新型松香基苯并咪唑类微管蛋白聚合抑制剂的合成、构效关系及抗肿瘤机制研究

Tubulin participates in the mitosis and apoptosis of cells and plays a vital role in the process of tumor growth and angiogenesis. Therefore, it is an important target for the investigation of anticancer drugs. In this project, new benzimidazole derivatives of dehydroabietic acid are to be designed and synthesized from resin acid, a special forest product in China. A highly active tubulin polymerization inhibitor found in preliminary research is taken as the lead compound. Based on the deep understanding of binding modes between tubulin and lead compound, four key structural sites of the lead molecule will be modified. The different series of synthesized derivatives from dehydroabietic acid will be subject to in vitro antitumor assay and tubulin polymerization inhibition assay. Based on the results of bio-screening, 3D-QSAR study will be carried out in order to explore the effect of structural diversity on bioactivities. Further study will be carried out to explore the antitumor molecular mechanisms of the compounds with good activities. The target of this project is to synthesize 120~160 new benzimidazole derivatives of dehydroabietic acid, and hope to discover 4~5 new tubulin polymerizaion inhibitors with high activity, low toxicity and low drug resistance, which will offer theoretical foundations for developing new forest-derived antitumor drugs and expanding the application of rosin resource in China.

微管蛋白参与细胞有丝分裂和凋亡，在肿瘤的生长和血管生成过程中发挥重要作用，因而微管蛋白是抗肿瘤药物研究的重要靶点。本课题以我国特色林产资源松香树脂酸为研究对象，设计、合成具有微管蛋白聚合抑制作用的新型脱氢枞酸苯并咪唑衍生物。以前期研究获得的高活性微管蛋白聚合抑制剂作为先导物，在深入理解微管蛋白和先导物结合模式的基础上，对化合物分子四个关键结构部位进行改造和修饰。将合成的不同系列脱氢枞酸衍生物进行抗肿瘤活性和微管蛋白聚合抑制活性的评价，在活性筛选的基础上进行三维定量构效关系研究，探讨结构多样性对生物活性的影响；深入探索活性化合物的抗肿瘤作用分子机制。通过本项目的研究，合成120~160个新型脱氢枞酸苯并咪唑衍生物，力争发现4~5个高效低毒、低耐药性的新型微管蛋白聚合抑制剂，为开发新型林源抗肿瘤药物，拓展我国松香资源的应用领域提供理论研究基础。

本项目以我国特色林产资源——松香树脂酸为研究对象，成功设计并合成了6个系列的新型脱氢枞酸2-芳基苯并咪唑衍生物、脱氢枞酸苯并咪唑酰胺/磺酰胺衍生物、脱氢枞酸1,3,4-恶二嗪-5-酮衍生物、脱氢枞酸吲哚衍生物、脱氢枞酸苯并咪唑2-芳硫基/2-芳胺基衍生物、脱氢枞酸苯并咪唑席夫碱衍生物。通过波谱方法对所合成的系列杂环化合物的结构进行表征，探索了这些新化合物的抗肿瘤活性，研究不同官能团结构对活性的影响，探索了化合物结构与生物活性之间的构效关系。对于具有优良抗肿瘤活性的化合物，深入探索活性化合物的抗肿瘤作用分子机制。通过研究，成功合成了162个新型脱氢枞酸杂环化合物，从中筛选出8个具有优良生物活性的新化合物，其中2个为新型微管蛋白抑制剂，具备良好应用前景。为开发新型林源抗肿瘤药物提供了理论研究基础，对拓展我国松香资源的应用领域具有重要的意义。