Synthesis and modification of pamam dendrimers as histone replacement molecules

摘要

The primary objective of this work was to synthesise and structurally modify a series of PAMAM dendrimers with a view to investigating and controlling their complexation with, and compaction of, DNA. The Introduction gives an overview to the origins of polymer and dendrimer science, and describes the synthetic approaches and resulting properties of dendrimers together with their impact on biological systems. The preparation of poly(amidoamine) (PAMAM) dendrimers utilising a number of different core materials are reported and characterised in Chapter 2. The conformational motion of the dendritic branches has been studied using 1H spin-lattice relaxation time experiments, and the results have been compared for the differently cored materials. Chapter 3 examines the modification of the dendrimer surfaces with acetyl, poly(ethylene glycol) and fluorescent groups and reports the results of a study of how the degree of DNA condensation affects gene expression by analysing dendrimer-DNA compaction using linear dichroism, dynamic light scattering and competitive binding of ethidium. Experiments designed to investigate modified dendrimer-lipid interactions are also discussed and the results of these are compared to molecular dynamic simulations. The synthesis of novel small molecules based around L-histidine and photo-responsive azobenzene, and the use of these to modify the surface of 4th and 5th generation PAMAM dendrimers is reported in Chapters 4 and 5 respectively. There follows a final chapter containing detailed descriptions of the synthetic procedures and characterisation for each of the compounds studied and the experimental methods used for exploring their behaviour