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dc.contributor.advisorHouston, Todd
dc.contributor.authorWilkinson, Brendan Luke
dc.date.accessioned2018-01-23T02:30:08Z
dc.date.available2018-01-23T02:30:08Z
dc.date.issued2007
dc.identifier.doi10.25904/1912/557
dc.identifier.urihttp://hdl.handle.net/10072/366473
dc.description.abstractWithin a short timeframe, the CuI-catalysed 1,3-dipolar cycloaddition (1,3-DCR) of an organic azide to a terminal acetylene to form a 1,4-disubstituted-1,2,3-triazole, has emerged as a powerful synthetic transformation in combinatorial chemistry, organic synthesis and bioconjugation research. This synthetic methodology, now known as click chemistry, has had an appreciable impact in the drug discovery and biotechnology sectors and has shown broad scope and compatibility with small molecule and polymeric substrates. The application of this powerful synthetic transformation, specifically in carbohydrate based drug discovery and glycobiology is a recent and emerging trend. Chapter one of this thesis is a review of the current literature concerning the use of click chemistry in carbohydrate based drug discovery and glycobiology. Several examples have appeared within the literature highlighting the potential of click chemistry for rapidly generating structurally diverse neoglycoconjugates, ranging from small molecule drug leads to multivalent constructs, as well as a bioconjugation strategy for labelling cell-surface glycoconjugates. The review aims to be exhaustive in its coverage, with emphasis on future perspective. This thesis presents the investigation of click chemistry as a synthetic tool in carbohydrate chemistry, and its application for generating novel carbohydrate based enzyme inhibitor libraries for lead discovery and optimisation purposes. Chapter two describes the utility of click chemistry and the glycosyl triazole moiety in synthetic carbohydrate chemistry. The reaction is well suited to the synthesis of mimetics of complex oligosaccharides and glycoconjugates, owing to the mild ambient nature and remarkable regio- and stereo- selectivity. The transformation was therefore interrogated under conditions typically encountered in carbohydrate chemistry, including glycosylation reactions and protective group manipulations. The study represents the first exhaustive investigation into the stability of the triazole moiety under these conditions as well as the synthetic utility of the CuI-catalysed 1,3-DCR as a potential orthogonal transformation in carbohydrate chemistry and an adjunct to existing methods. The first aspect of the study aimed to examine the stability of the glycosyl triazole moiety under conditions employed in protective group chemistry and the compatibility of the transformation with pre-installed functional groups. Using click chemistry, the triazole moiety could be introduced onto the carbohydrate scaffold in the presence of a wide range of protective functional groups. In addition, the 1,2,3-triazole moiety was indeed shown to be a robust entity that is compatible with essential protecting group manipulations and glycosylation chemistry - an important outcome with respect to its potential utility as an additional tool for the synthesis of oligosaccharide/glycoconjugate mimetics, which are often heavily reliant on orthogonal reaction sequences. Next, the utility of the reaction with respect to solvent and catalyst conditions was examined. The reaction was performed in different organic and aqueous solvents in the presence of two different CuI-catalyst systems. It was shown that the reaction is reasonably insensitive to the nature of the solvent or aqueous co-solvent and the catalyst system. Reaction times and yields displayed little variation with respect to the solvent and catalyst system. In all cases, the 1,4-disubstituted 1,2,3-glycosyl triazole model compound was isolated in high yields and required minimal purification. The work also amply demonstrated, in a proof-of-concept manner, the powerful scope of the reaction for preparing structurally diverse neoglycoconjugates in high yield and purity. Several artificial glycomimetics were prepared using a suite of glycosyl azides through the facile 1,3-DCR to a series of acetylenes. Chapter three presents an extensive study into the preparation and biological activity of glycoconjugate benzene sulfonamides as a novel class of carbonic anhydrase (CA) inhibitor. The conjugation of carbohydrate “tails” to a benzene sulfonamide pharmacophore provides access to CA inhibitors which are neutral, water-soluble and features high chiral density and polyfunctionality that may be exploited for tissue delivery applications and to survey active site architectures in order to impart isozyme selectivity. Glycoconjugate benzene sulfonamides could also display compromised plasma membrane permeability allowing for the selective targeting of tumour associated isozymes with extracellular catalytic domains. Glycoconjugate benzene sulfonamides have received little attention as CA inhibitors, and this work represents the first comprehensive study in the area. By utilising a novel “click-tailing” strategy developed in our laboratory, a panel of structurally diverse carbohydrate “tails” were appended to the primary arylsulfonamide (ArSO2NH2) pharmacophore. A panel of azido sugars and propargyl glycosides were reacted with acetylene- and azide-functionalised benzene sulfonamide scaffolds, respectively, and subsequently evaluated for their inhibition of human carbonic anhydrase (hCA) isozymes hCA I, II, IX, XII and XIV in vitro. In this manner, a total of 50 glycoconjugate benzene sulfonamides belonging to three libraries were prepared and assessed for their inhibition of human cystolic isozymes hCA I, II and transmembrane isozymes hCA IX, XII and XIV. Selective inhibition among CA isozymes is challenging owing to conservation of active site topology within this enzyme family, yet the design of selective CA inhibitors is necessary for the development of efficacious and safe CA-based therapeutics which are void of side effects arising from systemic CA inhibition. Many of the glycoconjugate benzene sulfonamides exhibited a non-clustered in vitro inhibition profile, demonstrating that the carbohydrate tail was a powerful structural element able to distinguish isozyme selectivity. A significant outcome of this study was the discovery of several potent and selective CA inhibitors of the tumour-associated transmembrane isozyme, hCA IX, and the physiologically dominant cytosolic isozyme, hCA II. Chapter four of this thesis explores the synthetic utility of click chemistry for the solution-phase synthesis of N-alkylated azasugar libraries. To date, click chemistry has seen limited application for the synthesis and screening of natural product-based libraries. To the best of my understanding, this work represents the first example of the use of click chemistry for the generation of azasugars containing structurally diverse N-alkyl substituents as potential glycosidase and glycosyltransferase inhibitors. By employing the click chemistry methodology, various synthetically accessible aliphatic and aromatic azides were conjugated to the acetylene-functionalised 6- and 7-membered ring N-propynyl azasugar scaffolds using click chemistry, thus providing expedient access to N-methylene triazole-substituted azasugars in a single, high yielding step. The work demonstrates the applicability of the reaction for generating not only the structural diversity deemed necessary for distinguishing inhibitory potency and selectivity, but also a powerful means of tuning the physicochemical properties of the azasugar for in vivo targeting and lead optimisation purposes.
dc.languageEnglish
dc.publisherGriffith University
dc.publisher.placeBrisbane
dc.rights.copyrightThe author owns the copyright in this thesis, unless stated otherwise.
dc.subject.keywordsclick chemistry
dc.subject.keywordscarbohydrate based enzyme inhibitor libraries
dc.subject.keywordssynthesis
dc.subject.keywordscombinatorial chemistry
dc.subject.keywordsorganic synthesis
dc.subject.keywordsbioconjugation research
dc.subject.keywordsdrug discovery
dc.subject.keywordsbiotechnology
dc.subject.keywordsglycobiology
dc.subject.keywordscarbohydrate based drug discovery
dc.subject.keywordscarbohydrate chemistry
dc.subject.keywordsglycoconjugates
dc.subject.keywordsoligosaccharides
dc.subject.keywordstriazole moiety
dc.subject.keywordsprotective group chemistry
dc.subject.keywordsglycosylation chemistry
dc.subject.keywordsmimetics
dc.subject.keywordsglycoconjugate benzene sulfonamides
dc.subject.keywordscarbonic anhydrase inhibitor
dc.subject.keywordsCA inhibitors
dc.subject.keywordstissue delivery applications
dc.subject.keywordsplasma membrane permeability
dc.subject.keywordstumour associated isozymes
dc.subject.keywordsclick-tailing
dc.subject.keywordshuman carbonic anhydrase isozymes
dc.subject.keywordshCA
dc.subject.keywordscarbohydrate tail
dc.subject.keywordsisozyme
dc.subject.keywordsN-alkylated azasugar libraries
dc.subject.keywordsglycosidase inhibitor
dc.subject.keywordsglycosyltransferase inhibitor
dc.subject.keywordsclick chemistry methodology
dc.titleSynthesis of Novel Carbohydrate Based Enzyme Inhibitor Libraries Utilising Click Chemistry
dc.typeGriffith thesis
gro.rights.copyrightThe author owns the copyright in this thesis, unless stated otherwise.
gro.hasfulltextFull Text
dc.contributor.otheradvisorPoulsen, Sally-Ann
dc.contributor.otheradvisorBornaghi, Laurent
dc.rights.accessRightsPublic
gro.identifier.gurtIDgu1316750139978
gro.identifier.ADTnumberadt-QGU20080410.100034
gro.source.ADTshelfnoADT0625
gro.source.GURTshelfnoGURT
gro.thesis.degreelevelThesis (PhD Doctorate)
gro.thesis.degreeprogramDoctor of Philosophy (PhD)
gro.departmentSchool of Biomolecular and Physical Sciences
gro.griffith.authorWilkinson, Brendan L.


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