Carbocyclic C-Nucleosides Derived from Formycin

Abstract

Analogs of naturally occurring nucleosides have served as structural models for the design of antitumor, antiviral, and antibacterial agents. Some modified nucleosides have become major therapeutic agents for the treatment of viral infectious diseases such as human immunodeficiency virus (HIV), hepatitis B virus (HBV) and the herpes viruses. Carbocyclic nucleosides (carbanucleosides) are nucleoside analogs in which the oxygen in the furanoses of traditional nucleosides is replaced by a methylene moiety. One relevant feature of these derivatives is their metabolic stability against phosphorylases as a consequence of the absence of the natural N-glycosidic bond. Much like carbanucleosides, C-nucleosides represent another class of nucleosides resistant to chemical and the enzymatic hydrolytic cleavage of the glycosidic bond. This results from the structural arrangement in which the ribofuranosyl moiety is liked to a heterocyclic base through a C-C bond rather than the traditional C-N bond. Recently, nucleoside analog discovery has been focused on the hybrid nucleosides, carbocyclic C-nucleosides. This has been due to the challenging enantiomeric syntheses posed by carbocyclic C-nucleosides. Consequently, no significant biological activities for this class of compounds have been reported. Thus, it was of interest to undertake a study of carbocyclic C-nucleosides. The main body of this research work deals with the progress towards carbocyclic formycin analogs as representative carbocyclic C-nucleosides by combining the structural components of formycin and 5'-noraristeromycin, a broadly active antiviral candidate that is devoid of the toxicity of aristeromycin. Synthesis of related N-methylated carbocyclic formycin analogs and their structural assignments are also described.