title: Synthesis and biological evaluation of phloridzin analogs as human concentrative nucleoside transporter 3 (hCNT3) inhibitors.
abstract: Nucleoside transporter inhibitors have potential therapeutic applications as anticancer, antiviral, cardioprotective and neuroprotective agents. Although quite a few potent inhibitors of the equilibrative nucleoside transporters are known, largely missing are the concentrative nucleoside transporter inhibitors. Phloridzin (3, K(i)=16.00 microM) is a known moderate inhibitor of the concentrative nucleoside transporters. We have synthesized and evaluated analogs of phloridzin at the hCNT3 nucleoside transporter. Within the series of synthesized analogs compound 16 (K(i)=2.88 microM), possessing a ribofuranose sugar unit instead of a glucopyranose as present in phloridzin, exhibited the highest binding affinity at the hCNT3 transporter. Phloridzin and compound 16 have also been shown to be selective for the hCNT3 transporter as compared with the hENT1 transporter. Compound 16 can serve as a new lead which after further modifications could yield selective and potent hCNT3 inhibitors.
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: D002626:Chemistry, Pharmaceutical / Q000379:methods*; D015195:Drug Design; D033721:Equilibrative Nucleoside Transporter 1 / Q000037:antagonists & inhibitors*; D005663:Furans / Q000737:chemistry; D006801:Humans; D007700:Kinetics; D008024:Ligands; D026901:Membrane Transport Proteins / Q000737:chemistry / Q000378:metabolism; D008956:Models, Chemical; D033703:Nucleoside Transport Proteins / Q000737:chemistry / Q000378:metabolism; D009705:Nucleosides / Q000737:chemistry; D010695:Phlorhizin / Q000031:analogs & derivatives* / Q000138:chemical synthesis*
chemical_list: D033721:Equilibrative Nucleoside Transporter 1; D005663:Furans; D008024:Ligands; D026901:Membrane Transport Proteins; D033703:Nucleoside Transport Proteins; D009705:Nucleosides; C065171:cif nucleoside transporter; D010695:Phlorhizin