| Summary: | Thesis advisor: Evan R. Kantrowitz === Thesis advisor: Mary F. Roberts === In this work, a series of inhibitors of two enzymes, aspartate transcarbamoylase (ATCase) and fructose 1,6-bisphosphatase (FBPase) were designed, synthesized and characterized. ATCase catalyzes the committed step in pyrimidine nucleotide biosynthesis, the reaction between carbamoyl phosphate (CP) and L-aspartate to form N-carbamoyl-L-aspartate (CA) and inorganic phosphate. This step is exceptionally important because once CA is formed, it is committed to the biosynthesis of pyrimidines, a necessary component for nucleic acid biosynthesis. The pyrimidine biosynthetic pathway plays an important regulatory role in cell proliferation since there is evidence that intracellular nucleotide pools control DNA replication and consequently cell division. Thus, the enzymes of pyrimidine biosynthesis, both in the de novo and salvage pathways, are targets for anti-proliferation drugs. Fructose 1,6-bisphosphatase (FBPase) is responsible for the hydrolysis of fructose 1,6-bisphosphate (F16BP) to fructose 6-phosphate (F6P). As the key enzyme at the control point in the gluconeogenesis pathway, FBPase presents an opportunity for the development of novel inhibitors against type-2 diabetes aimed at lowering the hepatic glucose production in type-2 diabetes. With ATCase, the design, synthesis and characterization of (1) T-state inhibitors composed of two phosphonacetamide groups linked together by a variety of functionalities and (2) analogs of N-phosphonacetyl-L-aspartate, a potent inhibitor of ATCase, were accomplished. With FBPase, a library of allosteric inhibitors, of which, the lead compound was initially identified through a virtual high-throughput screening system, was developed. In addition, this work also aimed to find the in vivo target for achyrofuran, a natural product derived from Achyrocline satureoides which has been shown to significantly lower blood glucose levels in db/db mouse for type-2 diabetes. The last project presents evidences that FBPase is the likely in vivo target for achyrofuran. This was accomplished through the use of computational docking experiments and by the synthesis of a new class of inhibitors based on the achyrofuran scaffold. === Thesis (PhD) — Boston College, 2009. === Submitted to: Boston College. Graduate School of Arts and Sciences. === Discipline: Chemistry.
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