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Title: Synthesis of novel heterocycles targeted at tumour vasculature
Author: Edwards, David John
ISNI:       0000 0004 2677 2180
Awarding Body: The University of Manchester
Current Institution: University of Manchester
Date of Award: 2004
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This thesis is concerned with the synthesis of novel heterocycles targeted at the destruction of tumour vasculature whilst leaving normal blood vessels intact. They do this by binding to tubulin and preventing its assembly into microtubules. Chapter 1 introduces tubulin and the concept of tubulin binding agents, clinically important compounds that bind tubulin and the problem of multi-drug resistance. Chapters 2, 3 and 4 contain a detailed analysis of the structural elements of two important tubulin binding agents colchicine 6 and the clinically important combretastatin A4 4j and introduces the concept of atropisomerism. Much research has been based on exploiting the ability of these two compounds to disrupt the assembly of tubulin and a review of the structural analogues synthesised in previous work is contained here. A summary of the main patterns present in the data is presented in Chapter 4. Chapter 5 contains an experimental plan proposed towards the synthesis of these novel heterocycles and a review of the various methods of synthesising the important biaryl-bond including methods which are atroposelective. Chapter 6 contains a discussion of the work carried out towards the synthesis of dibenzo[c,e]oxepines, dibenzo[c,e]azepines and dibenzo[c,e]thiepines including the use of the Suzuki and oxazoline-mediated displacement reactions culminating in the synthesis of the required biaryls by use of intramolecular copper(l) coupling of bisstannanes and the copper(O) Ullmann coupling reaction of aryl bromides. X-ray analysis of five new heterocycles was carried out and a detailed analysis of the data presented. Chapter 7 contains a discussion of the work carried out in the synthesis of biaryl lactams directed at the atroposelective synthesis of dibenzo[c,e]azepines and the development of new methodology for the control of axial chirality. In the final chapter full experimental procedures and analytical data for the compounds prepared are presented. Bibliographic references and publications are included after this chapter.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available