Synthesis and biological evaluation of analogues of a glycosyltransferase inhibitor

Persistent Link:
http://hdl.handle.net/10150/280751
Title:
Synthesis and biological evaluation of analogues of a glycosyltransferase inhibitor
Author:
Slavish, Peter Jacob
Issue Date:
2005
Publisher:
The University of Arizona.
Rights:
Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
Abstract:
Glycosphingolipids (GSLs) have been found to be involved in a myriad of cellular function, including the following: cell-cell communication, cell adhesion and proliferation, neuronal growth and repair, immune response and tumor progression (metastasis). To study the cellular effects of GSL depletion, Radin developed the first known inhibitors of the enzyme responsible for the initial glycosylation of the lipid portion (ceramide) of the glycosphingolipid. This inhibitor, PDMP (1-phenyl 2-decanoyl amino 3-morpholino 1-propanol), not only suppresses the initial glycosylation, but also inhibits the formation of all preceding glycosphingolipids and causes the accumulation of ceramide, an active participant in cellular apoptosis (or programmed cell death). Using a developed procedure, PDMP analogues with truncations about the aromatic region were synthesized. Aromatic PDMP analogues were more potent than the lead compound when tested against isolated embryonic cells from the Manduca sexta. Later procedures developed allowed for the manufacturing of head group analogue, which allowed for the generation of a water-soluble PDMP analogue. A new synthetic protocol, using a commercially available advanced intermediate, permitted the production of enantiomerically pure PDMP in five steps with an overall yield of 50%. As these compounds gain more medicinal attention, we hope to use PDMP and analogues, combined with the Manduca sexta as a model system, to gain a greater understanding of GSL functionality and cellular malfunctions---including cancer metastasis.
Type:
text; Dissertation-Reproduction (electronic)
Keywords:
Chemistry, Organic.
Degree Name:
Ph.D.
Degree Level:
doctoral
Degree Program:
Graduate College; Chemistry
Degree Grantor:
University of Arizona
Advisor:
Polt, Robin

Full metadata record

DC FieldValue Language
dc.language.isoen_USen_US
dc.titleSynthesis and biological evaluation of analogues of a glycosyltransferase inhibitoren_US
dc.creatorSlavish, Peter Jacoben_US
dc.contributor.authorSlavish, Peter Jacoben_US
dc.date.issued2005en_US
dc.publisherThe University of Arizona.en_US
dc.rightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.en_US
dc.description.abstractGlycosphingolipids (GSLs) have been found to be involved in a myriad of cellular function, including the following: cell-cell communication, cell adhesion and proliferation, neuronal growth and repair, immune response and tumor progression (metastasis). To study the cellular effects of GSL depletion, Radin developed the first known inhibitors of the enzyme responsible for the initial glycosylation of the lipid portion (ceramide) of the glycosphingolipid. This inhibitor, PDMP (1-phenyl 2-decanoyl amino 3-morpholino 1-propanol), not only suppresses the initial glycosylation, but also inhibits the formation of all preceding glycosphingolipids and causes the accumulation of ceramide, an active participant in cellular apoptosis (or programmed cell death). Using a developed procedure, PDMP analogues with truncations about the aromatic region were synthesized. Aromatic PDMP analogues were more potent than the lead compound when tested against isolated embryonic cells from the Manduca sexta. Later procedures developed allowed for the manufacturing of head group analogue, which allowed for the generation of a water-soluble PDMP analogue. A new synthetic protocol, using a commercially available advanced intermediate, permitted the production of enantiomerically pure PDMP in five steps with an overall yield of 50%. As these compounds gain more medicinal attention, we hope to use PDMP and analogues, combined with the Manduca sexta as a model system, to gain a greater understanding of GSL functionality and cellular malfunctions---including cancer metastasis.en_US
dc.typetexten_US
dc.typeDissertation-Reproduction (electronic)en_US
dc.subjectChemistry, Organic.en_US
thesis.degree.namePh.D.en_US
thesis.degree.leveldoctoralen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.disciplineChemistryen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.contributor.advisorPolt, Robinen_US
dc.identifier.proquest3158157en_US
dc.identifier.bibrecord.b48137649en_US
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