Synthesis and antiviral activity of carbocyclic purine analogues

Aristeromycin is one of the most potent S-adenosylhomocysteine hydrolase inhibitors and, as a consequence, it shows significant broad-spectrum antiviral activity. However, this antiviral potential is limited by toxicity as a result of nucleotide formation at its 5'-hydroxyl center. 5'-Noraristeromycin has been found to have broad-spectrum antiviral activity with reduced toxicity as a consequence of its inability to undergo phosphorylation. To develop new antiviral agents retaining aristeromycin-based antiviral activity while eliminating undesirable nucleotide formation, 5 '-methylaristeromycin (1 and 2) and 5',5'-dimethylaristeromycin ( 3) were synthesized. (5'R)-5 '-methylaristeromycin 2 exhibits significant activity against Epstein-Barr virus, yellow fever and hepatitis C virus while (5 'S)-5'-methylaristeromycin 1 and 5',5'-dimethylaristeromycin 3 shows no activity. To further explore the role of C-5' stereochemistry for antiviral activity, 5'- isopropenylDHCaA (4) and 5'-methylhomoaristeromycin (5 and 6) were synthesized. 5'-isopropenylDHCaA was found to have significant activity against varicella-zoster virus. 8-Methylaristeromycin 7 was prepared to investigate the role of syn-anti conformation and found to have moderate activity against Epstein-Barr virus and poxvirus.; 5'-Noraristeromycin also has served as an important prototype structure for uncovering other biologically active carbocyclic derivatives. Carbocyclic 5'-norguanosine was prepared and found to exhibit significant activity towards inhibition of Epstein-Barr virus. As part of a program to ascertain the structural features relevant to its activity and further understand the inhibition mechanism, attention in this dissertation focused on derivatives of carbocyclic 5'-norguanosine (8--10). Although none of these analogues was active, their antiviral data provides valuable structure-activity relationship information for future design of antiviral agents.