两种海南核果木属植物中新型抗肿瘤活性成分及其作用机制研究

Plants of genera Drypetes (Euphorbiaceae family) used as folk traditional medicines of Africa for the treatment of gonorrhea、cancer et al. But now, there has been no research on the antitumor activity of the chemical constituents of this genera. As part of our search for the novel natural product antitumor agents from Hainan medicinal plants, it was found that a crude ethanol extract of the stems of D. hainanensis and D. congestiflora exhibited good cytotoxicity against human lung cancer (SPCA-1) and human gastric cancer (SGC-7901) cell lines, and the petroleum ether- and chloroform-soluble fractions of the ethanol extract of D. congestiflora were further proofed to be the active components. This project intends to continue the cytotoxicity assay-guided fraction for this two species, and thus the following four scientific issues will be resolved: (1) The antitumor constituents of D. hainanensis and D. congestiflora were clarifyed; (2) The profile of active constituents in active components of D. hainanensis and D. congestiflora were established; (3) The analytical methods for separation and structure elucidation of active constituents from the genera Drypetes were established; (4) The action mechanism of active constituents on cell morphology、cell cycle、cell apoptosis、calcium ion concentration of intra-cellular were investigated. Based on these, one or two drug candidate molecules with novel structure、low toxic、well activity and selectivity will be screened out，and lay the foundation for creating the independent intellectual property rights of new antitumor agents.

大戟科(Euphorbiaceae)核果木属(Drypetes)植物为非洲民间传统药材，用于治疗淋病、恶性肿瘤等。但是,目前国内外并未针对其抗肿瘤活性成分进行研究。本课题组前期研究发现，海南核果木和密花核果木的乙醇提取物对人肺癌细胞（SPCA-1）和人胃癌细胞（SGC-7901）具有很好的毒活性，石油醚和氯仿萃取部位被确认为密花核果木的抗肿瘤有效部位。本项目拟继续采用活性追踪分离的方法，深入开展这两种药用植物的化学成分研究，重点解决以下4个科学问题：（1）阐明抗肿瘤有效部位的活性成分；（2）构建有效部位活性成分轮廓谱；（3）建立核果木属植物抗肿瘤活性成分的化学研究方法；（4）阐述活性成分对肿瘤细胞形态、细胞周期、细胞凋亡及胞内钙离子浓度的作用机制。通过本项目的研究，有望优选出1-2个结构新颖、活性强、选择性好、毒性低的药物候选分子，为创制自主知识产权的新型抗肿瘤药物奠定基础。

大戟科(Euphorbiaceae)核果木属(Drypetes)植物为非洲民间传统药材，用于治疗淋病、恶性肿瘤等。但是，目前国内外并未针对其抗肿瘤活性成分进行研究。海南核果木是海南岛特有植物，在民间用于治疗恶性肿瘤等多种疾病；密花核果木则主要分布于海南、广东、云南等省的山地疏林中。本项目首次采用活性追踪分离的方法，深入开展这两种药用植物的化学成分研究，共分离得到52个单体化合物，5个为新化合物。其中从密花核果木中分离得到33个单体化合物，其中2个结构新颖的倍半萜和1个结构新颖木栓烷型三萜，这是第三次报道从核果木属植物中分离得到桉叶烷型倍半萜类化合物，而诸如羽扇豆烷、木栓烷和齐墩果烷型三萜均是核果木属植物的特征性成分，所有化合物均为首次从密花核果中分离得到；从海南核果木中分离得到19个单体化合物，其中2个结构新颖的齐墩果烷型三萜42和43，除化合物37和40，其余化合物均为首次从海南核果木中分离得到。抗肿瘤活性研究发现化合物42和43对宫颈癌Hela和肺腺癌A549细胞具有很好的增殖抑制活性，IC50值为3.04-3.85g/mL。进一步研究发现这两个化合物可以改变肿瘤细胞形态和引起细胞内的活性氧（ROS）水平的升高而表现出肿瘤细胞毒活性。