从藏药材植物中靶向分离抗癌活性新成分

To discover bioactive constitutes and lead compounds with novel structures are crucial to the development of new drugs with independent intellectual property rights. Tibetan plateau, with hundreds of endemic Tibetan herbs, exhibits unique geographical and ecological features such as high altitude, strong radiation, and large temperature difference. Special environment makes it possible for these herbal plants to produce unique secondary metabolites. By now, more than one hundred Tibetan herbs were found to possess different bioactive effects, such as clearing heat and removing toxicity, eliminating phlegm and diminishing swelling, vermicide and etc. These herbs have been using for many years to treat diseases like sarcoma, carbuncle and abdominal distension and so on. These investigations indicated that some constitutes of these herbs might have antitumor activities. Based on this hypothesis, we are planning to perform a systematic investigation on some above Tibetan herbs which have not been or have only been slightly investigated, such as Przewalskia tangutica, Heracleum millefolium Diels, and Sinopodophyllum hexandrum (Royle) Ying etc. Tandem mass spectrometry and HPLC-MS will be used to obtain chemical structural information, and cytotoxic activity assay will be employed to evaluate the anticancer activity of the herbs. One to three herbs which contain more bioactive new compounds will be chosen for further study by means of cytotoxic activity assay and LC-MS guided isolation to targeted separate bioactive new compounds. Followed by the evaluation of anticancer activities and synergistic actions of the obtained new compounds.

结构新颖奇特的活性成分和先导结构是我们研发具有自主知识产权新型药物的基础。由于青藏高原具有高海拔、高辐射、强光照、大温差等独特的生态环境，造就了植物生长及其次生代谢产物的特殊性，形成了数百种神奇高原独特的藏药植物。其中有上百种具有清热解毒、杀虫、消肿等功效，用于治疗肉瘤、痈疮、腹胀等疾病的藏药植物，当中部分可能含有抗肿瘤活性成分。我们拟选用马尿泡（藏药名：唐冲嘎保）、裂叶独活（藏药名：巴木保）、唐古特铁线莲（藏药名：叶芒那布）等迄今还未进行过活性成分研究，或是已有研究但很不深入的上述可能含有抗肿瘤活性的10种藏药植物，通过串联质谱和液-质联用所提供的化学结构信息并结合细胞毒活性和诱导细胞凋亡活性追踪，筛选出3种可能含有较多新结构且具有抗肿瘤活性的高原植物放大采集量，然后在化学信息和抗肿瘤活性追踪下，靶向分离具有抗肿瘤活性的新化合物，力争发现具有开发价值的先导结构。

本项目对三种藏药材化学成分进行研究，从唐古特铁线莲全草的正丁醇部位分离得到18个三萜皂苷类化合物，其中新化合物8个，并水解制备1个新的次级苷。细胞毒活性测试显示，化合物11-14对SGC-7901、HepG2和HL-60具有较强的细胞毒性，对U251MG显示中等强度的细胞毒活性；其中，化合物14的细胞毒活性最强，对这四种细胞株（SGC-7901、HepG2、HL-60和U251MG）的IC50依次为8.18、1.88、5.21和17.32 μmol/L；化合物4和6只对SGC-7901显示出微弱的细胞毒活性，IC50分别为24.14和21.35 μmol/L。.从马尿泡全草正丁醇部位分离鉴定出20个极性化合物，其中新化合物3个，均为氯代酚苷类化合物。3个新化合物（30-32）中只有32对SMMC-7221显示微弱的细胞毒活性，IC50为38.1 μmol/L。.从藏橐吾全草的甲醇提取物中共分离鉴定化合物37个，其中倍半萜类化合物32个，包括新化合物17个。细胞毒活性测试显示，艾里莫芬烷型（eremophilane）倍半萜表现出很好的细胞毒活性，其中新化合物21、22、23、24对MV4-11的IC50值小于0.9 μg/mL；新化合物23和24对A549、HGC-27、HeLa三种细胞均表现较好的细胞毒活性，但两者之间存在明显的差异，可能是结构中OH的构象不同导致的。从藏橐吾植物中分离得到的三种骨架类型的型倍半萜，细胞毒活性最好的是艾里莫芬烷型，其次是没药烷型，最后是Oplopane型。