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Title: The design of a prodrug to utilise the thymidine phosphorylase enzyme
Author: Campbell, Robert Malcolm
Awarding Body: University of Aberdeen
Current Institution: University of Aberdeen
Date of Award: 2003
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The current study has investigated the design of a prodrug to utilise the thymidine phosphorylase enzyme, based on combining HPMA copolymer technology with a thymidine analogue to deliver 5-fluorouracil or other cytotoxic agents selectivity to cancer tumours.  A detailed review has been compiled covering, -  Thymidine phosphorylases and its biological activity -  The expression of thymidine phosphorylase in normal and cancer tissues. -  The crystallographic data on thymidine phosphorylase and the proposed models of the mechanism of thymidine phosphorylase. -  The literature on substrates and non-substrates for the thymidine phosphorylase enzyme.  This information in combination with the crystallographic and the proposed models has allowed a profile of the enzyme’s specificity and the substrate interactions involved to be built. -  The literature on thymidine phosphorylase inhibitors. Enzyme assay procedures and an HPLC technique for the quantification of the products of the thymidine phosphorylase enzyme reaction have been developed.  Allowing the steady state kinetics for the dual substrate reaction of thymidine phosphorylase to be investigated.  Apparent Michaelis-Menten kinetics has been shown to be a good first approximation for the enzyme and the true kinetic parameters have been determined for the E. coli thymidine phosphorylase. Thymidine and 2’-deoxyuridine have been synthesised by a new synthetic route from D-ribose and thymine and uracil respectively.  The synthesis and testing of a range of substituted thymidine analogues has been achieved using traditional nucleoside chemistry and new approaches such as alkene cross metathesis.  The compounds produced have been tested with thymidine phosphorylase to try and determine a linkage point for the HPMA.  To try and understand why some of the compounds were not substrates the inhibition of the enzyme by these compounds has also been investigated. As a result of this investigation the design of a prodrug to utilise the thymidine phosphorylase enzyme has been re-evaluated.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available