| dc.description.abstract | The carbocyclic nucleosides aristeromycin and neplanocin A are two of the most potent inhibitors of S-adenosylhomocysteine hydrolase, an enzyme that plays a critical role in methyl transfer reactions during a viral replication cycle. As a consequence, these two carbocyclic nucleosides have been found to have significant broad-spectrum antiviral activities. However, their clinical applications are limited due to the toxicity associated with their 5'-hydroxyl metabolites. To develop new antiviral agents that retain the antiviral activities of aristermycin and neplanocin A while avoiding their toxicities, homoaristeromycin (1) has been synthesized. Also, in order to detect the relationship between the syn-anti conformations of nucleoside analogues and antiviral activites, a series of 8-methyl carbocyclic nucleosides derivatives have been prepared. Among the analogues in this series 8-methylhomoaristeromycin (2) displayed a significant activity towards human cytomegalovirus (HCMV) and moderate activity against yellow fever virus.
3-Deazapurine carbocyclic nucleosides (that is 3-deazaaristeromycin and 3- deazaneplanocin A) have been discovered to possess remarkable antiviral activites, especially towards Ebola virus, with limited toxicity. Therefore, in this dissertation research, the 3-deaza structural element was introduced to supplement the library of 8-methylcarbocyclic nucleoside analogues that included 8-methyl-3-deaza-5′-
norneplanocin A (3), 8-methyl-3-deazaneplanocin A (4), 8-methyl-3-deaza-5′-homoneplanocin A (5) and 8-methyl-3-deazaaristeromycin (6).
Aristeromycin analogues modified at C-4′ (4′-isoaristeromycin 8a, 3-deaza-4′-isoaristeromycin 8b, 4′-isohomoaristeromycin 9a, 3-deaza-4′-isohomoaristeromycin 9b) have been also investigated as part of a program to further understand the structure-activity relationships in the adenine derived purine carbocyclic nucleosides. Although anologues 4, 9a and 9b were found to be inactive towards most viruses, the antiviral data still provide valuable information for structure-activity relationships.
A final feature of this dissertation arose from considering S-adenosyl-L-methionine (AdoMet) dependant methyl transferations. AdoMet plays a pivotal role in viral mRNA capping process and inhibition of this process offers another pathway to antiviral drug design. Sinefungin is one of the most potent inhibitors of AdoMet dependant methyltransferases and has shown potential in antiviral, antifungal, antiparasitic drug discovery. However, its toxicity due to inhibition of cellular methyltransferases limits its usefulness. In this direction, deamino-carbocyclic sinefungin (10) has been prepared and targeted for antiviral analysis.
The bioassay data for compounds 3, 5, 6, 10 will be forthcoming and under study in our laboratories. | en |
