Novel C2-purine position analogs of nitrobenzylmercaptopurine riboside as human equilibrative nucleoside transporter 1 inhibitors Original Research Article

Nucleoside transporter inhibitors have potential therapeutic applications as anticancer, antiviral, cardioprotective, and neuroprotective agents. S6-(4-nitrobenzyl)mercaptopurine riboside (NBMPR) is a prototype inhibitor of the human equilibrative nucleoside transporter (hENT1), and is a high affinity ligand with a Kd of 0.1–1.0 nM. We have synthesized and flow cytometrically evaluated the binding affinity of a series of novel C2-purine position substituted analogs of NBMPR at the hENT1. The aim of this research was to understand the substituent requirements at the C2-purine position of NBMPR. Structure–activity relationships (SAR) indicate that increasing the steric bulk at the C2-purine position of NBMPR led to a decrease in binding affinity of these ligands at the hENT1. New high affinity inhibitors were identified, with the best compound, 2-fluoro-4-nitrobenzyl mercaptopurine riboside (7), exhibiting a Ki of 2.1 nM. This information, when coupled with the information obtained from other structure–activity relationship studies should prove useful in efforts aimed at modeling the NMBPR and analogs pharmacophore of hENT1 inhibitors.