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

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.

The synthesis and flow cytometric investigation of structure–activity relationship of new C2-purine position substituted analogs of NBMPR as inhibitors of the human equilibrative nucleoside transporter (hENT1) is reported.Figure optionsDownload as PowerPoint slide