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Development of novel synthetic methodologies and their use in approaches for the preparation of lactacystin, lepadiformine and a Giardia lamblia fructose-1,6-bisphosphate aldolase inhibitor

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Please use this identifier to cite or link to this item: http://hdl.handle.net/1928/10338

Development of novel synthetic methodologies and their use in approaches for the preparation of lactacystin, lepadiformine and a Giardia lamblia fructose-1,6-bisphosphate aldolase inhibitor

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dc.contributor.advisor Alkaloids--Synthesis.
dc.contributor.author Zou, Jiwen
dc.date.accessioned 2010-02-09T21:53:43Z
dc.date.available 2010-02-09T21:53:43Z
dc.date.issued 2010-02-09T21:53:43Z
dc.date.submitted December 2009
dc.identifier.uri http://hdl.handle.net/1928/10338
dc.description.abstract The investigations carried out in my doctoral studies focus on (1) applications of pyridinium salt photochemical and tandem ene-yne-ene metathesis reactions to the synthesis of the natural products (+)-lactacystin and lepadiformine C, and (2) the preparation of a novel inhibitor for the class II Giardia lamblia fructose-1,6-bisphosphate aldolase. New developments in the area of pyridinium salt photochemistry were explored in the context of approaches to the natural product (+)-lactacystin. The results of this effort show that irradiation of a substituted 1,2-cyclopenta-fused pyridinium salt in aqueous solution followed by treatment with sodium bicarbonate leads to selective production of an unusual, structural and functional complex, and stereodefined tetracyclic carbamate. This substance contains structural features and a functionality array that would make it applicable as a late stage intermediate in a synthesis of the proteosome inhibitor, lactacystin. A novel strategy was developed for the synthesis of lepadiformine C, a structurally interesting, biologically active marine alkaloid derived from the marine organism Claveline moluccensis. that has a tricyclic structure. The approach, which begins with l-proline, relies on implementation of a ruthenium-alkylidene catalyzed, tandem ene-yne-ene metathesis process to construct the tricyclic structure. Class I and class II fructose-1,6-bisphosphate aldolases (FBPA), enzymes that exhibit no amino acid sequence homology and utilize different catalytic mechanisms, promote the retro-aldol conversion of fructose-1,6-bisphosphate (FBP) to dihydroxyacetone phosphate and D-glyceraldehyde-3-phosphate as part of energy producing glycolysis pathways in bacteria, protists and humans. The mammalian class I FBPA employs a Schiff base mechanism, involving an active site lysine amine group, whereas the parasitic protozoan Giardia lamblia relies on a class II FBPA that utilizes an active site Zn+2 to stabilize the forming enolate of dihdroxyacetone phosphate. One subgoal of my studies was to develop a novel strategy for the design of inhibitors of the class II Giardia lamblia FBP (glFBPA). As part of an overall effort in this area, potential inhibitors that possess Zn+2 binding 3-hydroxy-2-pyridone moieties were designed and prepared. The inhibitory properties of these substances against glFBPA were determined. The results show that the structure-based inhibitor design is effective in identifying new 3-hydroxy-2-pyridone based glFBPA inhibitors that have modestly tight (low micromolar) binding affinities. en_US
dc.language.iso en_US en_US
dc.subject Lactacystin en_US
dc.subject Lepadiformine en_US
dc.subject Aldolase en_US
dc.subject Inhibitor en_US
dc.subject.lcsh Organic photochemistry.
dc.subject.lcsh Pyridinium compounds.
dc.subject.lcsh Metathesis (Chemistry)
dc.subject.lcsh Protease inhibitors--Synthesis
dc.subject.lcsh Hydrolases--Synthesis.
dc.subject.lcsh Giardia lamblia--Metabolism.
dc.title Development of novel synthetic methodologies and their use in approaches for the preparation of lactacystin, lepadiformine and a Giardia lamblia fructose-1,6-bisphosphate aldolase inhibitor en_US
dc.type Dissertation en_US
dc.description.degree Chemistry en_US
dc.description.level Doctoral en_US
dc.description.department University of New Mexico. Dept. of Chemistry en_US
dc.description.advisor Mariano, Patrick S.
dc.description.committee-member Dunaway-Mariano, Debra
dc.description.committee-member Wang, Wei
dc.description.committee-member Feng, Changjian


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