5/7/6型紫杉醇类似物的设计、虚拟筛选、合成及生物活性评价

项目名称： 5/7/6型紫杉醇类似物的设计、虚拟筛选、合成及生物活性评价

项目编号： No.20802083

项目类型： 青年科学基金项目

立项/批准年度： 2009

项目学科： 轻工业、手工业

项目作者： 赵昱

作者单位： 中国科学院昆明植物研究所

项目金额： 18万元

中文摘要： 紫杉醇是以微管蛋白为靶点的最成功的天然来源药物。近年来紫杉醇面临耐药性和副作用问题，继续寻找全新、结构简化，类型丰富的紫杉醇类似物十分必要。本项目以5/7/6型紫杉烷二萜为原料，以微管蛋白为靶点，借助基于分子对接的虚拟筛选，设计、合成了三个系列5/7/6型紫杉醇类似物。同时，完成了5/7/6型紫杉烷二萜化学反应研究，发现了系列特有反应，该结果可用于合成更多结构类型丰富的紫杉醇类似物用于药物发现；随后，按计划对合成的5/7/6型紫杉醇类似物展开了广泛的活性评价和构效关系研究。从中首次发现了系列全新的，可同时作用于微管蛋白及NF-κ#36890;路的双功能紫杉烷衍生物。该类化合物在美国NCI 60肿瘤细胞筛选模型中表现出独特的活性变化规律，机理研究证实，其通过促进微管蛋白解聚和抑制NF-κ#36890;路激活，最终导致肿瘤细胞凋亡。由于结构新颖，构效关系明确，体外抗肿瘤活性显著，规律独特，且可同时作用于疾病网络中有紧密联系的两个重要抗肿瘤靶点，该类化合物有望成为一类新的抗肿瘤药物先导化合物。同时，本项目发展的通过基于天然产物骨架，并在此基础上合理构建相关药效团的设计思路也可以用于其他基于天然产物的药物研发。

中文关键词： 5/7/6型紫杉醇类似物；合成；生物活性；构效关系；双功能

英文摘要： Microtubule is the important target for the anticancer drug. Paclitaxel is the leading drug in cancer chemotherapies, which binds to microtubule and promotes tubulin polymerization. In recent years, the clinical use of paclitaxel has been limited due to the drug-resistantance and side effects. A search for new paclitaxel-like compouds with simple and diverse structure is thus highly desirable. In this project, with the natural taxanes possessing a skeleton of 5/7/6 ring-system as the parent compounds, using the computational docking technology, libraries of taxane-based compounds are designed and docked to the tubulin. Based on the docking results, three series of compounds were synthesized. The chemical behavior of the taxane with 5/7/6 ring-system have also been thoroughly investigated and a series of unique reactions have been discovered, which could be further applied in other abeo-taxoids, and will therefore benefit those efforts to synthesize biologically and pharmaceutically important taxoid derivatives. The bioactivities of all synthesized compounds were broadly evaluated and their structure-activity relationship (SAR) were thus established. As a result, a new type of abeo-taxoids-based analogues possessing potent activity against colon caner, melanmon and renal cancer were identified. The mechanism of action study indicated that this series of abeo-taxoids represented a new type of dual-fuctional agents that could not only block the tubulin polymerization but also inhibit the NF-κactivation, thereby inducing apoptosis. As a new class of natural dual-functional functional molecules with novel scaffold, potent activity, unique spectrum of actives and interesting SAR, this series of abeo-taxoids-based derivatives might offer great promises for drug or lead development and deserved to pay more attentions. The strategy used in current research might be generally applicable to dual functional drug design based on natural scaffolds.

英文关键词： paclitaxel-like compound with a skeleton of 5/7/6 ring system; synthesis; bioactivity; structure-activity relationship; dual-function