生物碱化合物成药性好，是新药发现的重要源泉。一叶萩型生物碱具有广泛的生物活性，具有研究开发前景。由于其结构的特异性，该类化合物展现出一些特殊的化学反应性质和生物活性规律。我们前期的研究发现，一些天然一叶萩型生物碱易于形成二聚体、三聚体甚至四聚体，推测其生物合成途径符合一些特定化学反应规律；研究还发现一叶萩型生物碱具有良好的抗肿瘤活性，且表现为二聚体的抗肿瘤活性强于单体化合物。为揭示这些科学问题，本项目拟开展如下研究工作：模拟生物途径合成出天然一叶萩型生物碱二聚体及其衍生物；以DNA拓扑异构酶为靶标研究该类化合物的抗肿瘤作用活性；研究二聚体及其衍生物的抗肿瘤作用构效关系，发现新型抗肿瘤先导化合物；通过研究其与人类拓扑异构酶以及超螺旋DNA（pBR322）的反应，探讨二聚体生物碱的抗肿瘤作用机制。为新型抗肿瘤药物的研究提供科学依据。

With excellent druggability, alkaloids were considered to be important sources of new drugs. Securinega-type alkaloids showed a wide range of biological activities with a fine developing prospect. They exhibited some unexpected characteristic reactions and biological properties due to their unique structural features. It was found that some securinega-type alkaloids could easily lead to the formation of dimers, trimers as well as tetramers, and displayed the biosynthetic pathways in distinict chemical reactions. Furthermore, it was demonstrated that securinega-type alkaloids exhibited potent cytotoxity against certain cancer cells, and the antitumor activity of dimers was prior to that of monomers. In order to solve these scientific puzzles, this project will launch the following issues: biomimetic synthesis of natural dimeric securinega-type alkaloids as well as their derivatives, and inhibition studies of human topoisomerases to evaluate their antitumor activity. The structure-activity relationship of dimers will be studied to identify their pharmacophore for antitumor, and to find leading compound of anticancer drug.In addition, we will further investigate the interaction between the topoisomerases and supercoiled DNA（pBR322）with dimeric securinega-type alkaloids to explore their action mechanism of antitumor. The results of this study will provide a scientific basis for research of novel anticancer agents.