Chemistry ETDs

Author

Jiwen Zou

Publication Date

2-9-2010

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.

Language

English

Keywords

Lactacystin, Lepadiformine, Aldolase, Inhibitor

Document Type

Dissertation

Degree Name

Chemistry

Level of Degree

Doctoral

Department Name

Department of Chemistry and Chemical Biology

First Advisor

Mariano, Patrick S.

First Committee Member (Chair)

Dunaway-Mariano, Debra

Second Committee Member

Wang, Wei

Third Committee Member

Feng, Changjian

Share

COinS