Enzymatic Properties of the Unnatural β-l-Enantiomers of 2‘,3‘-Dideoxyadenosine and 2‘,3‘-Didehydro-2‘,3‘-dideoxyadenosine

The β-l-enantiomers of 2‘,3‘-dideoxyadenosine and 2‘,3‘-didehydro-2‘,3‘-dideoxyadenosine have been stereospecifically synthesized. In an attempt to explain the previously reported antiviral activities of these compounds, their enzymatic properties were studied with respect to adenosine kinase, deoxycytidine kinase, adenosine deaminase, and purine nucleoside phosphorylase. Adenosine deaminase was strictly enantioselective and favored β-d-ddA and β-d-d4A, whereas adenosine kinase and purine nucleoside phosphorylase had no apparent substrate properties for the d- or l-enantiomers of β-ddA or β-d4A. Human deoxycytidine kinase showed a remarkable inversion of the expected enantioselectivity, with β-l-ddA and β-l-d4A having better substrate efficiencies than their corresponding β-d-enantiomers. Our results demonstrate the potential of β-l-adenosine analogues as antiviral agents and suggest that deoxycytidine kinase has a strategic importance in their cellular activation.