Synthesis of Substituted 5′-Aminoadenosine Derivatives and Evaluation of Their Inhibitory Potential toward CD73

Abstract

Derivatives of 5′-aminoadenosine containing methyl carboxylate, methyl phosphonate, gem-bisphosphonate, bis(methylphosphonate), and α-carboxylmethylphosphonate or phosphonoacetate moieties were synthesized from key intermediate 5′-aminonucleoside. These nucleotide analogues were envisaged as 5′-mono- or diphosphate nucleoside mimics. All compounds were evaluated for CD73 inhibition in a cell-based assay (MDA-MB-231) and toward the purified recombinant protein. Most of them failed to reach significant inhibition of AMP hydrolysis by CD73 at 100 μm. Among the new compounds, the most interesting candidates, 5 (5′-deoxy-5′-N-phosphonomethyladenosine) and 7 (5′-deoxy-5′-N-(ethoxyphosphorylacetate)adenosine), inhibited recombinant CD73 by 36 and 46 % and cellular CD73 by 61 and 45 % at 100 μm, respectively. Molecular modeling partially explains this lack of activity, as the initially predicted docking scores had been encouraging, especially for compound 9.