几类抗肿瘤天然产物及碳酸酐酶Ⅱ抑制剂的研究
其他题名Studies on several types of natural antitumor compounds and inhibitors of carbonic anhydrase Ⅱ
黄火强
学位类型博士
导师谭宁华
2008-06-05
学位授予单位中国科学院昆明植物研究所
学位授予地点昆明植物研究所
学位专业药物化学
关键词肿瘤 天然产物 碳酸酐酶ⅱ 水朝阳旋覆花 三角叶凤毛菊 倍半萜 细胞凋亡
摘要肿瘤是威胁人类生命健康的重要疾病,从天然产物特别是从植物中寻找抗肿瘤药物一直是一个研究热点,抗肿瘤细胞毒筛选模型是一种常用的高效快速的寻找抗肿瘤活性先导化合物的方法。骨质疏松症严重威胁人类特别是老年人的生活质量,寻找抗骨质疏松治疗药物的筛选方法很多,碳酸酐酶Ⅱ(CAⅡ)是其中的一个重要分子靶点。基于以上两种重要疾病和研究组方向,本论文工作开展了多个肿瘤细胞株和碳酸酐酶Ⅱ靶标模型的建立和筛选工作,累计筛选1万多个/次样品,发现10余个活性较强化合物;从粗提取物筛选结果中选取两种抗肿瘤活性强的菊科植物水朝阳旋覆花(Inula helianthus-aquatica)和三角叶凤毛菊 (Saussurea deltoidea)进行了系统化学和活性成分研究,分离鉴定了58个化合物,发现6个新化合物和14个抗肿瘤活性化合物;通过合作对水朝阳旋覆花中活性较强的bigelovin进行了抗肿瘤作用机制研究,发现它可能是通过降低G2期重要的转录因子E2F-1,致使细胞周期阻滞在G0/G1期,引起多发性骨髓瘤U266细胞凋亡;开展了7个新的天然酚类CAⅡ抑制剂的对接研究和61个合成的系列磺酰胺类CAⅡ抑制剂的3D-QSAR分析,结果表明计算与实验一致。以上研究结果为抗肿瘤天然产物和碳酸酐酶Ⅱ抑制剂的研究奠定了一定基础,具有一定的学术意义和应用价值。
其他摘要Tumor is a serious disease that destroys human lives and health. It is a highlight research field to find anti-tumor drugs from natural products, especially from plants. One of the most common and efficient methods for assessing anti-tumor candidates is the use of cancer cell lines. Osteoporosis is a serious disease to threaten human living quality. There are lots of screening methods normally used to find anti-osteoporotic drugs, and carbonic anhydrase Ⅱ (CAⅡ) is an important enzyme target. Based on these two diseases and the research field of our group, we investigated several studies. Several anti-tumor cell lines and carbonic anhydrase Ⅱ model were established. More than 10000 compounds and extracts from plants were screened using these models and about 10 compounds showed strong inhibitory activities. Two species of plants Inula helianthus-aquatica and Saussurea deltoidea were chosen to investigate chemical and bioactivity constituents based on the results of screening of extracts and fractions. 58 compounds were isolated and identified from these two plants, 6 compounds were found to be new and 14 compounds showed anti-tumor activities. We also studied the anti-tumor mechanism of the compound bigelovin isolated from Inula helianthus-aquatica. Bigelovin was found with apoptotic activity against cell line U266 by lowering the amount of important transcription factor E2F-1 which inhibits the cell cycle at G0/G1 stage. Docking study on 7 natural new phenolic inhibitors of CA Ⅱ and 3D-QSAR study on 61 sulfonamide inhibitors of CA Ⅱwere also investigated. The calculated results were in good correlation with experimental results. All these results established the foundation for further research of anti-tumor natural products and CA Ⅱ inhibitors. These results have important relevance for academic research and industrial applications.
页数204
语种中文
文献类型学位论文
条目标识符http://ir.kib.ac.cn/handle/151853/396
专题昆明植物所硕博研究生毕业学位论文
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黄火强. 几类抗肿瘤天然产物及碳酸酐酶Ⅱ抑制剂的研究[D]. 昆明植物研究所. 中国科学院昆明植物研究所,2008.
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