Design and Synthesis of AdoHcy Hydrolase Inhibitors as a Source of Antiviral Agents
Type of DegreeDissertation
DepartmentChemistry and Biochemistry
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The significant antiviral properties of the carbocyclic nucleosides aristeromycin and neplanocin A have been attributed to inhibition of AdoHcy hydrolase, which in turn affects viral mRNA capping methylation. However, their antiviral potential is limited due to toxicity, for most part, from phosphorylation of the primary hydroxyl group at the 5' position. 5'-Noraristeromycin and 3-deazapurine carbocyclic nucleosides (3-deazaneplanocin A and 3-deazaaristeromycin) have been found to have retained antiviral activity with significant reduction of toxicity as a result of their inability to undergo phosphorylation. To further exploit the 5'-nor and 3-deaza carbocyclic nucleoside platform as a source for new antiviral candidates, modifications at the C-3 position have been recognized as important means to promising compounds. 3-Deaza-5'-noraristeromycin derivatives possessing a halo atom (1-3) at the C-3 position have been synthesized and evaluated. 3-Chloro-3-deaza-5'-noraristeromycin (1) exhibits activity against heptatitis C virus (HCV). Meanwhile, 3-bromo-3-deaza-5'-noraristeromycin (2) and 3-iodo-3-deaza-5'-noraristeromycin (3) display marked activity against heptatitis B virus (HBV). Compound 1, 2, and 3 were also found to have a wide variety of other biological properties. As a logical extension of the 3-halo derivatives, 3-methy-3-deaza-5'-noraristeromycin (4) has been identified as an important target and prepared. Compound 4 only showed good activity against vesicular stomatitis virus (VSV) and vaccinia virus (VV), and affected none of the other viruses assayed. Derivatives of 3-deazaneplancin A possessing bromo (5) or methyl (6) groups at the C-3 position were sought as important targets. A convergent synthesis of this series of compounds employing Mitsunobu coupling was studied. Precedent suggested the derivative (7) of 3-deazaneplancin A which lacks the C-4' hydroxymethyl, would also be relevant to this study. Compounds 5, 6, and 7 were prepared and their bioassay is under study.