Investigations into 5ꞌ-Extended 3-Deazaaristeromycin Derivatives

Abstract

Nucleosides have provided a plentiful source in structural leads in antiviral drug discovery. Included in this class of compounds are the carbocyclic nucleosides, which because of the presence of a cyclopentyl moiety, offer sites for modification not possible with the typical ribofuranosyl analogues. Naturally occurring carbocyclic nucleosides aristeromycin and neplanocin A exhibit a broad-spectrum antiviral activity attributed to the inhibition of S-adenosylhomocysteine (AdoHcy) hydrolase. This, in turn, affects viral mRNA capping methylation, which is vital for the reproduction of viruses. While application of aristeromycin and neplanocin A is limited by their toxicity due to 5′-nucleotide formation, synthetic analogues thereof designed in our lab have shown significant antiviral activity without associated toxicity. The Ebola virus, for instance, is an emerging pathogen causing severe hemorrhagic fevers with a mortality rate as high as 90%. At this time, no treatment exists for Ebola, which is stimulating the search for new therapeutic agents. In this direction our lab has found that carbocyclic nucleosides offer a source for these agents. Herein is a reported the convergent and stereospecific syntheses of several 5ꞌ-extended 3-deazaaristeromycin analogues starting from D-ribose with potential to be effective anti-Ebola agents.