Synthesis of C6-substituted uridine-5'-monophosphate derivatives as potential inhibitors of orotidine-5'-monophosphate decarboxylase

UNCG Author/Contributor (non-UNCG co-authors, if there are any, appear on document)
Molly C. McDonald (Creator)
Institution
The University of North Carolina at Greensboro (UNCG )
Web Site: http://library.uncg.edu/
Advisor
Lakshmi P. Kotra

Abstract: Orotidine-5'-monophosphate decarboxylase (ODCase) is an enzyme that catalyzes the final step during the de novo synthesis of uridine-5'-monophosphate (UMP). Several UMP derivatives modified at the C6 position, including 6-iodouridine-5'-monophosphate, have exhibited potent inhibition of ODCase catalytic activity. As part of this thesis, various analogs of UMP were synthesized by attaching small heterocycle moieties at the C6 position through a C-C bond. This was achieved by exploring Stille-coupling and Click chemistry, to prepare four novel C6 derivatives of UMP. These derivatives are 6-(tetrazol-4-yl)-UMP, 6-(pyrazol-4-yl)-UMP, 6-(thiophen-2-yl)-UMP and 6-(thiophen-3-yl)-UMP, and the corresponding nucleosides. The nucleotide derivatives are under investigation as inhibitors of ODCase, and the nucleoside derivatives are investigated as potential antimalarial and anticancer agents. Synthetic strategies, the design of inhibitors, and the accomplishments to isolate C6-heterocycle substituted uridine derivates in the context of therapeutic potential are discussed.

Additional Information

Publication
Thesis
Language: English
Date: 2009
Keywords
Orotidine-5'-monophosphate decarboxylase, Uridine-5'-monophosphate
Subjects
Enzyme Inhibitors $x Research.
Antineoplastic agents $x Research.
Antimalarials $x Research.
Pyrimidine nucleotides $x Metabolism.