者单位： 中山大学

项目金额： 80万元

中文摘要： 传统的拓扑异构酶(Top)II抑制剂的缺点是在诱导双链DNA损伤和细胞凋亡的同时，增加染色体突变的机会并激活体内DNA修复系统，从而产生明显的耐药性和基因毒性。同时对Top IIa和TopIIb的选择性不大。靶向TopIIa的ATPase位点因无上述缺点，被认为是重要的抗肿瘤新靶标。在前期研究中发现：曼宋酮类化合物对TopII的抑制活性比依托泊苷大30-40倍并具有较好的TopIIa选择性。进一步的研究显示，该类化合物既不能诱导形成断裂DNA，无DNA嵌入作用，也不能与酶的催化活性中心识别结合。通过ATP竞争实验及表面等离子共振等技术，证实该类化合物是一靶向TopIIa的 ATPase位点的新型抗肿瘤先导物。在此基础上，对该先导物进行合理的设计和结构优化，建立系列筛选和评价体系，阐明其作用机制，为发展靶向TopIIa ATPase位点的新型抗肿瘤药物提供理论和实验依据。

中文关键词： 曼宋酮；抗肿瘤；拓扑异构酶抑制剂；催化型抑制剂；药物设计

英文摘要： The disadvantage of traditional topoisomerase(Top)II inhibitors is to increase the gene mutation and activate DNA repair system while inducing DNA cleavage and cell apoptosis, which can produce remarkable drug resistance and genotoxicity. In the mean time, these inhibitors have little selectivity between Top IIa and Top IIb. The ATPase site of Top IIa is suitable to be a novel crucial anti-tumor target, because targeting on this site can overcome above disadvantage.In our previous works, we found that the Mansonone F compounds have 30-40 times activity of etoposide on Top IIa inhibition. Our further study has shown that the compounds can neither induce DNA cleavage, nor intercalate DNA or interact with catalysis site of Top IIa. Through ATP competition assay and SPR assay, it has been confirmed that the mansonone F analogues are a class of novel anti-tumor lead compounds targeting ATPase of Top IIa. Based on our previous work, we plan to carry out rational drug design and structure optimization of the lead compounds, followed by setting up a serial screening and evaluation systems for further mechanistic study. This research will shed light on further development of promising anti-tumor drugs targeting the ATPase site of Top IIa.

英文关键词： mansonone；anti-tumor；topoisomerase；catalytic inhibitor；drug design