微管靶向药物在肿瘤治疗中占有重要地位，靶向微管蛋白新位点、克服耐药的新型抑制剂仍为临床所需。美登素位点抑制剂显示独特的抗肿瘤特性，目前发现三个天然产物作用于该位点，克服分子结构复杂等不足的新一代结构简单的抑制剂研究具有重要意义。本项目从三个天然产物中唯一的线性分子—海洋聚酮PM060184出发，基于前期工作基础，根据它与微管蛋白复合物晶体提供的微观信息及与美登素等演化的药效团模型，通过合理设计类似物，系统考察晶体中每个相互作用对活性的影响，建立构效关系，确定活性必需的结构单元，实现分子结构的简化。进一步，采用骨架迁越等策略，对简化物进行结构再简化和优化，增强分子的可合成性和化学稳定性等，提高分子的类药性，获得具有自主知识产权、全新结构的新一代抑制剂，最终实现从复杂天然产物到药物的转变，并验证药效团的真实性和骨架迁越的可行性。本项目的研究策略和方法将对其他天然产物的结构改造具有指导作用。

Microtubule-targeting agents play an important role on cancer therapy. New tubulin inhibitors targeting against new tubule-binding site and overcoming multidrug resistance are still clinical urgently demanded. The maytansine site inhibitors have unique and potent antitumor activities. So far only three structurally complex natural products have been reported to bind to this site, therefore to overcome the shortcomes and to discover new-generation of inhibitors with novel structures, as well as good physical-chemical properties is of significant importance. This project is going to select the only linear molecule PM060184 from the three reported natural products as starting point for the discovery of new-generation of maytansine site inhibitors. Based on our earlier research work and the information of key binding mode of marine polyketide PM060184 with tubulin and the corresponding common pharmacophore model, the novel analogues will be designed to evaluate the essential interactions with tubule for bioactivity, to investigate the structure-activity relationship, to define pharmacophores, and to simplify PM060184 through elimination of unnecessary residues while retaining the key bioactive configurations and conformations. Furthermore, the structure re-simplification and optimization will be carried out to acquire novel structural inhibitors using scaffold hopping strategy. This will lead to the simplification of synthetic routes and improvement of physical-chemical properties. It will also improve drug-likeness, attain intellectual properties, and may achieve a transformation from complex natural product to drug molecule. The current research strategies and tactics will be meaningful for the drug discovery starting from natural products.