基于天然产物Millepachine的新型微管蛋白抑制剂的设计、合成及抗肿瘤活性研究

Microtubules are major components of the cytoskeleton and play an important role in a number of cellular functions such as maintenance of cell shape, cell signaling and cell division. Given their significant role in the process of cell division, the microtubule has become an important target for the design and development of new antitumor agents. Structural modification of natural products by chemical synthesis is an important method of drug discovery. In our previous work, it was found that natural product millepachine, a novel anti-tubulin agent, displays potent antitumor activity. Therefore, this project is planned to design and synthesize a library of 300 compounds based on previous knowledge of structure-activity relationships, bioisosterism, computer aided drug design and lead compound millepachine, and evaluate them by using in vitro antitumor assay for the detailed study of structure-activity relationship. Furthermore, we evaluate the biological properties, pharmacokinetics and toxicology of these candidate compounds to obtain novel, potent, low toxicity, low drug resistance and high bioavailability anti-tubulin agents. The project not only provides reference and guide for the structural modification and optimization of biologically active natural products, but also offers new ideas of researching tubulin inhibitor and developing antitumor drugs with independent intellectual property rights.

微管是细胞骨架的基本组成部分，参与维持细胞形态、信号传导和细胞分裂等重要过程。由于微管在细胞分裂过程中的重要作用，现已成为研究与开发抗肿瘤药物的重要靶点之一。对天然产物进行结构修饰与优化是一种发现新药的重要方法。前期研究发现，天然产物millepachine具有良好的抗肿瘤活性，是一种新型的微管蛋白抑制剂。本项目基于前期研究得到的构效关系，运用生物电子等排原理和计算机辅助药物设计技术，以millepachine为先导化合物，拟设计并合成一个含300个小分子的化合物库，通过体外活性筛选，阐明此类化合物的详细构效关系。同时对筛选得到的候选化合物进行药理药效学、药代动力学和初步毒性评价，以期获得高效、低毒、低耐药性和高生物利用度的新型微管蛋白抑制剂。本项目对活性天然产物的结构修饰与优化研究具有很好的借鉴和指导价值，为微管蛋白抑制剂的研究提供了新的思路，为开发具有自主知识产权的抗肿瘤药物奠定基础。

天然产物millepachine是本课题组在前期研究中发现的一种新型的微管蛋白抑制剂。本项目在前期研究的基础上，运用生物电子等排原理和计算机辅助药物设计技术，对millepachine的A环、B环和中间链进行全面的结构修饰与优化研究。本项目设计并合成了萘环-查尔酮类、二苯醚查尔酮类、含萘环二芳基吡唑类、含萘环二芳基异噁唑类、含萘环二芳基甲酮类和α-氰基类六大类共计169个millepachine衍生物。通过对制备得到的millepachine衍生物库进行抗肿瘤活性筛选和作用机制研究，阐明了millepachine衍生物抗肿瘤活性的详细构效关系，并获得了多个高活性的新型微管蛋白抑制剂。其中化合物4活性较强，对前列腺癌DU145细胞的抑制IC50为18 nM，对微管蛋白聚合的抑制IC50为7.1 μM，并且毒性较低，具有进一步研究和开发的价值。本项目在执行期间，相关研究结果目前共发表SCI收录学术论文10篇，其中6篇为JCR 1区期刊。申请中国发明专利5项，其中1项已获得发明专利授权。