滇产两面针中靶向作用于Fli-1基因的抗白血病活性物质研究

Leukemia seriously endangered the patients' health and their family happiness. Currently, there is not a specific treatment for leukemia. By starting from the medicinal plants, finding the new drug candidate for the new targets to treat leukemia is still the effective way of developing innovative drug. Fli-1 gene as the Ets family of transcription factors, plays an important regulatory role in the development of leukemia and other cancers, and the study shows that it can be used as the best new target for cancer therapy. In the early work study, effective extracts of Zanthoxylum nitidum from Yunnan province were found, which had specific effects on Fli-1 target gene and have significant impact on its expression.. So these extracts may be the potential material basis for developing novel anti-leukemia drugs. Therefore, the project combined with the preliminary studies will chose Zanthoxylum nitidum from Yunnan province as the research object, and the activity screening acts as the separation orientation. By using modern natural products chemistry technology, the substances of the effective extracts which had specific effects on Fli-1 target gene will be studied for the system isolation and structure identification. On the basis of the above, the activities of obtained compounds targeting Fli-1 gene against leukemia will be evaluated. By the chemical modification and re-evaluation of the active derivative, derivatives of the significant compound and their activities will be obtained, and the structure-activity relationship will explored. Furthermore, in order to elucidate the molecular mechanism of its anti-leukemia, the effects of compounds with the high activity and low toxicity to Fli-1 target gene expression will studied to provide material and scientific basis for the development of innovative anti-leukemia drug candidates.

白血病严重危害着患者健康及其家庭幸福，目前尚无治疗该病的特效药，从药用植物出发，从中寻找针对新靶标治疗白血病的新药候选分子是当前新药研发的有效途径。Fli-1基因作为Ets家族中的转录因子，在白血病及其他肿瘤发生发展中起重要调节作用，研究表明可将其作为肿瘤治疗的优秀新靶点。申请人从滇产两面针粗提物中发现了对Fli-1表达有显著影响的有效部位，该部位可能是研发新型抗白血病药物的潜在物质基础。本项目拟以滇产两面针为研究对象，以活性筛选为导向，采用现代天然产物化学研究技术，针对上述有效部位中的物质基础进行系统分离纯化和结构鉴定；并在此基础上，评价所得化合物靶向作用于Fli-1的抗白血病活性；通过化学修饰和活性再评价获取高活性化合物衍生物，并探讨其构效关系；研究高效低毒化合物对Fli-1靶基因表达的影响，并初探其对Fli-1的调控机制，为发展新型抗白血病药物候选分子提供物质基础和科学依据。

白血病严重危害着患者健康及其家庭幸福，目前尚无治疗该病的特效药，从药用植物出发，从中寻找针对新靶标治疗白血病的新药候选分子是当前新药研发的有效途径。Fli-1基因作为Ets家族中的转录因子，在白血病及其他肿瘤发生发展中起重要调节作用，研究表明可将其作为肿瘤治疗的优秀新靶点。申请人前期从滇产两面针粗提物中发现了对Fli-1表达有显著影响的有效部位，该部位可能是研发新型抗白血病药物的潜在物质基础。因此，本项目对滇产两面针植物根部乙醇提取物有效部位（石油醚萃取部位和氯仿萃取部位）中的化学成分进行系统的分离纯化、结构鉴定和抗白血病活性筛选研究，从中分离鉴定了43个化合物，其中8个化合物为首次从两面针植物中分离得到，4化合物首次对其进行完整的二维波谱数据归属。并评价了部分化合物的抗白血病活性，达到了阐明其中主要抗白血病的活性物质基础的目的；并在此基础上借助HPLC-MS技术获得两面针植物根部的指纹特征谱系，比较滇产两面针与其他不同产地中草药两面针中化学成分的异同，尤其是以活性为导向建立了两面针总生物碱的特征图谱及其谱效关系；针对活性显著含量高的两个苯骈菲啶类生物碱成分进行合理化衍生物分子设计，通过结构修饰优化制备了37个相关衍生物，大部分衍生物为首次合成，并评价了衍生物的抗白血病活性，探讨了初步的构效关系；选择抗肿瘤活性显著的化合物探讨了其作用于Fli-1基因的影响和抗白血病的可能作用机制，为发展创新型抗白血病药物的研发提供新思路和理论依据。