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dc.contributor.advisorConway, Stuart J.
dc.contributor.authorNemeth, Joseph
dc.coverage.spatial202en
dc.date.accessioned2008-12-02T16:31:00Z
dc.date.available2008-12-02T16:31:00Z
dc.date.issued2008-06-25
dc.identifieruk.bl.ethos.552139
dc.identifier.urihttp://hdl.handle.net/10023/572
dc.description.abstractPhosphatidyl D-myo-inositol (3,4,5)-trisphosphate [PtdIns(3,4,5)P3] contributes to the activation of protein kinase B (PKB) by interacting with the PKB PH domain. PKB is known to be up-regulated in several cancer cell types. Compounds that can display selective inhibition of this kinase have promising chemotherapeutic potential, and inhibition of the PH domain of PKB represents a realistic means by which to achieve this. Analysis of the X-ray crystal structures of apo PKBαPH and PKBαPH bound to D-myo-inositol 1,3,4,5-tetrakisphosphate [InsP4, the inositol head group of PtdIns(3,4,5)P3] led to the design of PtdIns(3,4,5)P3 and InsP4 analogues as potential PKB PH domain inhibitors. The synthesis of PtdIns(3,4,5)P3 analogues modified at the C-4 position was investigated, but it was discovered that such compounds were prone to migration of the 1-position phosphate. Subsequently, a range of racemic InsP4 analogues, modified at the C-1 or C-4 position, were successfully synthesised. Advanced progress has also been made towards the synthesis of enantiomerically pure analogues of InsP4.en
dc.format.extent2675 bytes
dc.format.mimetypeapplication/pdf
dc.language.isoenen
dc.publisherUniversity of St Andrews
dc.subjectProtein kinase Ben
dc.subjectPhosphatidylinositol-3,4,5-trisphosphateen
dc.subjectPH domainen
dc.subjectPhosphoinositide-3-kinaseen
dc.subjectAkten
dc.subjectInsP4 analogueen
dc.titleDesign and synthesis of chemical probes for the protein kinase B PH domainen
dc.typeThesisen
dc.contributor.sponsorEngineering and Physical Sciences Research Council (EPSRC)en
dc.contributor.sponsorProsidion Limiteden
dc.type.qualificationlevelDoctoralen
dc.type.qualificationnamePhD Doctor of Philosophyen
dc.publisher.institutionThe University of St Andrewsen


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