Thesis

The synthesis and application of tetrahydrobiopterin mimetics

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Awarding institution
  • University of Strathclyde
Date of award
  • 2012
Thesis identifier
  • T13670
Qualification Level
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Department, School or Faculty
Abstract
  • Nitric oxide is a small inorganic free radical which plays an essential role in mammalian biology. Nitric oxide synthases (NOSs) are responsible for producing nitric oxide within differing areas of the body and have crucial roles in various disease states, such as hypertension, septic shock and Alzheimer's disease. Modulating the activity of nitric oxide synthases may provide a viable route towards treating these and other disease states. Tetrahydrobiopterin (BH4) is an important coenzyme for nitric oxide synthase and, without it, nitric oxide production halts. It is with this in mind that synthetic analogues of BH4 have been prepared and tested previously. This led to the discovery of a particularly active pteridine known as WSG1002, which fell under the category of blocked dihydropteridines. One of the main aims of this PhD was to synthesise and assess various analogues of WSG1002, primarily for their NOS-activating properties. This work was carried out, not only in the hope of discovering a pteridine or related compound with a better BH4 mimetic profile but also with the aim of elucidating some of the properties that make blocked dihydropteridines such successful activators of NOS. Chapter 1 provides an introduction to NOS and the field of pteridines and aims to put this work into its proper context. Chapter 2 describes the work carried out towards a synthesis of a library of pteridines with variation at the 2-position. It also describes the development of challenging chemistry at the edge of what can be done with poorly activated pyrimidines. Chapter 3 describes the targeted synthesis of an analogue of WSG1002 which has been expanded at the 2-position. This chapter presents some unusual and unpredictable chemistry observed when working with pyrimidines and the fused systems derived from them. Chapter 4 presents the use of the Boon synthesis in an attempt to discover more active analogues of WSG1002. Variation was sought at the 5-, 6-, 7- and 8-positions on the pteridine ring system. Resynthesis of two compounds for further study was also carried out. Chapter 5 presents the work carried out in a bid to synthesise a deaza analogue of WSG1002. Here, pyridine chemistry was used extensively to provide a route to deazapteridines and other fused pyridines and the limitations of this chemistry are also presented. Chapter 6 provides the biological and computational assessment of some of the compounds made and describes the in-depth evaluation of a select few. Two compounds in particular have an excellent profile when concerned with NOS activation and the data presented herein are being used to shape the development of future BH4 mimetics. Chapter 7 presents all of the experimental and analytical details.
Advisor / supervisor
  • Suckling, Colin J.
  • Gibson, Colin L.
Resource Type
DOI
Date Created
  • 2012
Former identifier
  • 1005315

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