【作者】 丁红霞；

【导师】 赵昱； 吕伟；

【作者基本信息】 浙江大学 ， 药物分析学， 2006， 博士

【摘要】 以活性天然产物为先导化合物,对其进行合成或结构修饰是发现抗肿瘤药物的重要途径之一。鬼臼毒素类化合物和异喹啉类生物碱是植物界分布很广的两大类抗肿瘤天然产物。本论文的研究工作主要是围绕这两类天然产物展开。 论文的第一部分阐述的是鬼臼毒素类衍生物的设计与合成,以及对它们进行的抗肿瘤活性和构效关系研究。我们共设计合成得到了两大类,四系列目标化合物。第一大类是由鬼臼毒素与不同异喹啉母环杂合而成的三系列类似物,分别为B、E环上不同取代的1-芳基-3,4-二氢异喹啉系列、1-芳基-芳香异喹啉系列和N-苯甲酰基-1-芳基-1,2,3,4-四氢异喹啉系列。第二类是E环为不饱和长链取代或D环开环的4-去氧异鬼臼毒素衍生物。 体外生物活性测定表明一些合成的目标化合物具有显著的细胞毒活性,它们的IC₅0值达到了10^-6 mol/L级别。根据活性测定结果我们对杂合了鬼臼毒素和异喹啉结构特征的三系列化合物进行了构效关系研究,并利用计算机模拟运算（coMFA）分析,构建了一个初步的3D-QSAR模型,为进一步的药物设计提供指导。 论文的第二部分是对从植物中分离得到的一个新颖的细胞毒性4,5-二羰基阿朴菲类异喹啉生物碱Artabotrine（6.1）及其类似物N-methoxycepharadion B（6.2）的全合成研究。我们以简单易得的2-甲氧基苯酚为起始原料,运用Suzuki交叉偶联反应得到关键中间体联苯乙酰胺,再经草酰氯/四氯化锡作用,一体化依次构建C/B双环,即可简便地合成目标化合物。这条路线仅需5-7步反应,大大简化了4,5-二羰基阿朴菲类生物碱的合成,对此类化合物的深入研究具有重要意义。 同时,我们也对6.1和6.2进行了体外细胞毒活性测定。Artabotrine并没有显示出很好的抑制活性,而其类似物6.2却对Hela细胞有比较强的抑制作用,可以作为进一步研究的先导化合物。更多还原

【Abstract】 An important approach for the discovery of antitumor drugs is the synthesis and structure modifications of active natural products. Podophyllotoxins and isoquinoline alkaloids, wide-spreaded in plants, are two kinds of antitumor natural products. In this thesis, the studies were carried out on them and consisted of two parts.The first part is the design, synthesis, anti-tumor activity and SAR studies of podophyllotoxin derivatives, including two classes, four series of new compounds. One class of compounds is composed of three series of novel compounds as hybrids of podophyllotoxin with different types of isoquinolines. These three series of compounds we designed were 1-phenyl-3,4-di-hydroisoquinolines, 1-phenylisoquinolines and N-benzoyl-1-phenyl-1,2,3,4-tetra-hydroisoquinolines with different substitutes on B and E rings. The other class of compounds is 4-deoxyisopodophyllotoxins with unsaturated aliphatic side chains on the E-ring or with the D-ring opened.In vitro biological evaluation indicated that some of the synthetic compounds existed remarkable cytotoxicities with IC50 Values on selected tumor cell lines at 10^-6 mol/L scale. With the cytotoxicitic results, SAR studies of three series of hybrids were performed, and a 3D-QSAR model was built by the preliminary CoMFA molecular-modelling study, which could be a guide for further drug design.The second part is the total synthesis of a novel cytotoxic 4,5-dioxoaporphine alkaloid, artabotrine （6.1）, and one of its analogue N-methoxycepharadione B （6.2）. The syntheses started from guaiacol, which was commercially available. By Suzuki cross-coupling reaction, the key intermediates biphenylacetamide were obtained. Following with the condition of （COCl）₂/SnCl₄, the target compounds were facilely achieved by one-pot sequential C/B ring formation. This pathway simplifies the synthesis of 4,5-dioxoaporphines, which is significant for future research of this kind of alkaloids.Moreover, the two targets were subjected to the screening of cytotoxicity in vitro. Artabotrine did not exhibit potent activity, while its analogue 6.2 was cytotoxic to Hela cells and could be a lead compound for further study.更多还原