一种活性海洋天然产物的合成、衍生化及生物活性分析-synthesis, derivatization and biological activity analysis of an active marine natural product.docx

第四章，采用多样性合成策略，设计合成了 12 个骨架各异的愈创木薁类衍生物，包括单体、二聚体及三聚体。综合运用 TLC、HPLC 等分析分离手段，结 合多种波谱学技术(NMR、MS、IR、UV)鉴定了它们的化学结构，其中 7 个新化 合物，4 个为新骨架化合物。对获得的系列薁类衍生物进行了体外抗肿瘤、抗炎、 抗病毒、抗菌、群体感应抑制等生物活性评价。结果显示化合物 GA、2b、2d、 2e、3a、3b 对流感病毒 H1N1 具有强抑制活性；单体化合物 1a-c 及二聚体 2d、2e 对 HeLa(人宫颈癌细胞株)、HL-60(人早幼粒白血病细胞株)、K562(人慢性髓 原白血病细胞株)三种细胞株具有中等强度的细胞毒活性；化合物 1a、1c、2d 在 50μg/ml 水平对铜绿假单胞菌群体感应系统存在一定的抑制作用。综上所述，本论文首次完成了目标物 7-异丙基-1, 4-二甲基薁-3, 5-二酮的制 备工艺优化，为后续广谱活性筛选奠定了物质基础；采用多样性合成策略，设计 合成了系列愈创木薁类衍生物，为生物活性筛选奠定了物质基础；并对其进行生 物活性评价，发现了新的抗流感病毒 H1N1 的愈创木薁类衍生物，为抗病毒药物 研究提供了新的活性结构；本论文将多样性合成策略运用到薁类化学相关研究 中，显示出多样性合成的研究方法在寻找新型高活性薁类衍生物中的重要意义。关键词：薁类衍生物；单因素逐因子；目标物定向合成；多样性导向合成；生物 活性The Synthesis, Derivatization and Biological Activity of An Active Marine Natural ProductAbstractNatural products with rich structure diversity and novelty provide an important template structure for drug research. However, limited resources of natural product impact the follow-up research work of the template molecules. Semi-synthetic chemistry is one important way for solving the quantifing of natural product to explore in depth the biological activity of the template molecules; Secondly, based on the reactivity of the template molecules using diversity-oriented synthesis strategy to synthesize “Natural product-like” compounds with structure diversity and novelty aiming to discover new active molecules, is an important exploring field for the synthesis of natural product.In the previous study, our research group obtained a new natural product 7-isopropyl-1, 4-dimethylazulene-3, 5-dione from a gorgonian Muriceides collaris collected in South China Sea. This compound showed very strong antibacterial activity against Vibrio anguillarum by the preliminary bioassay. Subsequently, the further studies on broad spectrum antibacterial tests for the compound encountered a serious difficulty due to the insufficient amount obtained from the marine organism. Meanwhile, azulene derivatives show good biological activities. So, the following work were carried out base