【作者】 杜祖银；

【导师】 赵康；

【作者基本信息】 天津大学 ， 应用化学， 2013， 博士

【摘要】 树状大分子由于其独特的结构与性能，如单分散性、纳米级尺寸、规整的结构、丰富的表面官能团和特定的内部空穴，使其在催化、光电材料、药物传递等众多领域受到了广泛的关注。作为药物载体，树状大分子有其独特的优势，它们可以通过多种途径与药物分子作用，如包合、表面键连等。本论文的工作就是利用上述优点来制备树状大分子前药。1.我们对整个树状大分子研究领域做了广泛的调研，对树状大分子的结构与性质、合成方法以及应用，特别是在医药和生物技术领域中的应用做了回顾与总结。在此基础上，我们提出了课题设计的主体框架。2.为了能够更有效地合成所需要的树状大分子前药，我们对合成方法和合成途径做了探索性试验。以邻甲氧基苯甲酸为药物模拟物，合成了3代的树枝元和3代的树状大分子，并对合成过程中的关键酯化步骤做了充分的条件筛选，找到了酯化的最佳条件，即DCC/DPTS体系。此外，发散法被证明更有利于得到高代数的树状大分子。3.非甾体抗炎药树状大分子前药的合成。首先，将布洛芬或者阿司匹林连接到酒石酸二苄酯的其中一个羟基上，得到单羟基酯，然后用该结构单体与多元酸中心核反应，再经去保护与偶联反应，得到了两种2代的布洛芬树状大分子前药和一种2代的阿司匹林树状大分子前药；另外，我们还对两种1代的布洛芬树状大分子前药的表面基团做了修饰，得到了载药量更高的前药。值得指出的是，酒石酸的多官能团特点赋予了结构单体的多样性，这样不仅可以得到许多内外连有相同药物分子的树状大分子前药，而且还可以依据药物拼合原理将不同的药物连接到树状大分子的骨架上，且能很方便地调控药物分子在树状大分子骨架结构中的位置。这种基于酒石酸的树状大分子前药的设计思想未见文献报道，使得我们所合成的这些树状大分子前药具有一定的新颖性。4.一氧化氮释放型非甾体抗炎药树状大分子前药的合成。采用三组分的Passerini反应将表面为羧基的树状大分子、布洛芬或者阿司匹林的醛类衍生物以及连有硝酸酯基团的异腈化合物经“一锅法”组合到一起，得到了4个一氧化氮释放型非甾体抗炎药树状大分子前药。多组分反应是获得分子多样性的有效途径，已经被用于组合化学中药物库的合成。然而，以树状大分子或者是其它高分子为载体，通过多组分反应来构建大分子或者高分子前药却未见文献报道。通过这一途径，我们可以将药物拼合原理、前药原理和载体药物设计理论融合到一步反应中，从而极大地促进新药，特别是新型药物传递系统的开发进程。因此，不管是从研究价值还是从应用前景来看，开展基于多组分反应的树状大分子前药的研究都具有深远的意义。更多还原

【Abstract】 Dendrimers have attracted much attention in the fields of, for example, catalysis,electrooptic materials and drug delivery due to their unique properties such asmonodispersity, nanoscale sizes, well-defined structures, plenty of terminal surfacegroups and specific cavities in the interior. As drug carriers, dendrimers havedistinctive advantages and can interact with drugs via encapsulation, attachment ontothe surface etc. This thesis focuses on the preparation of dendritic prodrugs.1. An extensive survey has been done for dendrimers, in which the profiles ofstructures, chemophysical properties, synthetic approaches, and applicationsespecially in medicine and biotechnology have been reviewed. Thereafter, a projecton dendritic prodrugs was proposed based on this survey.2. In order to get these desired dendritic prodrugs some preliminary experimentswere carried out to find out the optimized routes and methods. In the exploration, onethird-generation dendron and one dendrimer with the same generation were obtainedusing2-methoxybenzoic acid as a drug surrogate. Meanwhile, it was found thatDCC/DPTS was the optimum condition for the key esterification step. Moreover, incontrast to the convergent approach, the divergent one proved itself a better way tosynthesize higher generation dendrimers.3. Synthesis of dendritic prodrugs incorpoarting non-steroidal anti-inflammatorydrugs (NSAIDs). Initially, the reaction of dibenzyl tartrate with ibuprofen or aspirinyielded a certain monomer with only one hydroxyl group which was subsequentlycoupled to the multi-carboxylic acid core, and then the product obtained wassubjected to hydrogenolysis and coupled with the monomer again. In this iterativeway, two ibuprofen dendritic prodrugs of generation2and one aspirin dendriticprodrugs of the same generation were produced. At the same time, two dendriticprodrugs with higher drug payload were obtained through the reaction ofbromomethyl ibuprofen with the carboxyl groups on the surface of two kinds offirst-generation ibuprofen dendritic prodrugs. It is noteworthy that themulti-functionality of tartaric acid makes itself versatile, which allows for thepreparation of dendritic prodrugs with the same drugs in the interior and at theperiphery of dendrimers, as well as dendritic prodrugs with different drugsincorporated into the dendrimer scaffolds just by using different monomers. So far the dendritic prodrugs based on tartaric acid have not been reported.4. Synthesis of dendritic prodrugs conjugated with both nitric oxide(NO)-releasing moieties and non-steroidal anti-inflammatory drugs (also referred toas NO-NSAID dendritic prodrugs). Four NO-NSAID dendritic prodrugs weresynthesized through the way that dendrimers with surface carboxyl groups,aldehydes derived from ibuprofen or aspirin and the isocyanide coupled to anorganic nitrate were combined together via Passerini reaction, a “one-pot” reactioninvolving three components. Now multi-component reactions are among the mostefficient tools for the construction of drug candidate library in combinatorialchemistry. However, there is no report on the preparation of dendritic ormacromolecular prodrugs via a multi-component reaction using dendrimers or anyother macromolecules as carriers. Admittedly, this strategy can take combinationprinciples, prodrug principles and theory of drug-carrier design into a single reaction,which will probably boost the drug development, and particularly the research anddevelopment of drug delivery systems. To sum up, it deserves to make efforts toapply more multi-component reactions to the synthesis of dendritic prodrugs fromthe views of both academics and industry.更多还原