title: Novel halogenated nitrobenzylthioinosine analogs as es nucleoside transporter inhibitors.
abstract: Nucleoside transporter inhibitors have potential therapeutic applications as anticancer, antiviral, cardioprotective, and neuroprotective agents. We have synthesized and flow cytometrically evaluated the binding affinity of a series of novel halogenated nitrobenzylthioinosine analogs at the human es nucleoside transporter. Structure-activity relationships indicate the importance of hydrophobicity and electron withdrawing capacity of substituents at the para-position of the 6-position benzyl substituent. All of the compounds showed high binding affinity as shown by their ability to displace the fluorescent es transporter ligand, SAENTA-X8-fluorescein. Compound 16 (6-S-(para-iodobenzyl)-6-thioinosine) was the most tightly bound within the series with a K(i) of 3.88 nM (NBMPR exhibited a K(i) of 0.70 nM). This compound has higher affinity than the widely used nonnucleoside, nucleoside transport inhibitor, dipyridamole (K(i) = 8.79 nM), and may serve as a new lead compound.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Sciences Center, 847 Monroe Avenue Suite 327, Memphis, TN 38163, USA.
authors.forename: Amol
authors.initials: A
authors.lastname: Gupte
authors.forename: John K
authors.initials: JK
authors.lastname: Buolamwini
mesh_terms: D005434:Flow Cytometry; D049990:Membrane Transport Modulators; D026901:Membrane Transport Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009705:Nucleosides / Q000378:metabolism*; D013868:Thioinosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D049990:Membrane Transport Modulators; D026901:Membrane Transport Proteins; D009705:Nucleosides; D013868:Thioinosine; C001789:4-nitrobenzylthioinosine