Enzymatic inhibition of biological methylation pathways essential for viral and cancer replication has shown promise in the design of new chemotherapeutics. Disruption of the action of critical enzymes such as S-adenosyl-L-homocystine hydrolase (SAHase), and DNA methyltransferases (DNMT) has been shown to affect viral and tumor cell replication. In that regard, carbocyclic nucleoside derivatives, as a class, have shown potent inhibitory activity in both areas. Carbocyclic nucleosides are structurally modified such that they mimic the natural nucleosides enough to be recognized, but ultimately have the ability to disrupt subsequent biological processes. Aristeromycin and neplanocin are two of the naturally occuring carbocyclic nucleosides that showed potent inhibitory activity against SAHase, and as a result exhibit potent antiviral activity against several viruses. These nucleoside analogues, however, suffer from cytotoxicity and several other side effects.

As part of our ongoing research on new nucleoside analogues with potential antiviral and anticancer activities, we have synthesized a new series of purinepyrimidine hybrid carbocyclic isonucleoside analogues as inhibitors of SAHase. The novel nucleosides have been evaluated for their antiviral and anticancer properties. We have also synthesized truncated thymidine analogues and they have been evaluated for their inhibitory activity against SAHase and DNMT. One of the analogues has shown 95.8% inhibition of Hepatitis C virus (HCV) at a concentration of 20 μM and is undergoing further testing. Also, the truncated nucleoside analogue inhibits SAHase (Ki=5 μM). The design and synthesis of this new series of nucleoside analogues will be discussed.