Synthesis and biological evaluation of 5R- and 5S-methyl substituted d- and l-configuration 1,3-dioxolane nucleoside analogs

Abstract 1,3-Dioxolane and 1,3-oxathiolane nucleoside analogs play an important role in anti-viral and anti-neoplastic chemotherapy. We report here the synthesis of 2-hydroxymethyl-5-methyl-1,3-dioxolanylpurine nucleosides from 4-acetoxy-2-(benzyloxymethyl)-5-methyldioxolane. Dioxolanes of α- d -, β- d -, α- l -, and β- l -configuration were prepared, that included 5-methyl derivatives of both 5 R and 5 S configuration. Molecular mechanics calculations indicate that the 5 S and 5 R diastereoisomeric 1,3-dioxolanes possess distinct conformational bias, suggesting that methyl substitution may alter the conformational preference of 1,3-dioxolanes. The ability of the 1,3-dioxolanes to inhibit HCV RNA replication was evaluated in a cell-based, subgenomic replicon assay. In addition, activity against vaccinia and HIV was evaluated in cell-based assays. The 2-hydroxymethyl-5-methyl-1,3-dioxolanes were found to be inactive.