基于骆驼蓬生物碱为模板的β-咔啉类的二聚化合成、抗癌活性及其机理研究

项目名称： 基于骆驼蓬生物碱为模板的β-咔啉类的二聚化合成、抗癌活性及其机理研究

项目编号： No.31270388

项目类型： 面上项目

立项/批准年度： 2013

项目学科： 生物科学

项目作者： 王俊儒

作者单位： 西北农林科技大学

项目金额： 78万元

中文摘要： 恶性肿瘤严重威胁人类生命和健康，从植物中寻找抗肿瘤模板化合物仍是主要途径之一。前期本课题组从骆驼蓬中分离得到14个生物碱，其中7个β-咔啉类生物碱对人肺腺癌细胞A549生长具有明显的抑制作用。在此基础上，本项目拟选取从骆驼蓬中分离出的体外活性较好的基于芳香型咔啉类生物碱为先导模板的降哈尔满、哈尔满和去氢骆驼蓬碱等7个β-咔啉生物碱，通过化学合成的方法，在合适位置修饰和链接合成80多个二聚体孪药衍生物；在设置阳性、阴性对照以及单体对照多重实验控制的基础上，进行β-咔啉类二聚体体外细胞毒活性、活体抗肿瘤活性双重测试，筛选并确认出至少3-4种高抗肿瘤活性、低毒性β-咔啉类二聚体生物碱,并揭示该类化合物的抗肿瘤活性／毒性的构效关系；探讨β-咔啉类化合物的抗肿瘤作用机制，分析可能的作用靶点。上述结果将为筛选具有潜在临床应用前景的高效低毒β-咔啉类二聚体的新型抗肿瘤药物提供重要理论依据和物质支撑。

中文关键词： β-咔啉；二聚体；抗肿瘤；构效关系；作用机制

英文摘要： Therioma is a serious threat to human life and health. One of the main routes is still looking for anti-tumor template compounds from plants. During the former research 14 β-carboline alkaloids were isolated from Peganum L. by our group, and 7 of them were found to inhibit the growth of human lung cancer cell A549. On this basis, the present project intends to select these 7 aromatic-type β-carboline alkaloids as lead template, such as norharmalan, harmane and harmine, with in vitro good cell toxic activity separated from Peganum Harmala. Through chemical synthesis, more than 80 β-carboline dimmers(twin drug) derivatives will be synthesized with the modification in the appropriate location and links; With the multi-controls of the positive, negative and monomeric samples, these β-carboline dimeric alkaloids will be investigated with in vitro cytotoxic activity and in vivo anti-tumor activity,screening out at least 3 to 4 β-carboline dimeric alkaloids with highly antitumor activity and low cell toxicity, in order to reveal the structure-activity relationship of these compounds; and the antitumor mechanism of beta-carboline compounds will also be investigated, with the analysis of the possible functional targets. The results from these studies will provide an important theoretical basis and matter support for the

英文关键词： β-carboline；dimer；antitumor；structure-activity relationships；mechanism