Synthesis of Substituted 5′‐Aminoadenosine Derivatives and Evaluation of Their Inhibitory Potential toward CD73
Résumé
Derivatives of 5'-amino-adenosine containing methyl carboxylate, methyl phosphonate, gem-bisphosphonate, bis(methylphosphonate), and -carboxylmethylphosphonate or phosphonoacetic moieties were synthesized from a key intermediate 5'-aminonucleoside. These nucleos(t)ide 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 towards 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 ones were derivatives 5 and 7, inhibiting recombinant CD73 by 36 and 47% and cellular CD73 by 61 and 45% at 100 µM, respectively. Molecular modeling allowed to explain partially this lack of activity as predicted docking score calculated beforehand were initially encouraging, especially for compound 7.
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