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

Abstract

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.

Recent Advances in Synthetic Routes to Azacycles

“…N -heterocycles have been employed in many industries, including as dyes, agrochemicals, and materials [ 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 ]. In pharmaceuticals, small-molecule drugs contain nitrogen-containing heterocycles and exhibit diverse bioactivities including anti-Alzheimer’s, antivirus, and anticancer behavior [ 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 ]. Thus, a series of studies on the synthesis and functionalization of many N -heterocyclic compounds, such as indoles, imidazoles, pyrrolidines, indolizines, and quinolines, as well as their application, has been carried out.…”