Synthesis and Characterization of NUC-7738, an Aryloxy Phosphoramidate of 3′-Deoxyadenosine, as a Potential Anticancer Agent

3′-Deoxyadenosine
(3′-dA, Cordycepin, 1) 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 (7a), a 5′-aryloxy
phosphoramidate prodrug of 3′-dA. We show in vitro evidence that 7a 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 7a was independent
of hENT1 and kinase activity. Furthermore, it was resistant to ADA
metabolic deactivation. Consistent with these findings, 7a showed increased levels of intracellular 3′-deoxyadenosine
triphosphate (3′-dATP), the active metabolite. Mechanistically,
levels of intracellular 3′-dATP were strongly associated with in vitro potency. NUC-7738 is now in Phase II, dose-escalation
study in patients with advanced solid tumors.