Thesis (M.S.)--Rochester Institute of Technology, 2006. / Typescript. Includes bibliographical references (leaves 68-71).

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Les analogues de nucléosides ont été largement utilisés dans le traitement d’affections d’origine virale grâce à l’activité biologique de ces dérivés. Nous nous sommes particulièrement intéressés dans ce travail à l’étude de carbonucléosides phosphonates. Le premier chapitre de cette thèse rapporte une étude bibliographique sur les virus et les analogues nucléosidiques approuvés par la FDA. Les mécanismes d’action de ces analogues ont été également abordés dans ce chapitre. Dans le deuxième chapitre, nous avons décrit la synthèse des dérivés 2’- ou 4’-hydroxy-4’-carbonucléoside méthyle phosphonates en série d’adénine et guanine. Le troisième chapitre est consacré à la mise au point d’une réaction d’hydrophosphonylation sous irradiation UV d’alcènes/alcynes conduisant aux alkyle/vinyle phosphonates correspondants. Enfin, le dernier chapitre présente la synthèse des dérivés 4’-hydroxy-4’-carbonucléosides éthyle phosphonates utilisant la méthodologie développée dans le troisième chapitre. Tous les carbonucléosides phosphonates synthétisés sont en cours d’évaluation biologique. / Nucleoside analogues have been widely used in the treatment of viral diseases owing to biological activity of these derivatives. We are particularly interested in carbonucleosides phosphonates. The first chapter of this thesis reports on a bibliographic study on viruses and on nucleosidic analogues approved by FDA for medical use. Antiviral mechanisms of action were also discussed in this chapter. In the second chapter, we described the synthesis of derivatives 2’- or 4’-hydroxy-4’-methyl carbonucleoside phosphonate in adenine and guanine series. The third chapter is devoted to the development of a hydrophosphonylation reaction under UV irradiation of alkenes/alkyne leading to the alkyl/vinyl corresponding phosphonates. Finally, the last chapter presents the synthesis of derivatives 4’-hydroxy-4’-ethyl carbonucleosides phosphonates using the methodology developed in the third chapter. All carbonucleoside phosphonates synthesized are ongoing biological evaluation.

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Thesis (Ph. D.)--Auburn University, 2008. / Abstract. Vita. Parts of this dissertation have been published as: Na₂[UO₂(IO₃)₄(H₂O)] (Ch. 2: Bray, T.H.; et al., Inorg. Chem., 2006, 45, 8251-8257.), An(IO₃)₄(An = Np, Pu) and Np(IO₃)₄·nH2O (Ch. 3: Bray, T.H.; et al., Inorg. Chem., 2007, 46, 3663-3668.), Pu(SeO₃)₂ (Ch. 4: Bray, T.H.; et al., J. Solid State Chem., 2008, 181, 493-498.), NpFPO₄ and Cs₂Np₂F₇PO₄ (Ch. 5: Bray, T.H.; et al., J. Solid State Chem., 2007, 180, 70-74.), [C₆H₁₄N₂][(UO₂)₄(HPO₄)₂PO₄)₂(H₂O)]·H₂O (Ch. 6: Bray, T.H.; et al., "Synthesis and Structure of [C6H14N2][(UO2)4(HPO4)2(PO4)2(H2O)]·H₂O: An Expanded Open-Framework Amine-Bearing Uranyl Phosphate," In press: Journal of Solid State Chemistry April 24, 2008.), and Np(CH₃PO₃)(CH₃PO₃H)(NO₃)(H₂O)·H₂O (Ch. 7: Bray, T.H.; et al., Inorg. Chem., 2007, 46, 10959-10961.). Includes bibliographical references.

Nucleotidylyltransferase inhibitors are designed to target enzymes responsible for one step of cell wall biosynthesis in Gram-positive, Gram-negative and mycobacteria. Glucose 1-phosphate thymidylyltransferase Cps2L/RmlA (EC 2.7.7.24) is an enzyme essential for the growth and proliferation of many bacteria, including Mycobacterium tuberculosis. Cps2L/RmlA serves to couple glucose 1-phosphate and deoxythymidine triphosphate to form deoxythymidine diphosphoglucose. dTDP-?-L-rhamnose acts as an inhibitor of RmlA. Phosphonates are synthetic analogues of natural phosphates that have shown widespread ability to probe biological systems. Several approaches were investigated toward the synthesis of dTDP-?-L-rhamnose analogues, which incorporated phosphonate functionality into their scaffolds. A series of L-rhamnose phosphonate and ketosephosphonate analogues, with varying degrees of fluorination about the 1C position, were synthesized. These compounds were evaluated as potential inhibitors of thymidylyltransferase Cps2L, the first enzyme in the L-rhamnose biosynthetic pathway, and a novel antibiotic target. Enzyme-inhibitor and enzyme-substrate binding experiments were performed using WaterLOGSY NMR spectroscopy for the phosphonate-based compounds and known enzyme sugar nucleotide substrates. IC50 values were measured and Ki values were calculated for the compounds determined to be inhibitors. New insights were gained into the binding promiscuity of various enzymes within the L-rhamnose biosynthetic pathway (Cps2L, RmlB-D) and the mechanism of inhibition for the most potent inhibitor, L-rhamnose-1C-phosphonate. Thiophosphates are analogues of natural phosphates in which the P—O bond has been replaced with a P—S bond. Methods were investigated for the preparation of O and S-glucosyl thiophosphates. A series new protected glucosyl thiophosphate compounds were synthesized and characterized as precursors to glucose-1-thiophopshate, a probable glucose 1-phosphate substrate analogue for Cps2L.

Thesis (Ph. D.)--University of Texas at Dallas, 2007. / Includes vita. Includes bibliographical references (leaves 101-105).

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