Use this URL to cite or link to this record in EThOS: | https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.492498 |
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Title: | A 'click chemistry' approach to the synthetics of nucleoside triphosphate mimetics | ||||
Author: | Rowan, Andrew Stephen |
ISNI:
0000 0001 3538 4815
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Awarding Body: | Queens University Belfast | ||||
Current Institution: | Queen's University Belfast | ||||
Date of Award: | 2008 | ||||
Availability of Full Text: |
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Abstract: | |||||
Nucleoside triphosphates (NTPs) are substrates for numerous NTP-dependent
enzymes within the body, and thus are crucial for a wide variety of biological
processes. NTP mimetics would therefore be ideal candidates for chemical genetics
programmes, to perturb intracellular processes with exquisite precision by the
inhibition of selected proteins. We believe that replacement of the ~,y-pyrophosphate
moiety of an NTP with a monosaccharide may still lead to favourable enzyme binding
but lead to inhibition. Replacement of the a-phosphate group with a triazole linker
would facilitate cell permeability by removing any remaining charge, as well as
increase stability of the mimetic. Triazoles can be formed via the Cu(I)-catalysed
Huisgen 1,3-dipolar cycloaddition reaction of azides and terminal alkynes. A series of
propargyl glycosides of various monosaccharides have been synthesised, in most
cases possessing anomeric purity, and reliable protocols developed. A number of 5'azido
nucleosides have also been synthesised, and coupling reactions carried out to
obtain a library of 45 novel sugar-triazole-nucleosides. These compounds have been
tested as potential inhibitors of the type III pantothenate kinase from Bacillus
anthracis and one potent inhibitor discovered with a Kj of 164 p.M. This shows that
the inhibitor binds approximately three times more tightly in the active site than the
natural substrate ATP (Km = 475 M).
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Supervisor: | Not available | Sponsor: | Not available | ||
Qualification Name: | Thesis (Ph.D.) | Qualification Level: | Doctoral | ||
EThOS ID: | uk.bl.ethos.492498 | DOI: | Not available | ||
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