3'-Deoxyadenosine (3'-dA, Cordycepin, <b>1</b>) is a nucleoside analogue with anticancer properties, but its clinical development has been hampered due to its deactivation by adenosine deaminase (ADA) and poor cellular uptake due to low expression of the human equilibrative transporter (hENT1). Here, we describe the synthesis and characterization of NUC-7738 (<b>7a</b>), a 5'-aryloxy phosphoramidate prodrug of 3'-dA. We show <i>in vitro</i> evidence that <b>7a</b> is an effective anticancer drug in a panel of solid and hematological cancer cell lines, showing its preferential cytotoxic effects on leukemic stem cells. We found that unlike 3'-dA, the activity of <b>7a</b> was independent of hENT1 and kinase activity. Furthermore, it was resistant to ADA metabolic deactivation. Consistent with these findings, <b>7a</b> showed increased levels of intracellular 3'-deoxyadenosine triphosphate (3'-dATP), the active metabolite. Mechanistically, levels of intracellular 3'-dATP were strongly associated with <i>in vitro</i> potency. NUC-7738 is now in Phase II, dose-escalation study in patients with advanced solid tumors.