Design and Synthesis of Novel Nucleoside Analogues: Oxidative and Reductive Approaches toward Synthesis of 2'-Fluoro Pyrimidine Nucleosides
Doctor of Philosophy (PhD)
First Advisor's Name
Stanislaw F. Wnuk
First Advisor's Committee Title
Second Advisor's Name
Kathleen S. Rein
Second Advisor's Committee Title
Third Advisor's Name
David A. Becker
Third Advisor's Committee Title
Fourth Advisor's Name
Anthony P. DeCaprio
Fourth Advisor's Committee Title
Fifth Advisor's Name
Salvatore D. Lepore
Fifth Advisor's Committee Title
Fluorination, Desulfurization, Desulfonylation, Pyrimidines, Purines, 7-Deazapurines, DBH, Click Chemistry, C-H Functionalization, One Electron Oxidation
Date of Defense
Fluorinated nucleosides, especially the analogues with fluorine atom(s) in the ribose ring, have been known to exert potent biological activities. The first part of this dissertation was aimed at developing oxidative desulfurization-fluorination and reductive desulfonylation-fluorination methodologies toward the synthesis of 2'-mono and/or 2',2'-difluoro pyrimidine nucleosides from the corresponding 2'-arylthiopyrimidine precursors. Novel oxidative desulfurization-difluorination methodology was developed for the synthesis of α,α-difluorinted esters from the corresponding α-arylthio esters, wherein the arylthio group is present on a secondary internal carbon. For the reductive desulfonylation studies, cyclic voltammetry was utilized to measure the reduction potentials at which the sulfone moiety of substrates can be cleaved.
The 5-bromo pyrimidine nucleosides and 8-bromo purine nucleosides act as crucial intermediates in various synthetic transformations. The second part of the present dissertation was designed to develop a novel bromination methodology using 1,3-dibromo-5,5-dimethylhydantoin (DBH). Various protected and deprotected pyrimidine and purine nucleosides were converted to their respective C5 and C8 brominated counterparts using DBH. The effect of Lewis acids, solvents, and temperature on the efficiency of bromination was studied. Also, N-bromosuccinimide (NBS) or DBH offered a convenient access to 8-bromotoyocamycin and 8-bromosangivamycin.
Third part of this research work focuses on the design and synthesis of 6-N-benzylated derivatives of 7-deazapurine nucleoside antibiotics, such as tubercidin, sangivamycin and toyocamycin. Target molecules were synthesized by two methods. First method involves treatment of 7-deazapurine substrates with benzylbromide followed by dimethylamine-promoted Dimroth rearrangement. The second method employs fluoro-diazotization followed by SNAr displacement of the 6-fluoro group by a benzylamine. The 6-N-benzylated 7-deazapurine nucleosides showed type-specific inhibition of cancer cell proliferation at micromolar concentrations and weak inhibition of human equilibrative nucleoside transport protein (hENT1).
In the fourth part of this dissertation, syntheses of C7 or C8 modified 7-deazapurine nucleosides, which might exhibit fluorescent properties, were undertaken. 8-Azidotoyocamycin was synthesized by treatment of 8-bromotoyocamycin with sodium azide. Strain promoted click chemistry of 8-azidotoyocamycin with cyclooctynes gave the corresponding 8-triazolyl derivatives. Alternatively, 7-benzotriazolyl tubercidin was synthesized by iodine catalyzed CH arylation of tubercidin with benzotriazole.
Rayala, Ramanjaneyulu, "Design and Synthesis of Novel Nucleoside Analogues: Oxidative and Reductive Approaches toward Synthesis of 2'-Fluoro Pyrimidine Nucleosides" (2015). FIU Electronic Theses and Dissertations. 2172.
Carbohydrates Commons, Heterocyclic Compounds Commons, Nucleic Acids, Nucleotides, and Nucleosides Commons
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