This Is AuburnElectronic Theses and Dissertations

Design and Synthesis of 3-Deazaaristeromycin Derivatives




Chen, Chun

Type of Degree



Chemistry and Biochemistry


Analogs of naturally occurring nucleosides have served as structural models for the design of antitumor, antiviral, and antibacterial agents. The carbocyclic nucleosides aristeromycin and neplanocin A are two examples that show significant broad-spectrum antiviral activity. The significant antiviral properties of these two nucleosides have been attributed to inhibition of AdoHcy hydrolase, which in turn affects viral mRNA capping methylation. However, their clinical potential is limited by toxicity, which is associated with phosphorylation of the primary hydroxyl group at 5′ position. 3-Deazapurine carbocyclic nucleosides (3-deazaneplanocin A and 3-deazaaristeromycin) have been shown to retain antiviral activity with significant reduction of toxicity as a result of their incapability of undergoing phosphorylation. In the search for effective antiviral agents, fluorinated nucleosides and nucleotides, where the fluorine has been introduced into both the base and the sugar moiety, have found use in the treatment of viral infections. The placement of a fluorine atom can have significant effects on a biological molecule due to imparting increased lipophilicity, powerful electronic effects and altered metabolic properties. To further explore new antiviral agents retaining 3-deazaaristeromycin-based activity while reducing undesired toxicity, modification at the C-3′ and C-2′ position have been recognized as important means to promising compounds. The synthesis and biological properties of the 3′-fluoro-3′-deoxy- and 2′-fluoro-2′-deoxy-3-deazaaristeromycin derivatives 1, 2, 4 and 5 have been investigated. As a logical extension of the 3′-deoxy- and 2′-deoxy-3-deazaaristeromycin derivatives 3 and 6 has been identified as important target. 4′-Substituted nucleosides were found to exert potent activity against HIV. In this dissertation, the 4′-methyl-3-deazaaristeromycin (7) was sought as an anti-HIV agent and an efficient route into the heretofore unknown 4′-alkylated-3-deazaaristeromycin framework was developed. The bioassays for all compounds will be forthcoming and under study.