Interaction of benzopyranone derivatives and related compounds with human concentrative nucleoside transporters 1, 2 and 3 heterologously expressed in porcine PK15 nucleoside transporter deficient cells. Structure-activity relationships and determinants of transporter affinity and selectivity.
Unlike the major equilibrative nucleoside transporters, there is a dearth of potent specific inhibitors of concentrative nucleoside transporters (CNTs). We investigated the interaction of benzopyranone derivatives and related compounds with human (h) CNTs in newly established PK15NTD transfectant cells stably expressing hCNT1 or hCNT2, and previously established PK15NTD/hCNT3 cells. Flavones exhibited the highest inhibitory activity against hCNT2 and hCNT3, whereas the most potent selective inhibitor of hCNT1 was a coumarin derivative. hCNT3 was the only transporter that exhibited moderate sensitivity to the chalcones tested. The most active compound was 6-hydroxy-7-methoxyflavone, which was hCNT3-specific with an IC(50) of 0.57+/-0.20 microM, and over 40-fold more potent than the standard CNT inhibitor, phloridzin (IC(50) of 25+/-3.5 microM). The SAR (Structure-Activity Relationship) shows that high potency against all three hCNTs is conferred by the presence of hydroxyl substituents at both the 7- and 8-positions of flavones and isoflavones. CoMFA (Comparative Molecular Field Analysis) and CoMSIA (Comparative Molecular Similarity Indices Analysis) 3D-QSAR (three-Dimensional Quantitative Structure-Activity Relationship) modeling indicated that electrostatic and hydrophobic properties were the most influential for interactions between the flavonoids and hCNT1, while electrostatic, hydrophobic and hydrogen bond donor properties were predominate for interactions with hCNT2 and hCNT3. The 3D-QSAR results also suggested possible commonalities in hydrogen bonding interactions of flavonoids and nucleosides, suggesting similarities between the hCNT-binding sites of the two classes of compounds. We report the most potent and selective non-nucleoside CNT inhibitors to date; which may serve as research tools and/or leads for further inhibitor development.
Wang
Chunmei
C
Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
Pimple
Surekha
S
Buolamwini
John K
JK
D000818:Animals; D001578:Benzopyrans / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D002460:Cell Line; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D026901:Membrane Transport Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D021381:Protein Transport / Q000187:drug effects / Q000235:genetics; D011684:Purine Nucleosides / Q000378:metabolism*; D021281:Quantitative Structure-Activity Relationship; D013552:Swine
D001578:Benzopyrans; D026901:Membrane Transport Proteins; D011684:Purine Nucleosides; C065171:cif nucleoside transporter