Importance of the Structural Components of C-linked Glycopeptides to Specific-antifreeze Activity: From Glycopeptides to Small Molecule Inhibitors of Ice Recrystallization

FieldValue
dc.contributor.authorTrant, John F.
dc.date.accessioned2012-02-22T16:24:00Z
dc.date.available2012-02-22T16:24:00Z
dc.date.created2012
dc.date.issued2012
dc.identifier.urihttp://hdl.handle.net/10393/20710
dc.identifier.urihttp://dx.doi.org/10.20381/ruor-5455
dc.description.abstractOne of the largest problems in current medicine is the shortage of organs for transplant due to technological limitations in the storage of organs for any length of time. A possible solution to this problem would involve cryopreservation. However, current cryopreservatives such as sucrose or DMSO have concerning cytotoxic issues that limit their possible applications. A major cause of cryoinjury is the uncontrolled recrystallization of inter and intra-cellular ice crystals that occurs during the thawing process leading to mechanical damage and dehydration. The Ben lab has thus been interested in the design of compounds that are capable of inhibiting this process but do not possess other undesirable properties found in the native compounds. These synthetic analogues have been shown to increase cellular viability post-thaw. A series of mixed α/β glycopeptides are prepared and analyzed for antifreeze properties. The results of this study imply that it is not the gross conformation of the glycopeptide that is responsible for activity, but rather that intramolecular relationships may be responsible for disrupting the reorganization of ice. A technique was devised for the incorporation of triazoles into the analogues to investigate the importance of the linker and to greatly simplify the synthesis of a library of glycoconjugates. It was found that the IRI activity of glycopeptides is very sensitive to the distance between carbohydrate and peptide backbone. The electron density at the anomeric oxygen is an important parameter with respect to intramolecular networks. A series of substituted galactosides is presented that modify the electronics of the anomeric oxygen. The results demonstrate that decreasing electron density at this position appears to improve IRI activity in a predictable manner. To better understand the remarkable IRI activity of a key analogue, it was systematically truncated. This study led to the serendipitous discovery of a series of very highly IRI active analogues that do not contain a peptide backbone. These compounds represent the first non-glycopeptides that can show very significant IRI activity even at very low concentrations. The final portion of the thesis reports the efforts towards the preparation of a carbasugar analogue of AFGP-8.
dc.language.isoen
dc.publisherUniversité d'Ottawa / University of Ottawa
dc.subjectAntifreeze
dc.subjectOrganic Synthesis
dc.subjectBioorganic chemistry
dc.subjectRecrystallization inhibition
dc.subjectcarbohydrates
dc.subjectsmall molecule
dc.subjectglycopeptide
dc.subjectbeta peptide
dc.subjectCuAAC
dc.titleImportance of the Structural Components of C-linked Glycopeptides to Specific-antifreeze Activity: From Glycopeptides to Small Molecule Inhibitors of Ice Recrystallization
dc.typeThesis
dc.faculty.departmentChimie / Chemistry
dc.contributor.supervisorBen, Robert N.
dc.embargo.termsimmediate
dc.degree.namePhD
dc.degree.leveldoctorate
dc.degree.disciplineSciences / Science
thesis.degree.namePhD
thesis.degree.levelDoctoral
thesis.degree.disciplineSciences / Science
uottawa.departmentChimie / Chemistry
CollectionThèses, 2011 - // Theses, 2011 -

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