Design And Synthesis Of Novel Dendritic Prodrugs

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.