Structure−Activity Relationship of Heterobase-Modified 2‘-C-Methyl Ribonucleosides as Inhibitors of Hepatitis C Virus RNA Replication

Hepatitis C virus infection constitutes a significant health problem in need of more effective therapies. We have recently identified 2‘-C-methyladenosine and 2‘-C-methylguanosine as potent nucleoside inhibitors of HCV RNA replication in vitro. However, both of these compounds suffered from significant limitations. 2‘-C-Methyladenosine was found to be susceptible to enzymatic conversions by adenosine deaminase and purine nucleoside phosphorylase, and it displayed limited oral bioavailability in the rat. 2‘-C-Methylguanosine, on the other hand, was neither efficiently taken up in cells nor phosphorylated well. As part of an attempt to address these limitations, we now report upon the synthesis and evaluation of a series of heterobase-modified 2‘-C-methyl ribonucleosides. The structure−activity relationship within this series of nucleosides reveals 4-amino-7-(2-C-methyl-β-d-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine and 4-amino-5-fluoro-7-(2-C-methyl-β-d-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine as potent ...