可跨越血脑屏障的倍半萜内酯类化合物的发现、衍生化及其抗脑胶质瘤干细胞活性研究

Glioma is the most common and the most difficult to cure intracranial tumor. The main problems existing in the treatment of glioma is recurrence and metastasis. Glioma stem cells are regarded as the origin of recurrence and metastasis, therefore selective removal of glioma stem cells may cure brain glioma. The most drugs can not pass through the blood-brain barrier is the biggest obstacle in the treatment of glioma, which led to the drugs can not achieve effective treatment. Project of National Natural Science Foundation of China (81001377) separated and synthesized 128 compounds, and investigated their structure-activity relationships. The research findings were published on JMC and JOC and filed 18 patents. The most important is that the research firstly revealed that eudesmane sesquiterpene lactones can selectively remove glioma stem cells. Moreover, eudesmane sesquiterpene lactones can penetrate the blood brain barrier, which suggested that eudesmane sesquiterpene lactones have great potential in the treatment of glioma. On this basis, the research intends to study the chemical composition and activity of the five species of plants (Inula helenium L., Inula japonica Thunb., Inula racemosa Hook.f., Inula hupehensis Ling, Saussurea lappa C. B. Clarke). Modifications, activity test, and the blood-brain barrier permeability experiments are made on the compounds with high content to reveal the relationships of structure–activity–blood-brain barrier penetrating ability. For the most active compounds, we will investigate their in vivo efficacy. The project is expected to find 3-5 compounds that show significant in vivo efficacy, which provide pharmacy and pharmacology basis for the discovery of novel anti-glioma compounds.

脑胶质瘤是颅内肿瘤中最常见、最难治愈的肿瘤。胶质瘤治疗存在的主要问题是复发和转移，胶质瘤干细胞被视为胶质瘤复发、转移的根源，因此选择性清除胶质瘤干细胞可能根治脑胶质瘤；胶质瘤治疗最大障碍是多数药物不能穿过血脑屏障，无法达到有效治疗。本人主持的青年基金(81001377)分离和合成化合物128个，研究了其构效关系，论文发表在JMC和JOC，申请专利18项，特别重要的是首次发现桉烷型倍半萜内酯可选择性清除胶质瘤干细胞，且桉烷型倍半萜内酯可跨越血脑屏障，具有治疗脑胶质瘤的巨大潜力。拟在此基础上选择富含桉烷型倍半萜内酯且资源丰富的土木香、旋覆花、总状土木香、湖北旋覆花、云木香进行化学成分及活性研究，对含量较大的化合物进行结构修饰、活性及血脑屏障通透测试，揭示结构-活性-血脑屏障通透关系，研究高活性物质体内药效，期望发现3-5个药效显著的活性物质，为发现新颖的抗脑胶质瘤活性物质提供药学和药理学依据。

脑胶质瘤是颅内肿瘤中最常见、最难治愈的肿瘤。胶质瘤治疗存在的主要问题是复发和转移，胶质瘤干细胞被视为胶质瘤复发、转移的根源，因此选择性清除胶质瘤干细胞可能根治脑胶质瘤；胶质瘤治疗最大障碍是多数药物不能穿过血脑屏障，无法达到有效治疗。特别重要的是首次发现桉烷型倍半萜内酯可选择性清除胶质瘤干细胞，且桉烷型倍半萜内酯可跨越血脑屏障，具有治疗脑胶质瘤的巨大潜力。在此基础上选择富含桉烷型倍半萜内酯且资源丰富的植物进行了化学成分及活性研究，对含量较大的化合物进行结构修饰，揭示了构效关系，研究高活性物质体内药效，发现1个候选药物ACT001用于治疗脑瘤，ACT001已进入澳大利亚临床试验，获得国内临床批件，获得FDA孤儿药认定。发表论文14篇，其中第一或通讯作者论文11篇，包括药物化学领域顶级期刊J Med Chem 3篇；授权专利6项，申请专利2项；为发现新颖的抗脑胶质瘤药物提供药学和药理学依据。