Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.597790
Title: Novel approaches towards the synthesis of heterocycles on solid phase
Author: Cobb, J. M.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2002
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Abstract:
The first chapter is an introduction to the field of combinatorial chemistry, particularly looking at the scope of this technique and some of the practical aspects. Solid phase combinatorial synthesis is covered, and the properties, use and analysis of resins are discussed. Solution phase and liquid-phase methods are also reported, and compared to solid phase synthesis. Chapter two describes the development of a new traceless linker for the solid-phase synthesis of heterocycles, and is divided into three main sections. The first is a literature review of linking strategies, focussing particularly on traceless linkers. The next section introduces the tyrosine kinases, particularly the epidermal growth factor receptor tyrosine kinase, and their role in the regulation of cell division. Various inhibitors of tyrosine kinases are discussed including the quinazoline pharmacophore, as are methods currently used to synthesise quinazolines. The feasibility of a decarboxylative linker for quinazolines is then investigated, using quinazolinone esters. The template is then loaded onto a specially functionalised resin, after which tests are carried out to determine the optimum conditions for functionalisation and cleavage of the desired product from the resin. Finally a small library of quinazolines is synthesised to test these conditions. The third section of chapter two concerns the application of the decarboxylative linker to other heterocycles, namely benzimidazoles. The pharmacological properties of benzimidazoles are briefly explored, as are current methods for synthesising benzimidazoles on solid phase. The feasibility of using a decarboxylative linker on this template is explored using a benzimidazole carboxylic acid, and then a method is developed to load this template onto resin via a Wang linker. Once loaded onto the resin, conditions for functionalisation and cleavage are explored. Chapter three concerns the development of a method for building nucleotide and nucleoside analogues on solid phase. It starts by reviewing the therapeutic areas that these analogues are implicated in, and the biological bases for their activities. The design of the analogues is then considered, from the point of view of both the potential activity and also ease of synthesis on solid phase. Next, a resin and linker are chosen which are compatible with the template and the proposed synthesis, and a range of chemistries are investigated for attachment of the substituents and removal of protection groups. Finally a small library of analogues is synthesised to test these conditions. The final chapter explores the application of dendrimers to solid phase synthesis and combinatorial chemistry. The chapter starts by introducing dendrimer chemistry and architecture, and briefly reviews the analysis and applications of dendritic macromolecules. The simple functionalisation of dendrimers is then investigated, along with purification and analysis of the products. Next, dendrimers are mono-functionalised and attached to resin beads in an attempt to increase the density of functionality of the resin. Techniques are developed to measure loading of the resin functionality and also the dendrimer functionality when attached to resin, and from these assays conclusions are drawn concerning the application of this method.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.597790  DOI: Not available
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