雷公藤叶中抗肿瘤环氧二萜内酯的发现及其构效关系研究

Cancer has now become the second killer for human health while the first is the cardiovascular diseases. HIF-1 can show selective high expression in the organization of Solid Tumors, regulator and target genes are closely related with tumor development, therefore research and found on the inhibition of HIF-1 has become an international hot spot in anti-cancer drug research.In the previous our study, we have found that the extract from leaves of Tripterygium wilfordii significantly inhibited HIF-1 and also showed a strong anti-tumor activity. We carried out a preliminary chemical composition study to the active extract, and 59 compounds were isolated, 42 of which were identified as new compounds. tri Thediterpenoid exposide lactones showed inhibitory activity of HIF-1 and tumor cytotoxic activity, then we modified the structure of active compounds. The derivative LB-1 showed a strong anti-tumor effect on animal models of pancreatic cancer, which is more effective than the anticancer drug Gemcitabine in clinical use. This provides a good foundation for further study on SAR. In addition, leaves of Tripterygium wilfordii have abundant resources, which are a renewable resources. For this reason we intend to set up the project on the in-depth research of the active ingredient with anti-tumor activity from leaves of Tripterygium wilfordii, to find strong activity, low toxicity and selective compounds as lead compounds, laying the foundation of anti-tumor drugs for further development of the future.

恶性肿瘤是仅次于心血管疾病的人类第二大杀手。缺氧诱导因子-1（HIF-1）在实体肿瘤组织内选择性持续高表达，下游关键调控基因与肿瘤的发生发展密切相关。在前期研究中首次发现雷公藤叶提取物具有显著的抑制HIF-1活性作用。对活性部位进行了初步的化学成分研究，得到了59个化合物（包括42个新化合物），其中24个为环氧二萜内酯类化合物，药理学实验结果显示环氧二萜内酯类化合物具有较强的抑制HIF-1活性和肿瘤细胞毒活性，并对活性化合物进行了初步的结构修饰，得到的衍生物LB-1在胰腺癌动物模型上具有较强的抗肿瘤作用，作用强度大于临床上使用的抗肿瘤药物吉西他滨，这为进一步探讨其构效关系提供了良好的物质基础。另外，雷公藤叶资源丰富，是可再生的资源，为此，我们拟立项对雷公藤叶中抗肿瘤的活性成分进行深入研究，发现活性强、毒性低、选择性好的化合物作为先导物，为今后进一步开发抗肿瘤新药奠定物质基础。

本课题对雷公藤叶提取物进行了系统的微量成分分离，共得到了206个化合物。通过结构鉴定发现，二氢沉香呋喃型倍半萜类化合物69个，二萜类化合物36个，橙花叔醇倍半萜类化合物7个，降异戊二烯萜类化合物39个，三萜类化合物6个，木脂素和黄酮类化合物28个，其他类型化合物21个。其中新化合物96个。活性筛选发现，部分雷公藤二萜类化合物具有显著的抗肿瘤、抗炎及抗HIV-1活性；二氢沉香呋喃型倍半萜类化合物显示出中等强度的神经保护活性。以雷公藤内酯醇为先导物，设计并合成了18个一氧化氮供体型雷公藤内酯醇衍生物。经体外生物活性筛选、体内药效学评价、初步急性毒性实验以及作用机制研究，发现化合物ZT01可作为治疗脓毒症及黑色素瘤的候选药物。以雷醇内酯为先导化合物，通过一系列的氧化、还原、脱水及酯化等反应对雷醇内酯进行了多个位点的结构改造，得到了一批新型的雷醇内酯衍生物，并发现化合物B13具有显著的抗黑色素瘤活性，具有深入研究价值。