茶茱萸科植物富含喜树碱等成分，从中寻找抗肿瘤活性生物碱存在巨大的潜力。该科植物定心藤为瑶药“十八钻”之一，民间用途广泛，已有动物实验证实其具有显著的体内抗肿瘤活性，但对其活性成分和作用机制缺乏系统研究。申请者前期对定心藤生物碱活性部位进行了初步的化学成分研究，发现6个β-咔啉生物碱，其中3个为骨架新颖的β-咔啉。体外抗肿瘤活性测试表明2个β-咔啉生物碱具有显著的肿瘤细胞生长抑制活性，并对其中1个骨架新颖的化合物进行了初步的作用机制研究。基于上述的研究工作基础，本项目拟采用活性跟踪的方法，对广西产定心藤和绒毛定心藤中生物碱活性部位进行系统研究，期望获得β-咔啉生物碱至少30个。对分离得到的化合物进行体外抗肿瘤活性评价，总结构效关系，并选择骨架新颖、活性显著的β-咔啉生物碱开展作用机制研究。优选出1-2个值得深入研究的新颖β-咔啉生物碱，为进一步创制具有我国自主知识产权的抗肿瘤药物奠定基础。

A number of plant species belonging to the family Icacinaceae contain camptothecin and its derivatives, so there is huge potential to find novel antitumor alkaloids from this family. Of the family Icacinaceae, Mappianthus iodoides, one of the Yao medicine “18 drill”, is used widely by local people for the treatment of hepatitis, and its extract also possessed significant in-vivo antitumor activity in animal experiments. However, the active constituents and mechanism are still lack of systematic investigation. In our previous research on M. iodoides by means of acid-base extraction, 6 β-carboline alkaloids were isolated from one alkaloid rich fraction, including 3 novel compounds. The in-vitro antitumor test showed that 2 β-carbolines have the effect of inhibiting all the tested cell lines, and one novel compound was chosen for preliminary mechanism study. On the basis of above work, we were intended to systematically isolate the alkaloids from M. iodoides and M. tomentosus yielded in Guangxi following a bioassay-guided approach, expect to obtain at least 30 β-carbolines. Then the isolated alkaloids will be screened for their antitumor activities. The structure-activity relationship will be summarized, as well as the mechanism of several novel alkaloids will be selectively evaluated, so as to discover 1 or 2 leading compounds for further antitumor research.

茶茱萸科植物富含喜树碱等成分，从中寻找抗肿瘤活性生物碱存在巨大的潜力。该科植物定心藤为瑶药“十八钻”之一，民间用途广泛，已有动物实验证实其具有显著的体内抗肿瘤活性，但对其活性成分和作用机制缺乏系统研究。前期研究发现定心藤富含β-咔啉生物碱，其中2个β-咔啉生物碱具有显著的肿瘤细胞生长抑制活性。在此基础上，对两种定心藤属植物进行了系统的化学成分研究，共分离鉴定了79个化合物，其中19个为新化合物（包括13个结构新颖的β-咔啉型生物碱）。对所有生物碱进行了体外抗肿瘤活性评价，发现了6个活性较好的化合物；对部分非生物碱进行了抗神经炎症活性测试，发现了13个活性较好的化合物。进一步通过Annexin V/PI共染色、Hoechst 33258荧光染色、JC-1、ROS测定实验等方法初步探讨了两个生物碱的凋亡诱导机制。以上研究内容为充分合理利用广西特色药用资源，从中发现抗肿瘤先导化合物提供理论依据。