title: Novel C2-purine position analogs of nitrobenzylmercaptopurine riboside as human equilibrative nucleoside transporter 1 inhibitors.
abstract: Nucleoside transporter inhibitors have potential therapeutic applications as anticancer, antiviral, cardioprotective, and neuroprotective agents. S(6)-(4-nitrobenzyl)mercaptopurine riboside (NBMPR) is a prototype inhibitor of the human equilibrative nucleoside transporter (hENT1), and is a high affinity ligand with a K(d) of 0.1-1.0 nM. We have synthesized and flow cytometrically evaluated the binding affinity of a series of novel C(2)-purine position substituted analogs of NBMPR at the hENT1. The aim of this research was to understand the substituent requirements at the C(2)-purine position of NBMPR. Structure-activity relationships (SAR) indicate that increasing the steric bulk at the C(2)-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 K(i) 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.
authors: Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Sciences Center, 847 Monroe Avenue Suite 327, Memphis, TN 38163, USA.
authors: Amol
authors: A
authors: Gupte
authors: John K
authors: JK
authors: Buolamwini
mesh_terms: D002460:Cell Line; D004353:Drug Evaluation, Preclinical; D033721:Equilibrative Nucleoside Transporter 1 / Q000037:antagonists & inhibitors*; D005434:Flow Cytometry; D006801:Humans; D015394:Molecular Structure; D011687:Purines / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013868:Thioinosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology
chemical_list: C526496:2-fluoro-4-nitrobenzyl mercaptopurine riboside; D033721:Equilibrative Nucleoside Transporter 1; D011687:Purines; D013868:Thioinosine; C001789:4-nitrobenzylthioinosine