Tunable GLUT–Hexose Binding and Transport via Modulation of Hexose C-3 Hydrogen-Bonding Capabilities

5 years ago

Tunable GLUT–Hexose Binding and Transport via Modulation of Hexose C-3 Hydrogen-Bonding Capabilities

Olivier-Mohamad Soueidan, Christopher I. Cheeseman, Venkata Pavan Kumar Kondapi, Frederick G. West

The importance of the hydrogen bonding interactions in the GLUT–hexose binding process (GLUT=hexose transporter) has been demonstrated by studying the binding of structurally modified d-fructose analogues to GLUTs, and in one case its transport into cells. The presence of a hydrogen bond donor at the C-3 position of 2,5-anhydro-d-mannitol derivatives is essential for effective binding to GLUT5 and transport into tumor cells. Surprisingly, installation of a group that can function only as a hydrogen bond acceptor at C-3 resulted in selective recognition by GLUT1 rather than GLUT5. A fluorescently labelled analogue clearly showed GLUT-mediated transport and low efflux properties of the probe. This study reveals that a single positional modification of a 2,5-anhydro-d-mannitol derivative is sufficient to switch its binding preference from GLUT5 to GLUT1, and uncovers general scaffolds that are suitable for the potential selective delivery of molecular payloads into tumor cells via GLUT transport machinery. A series of fructose mimics with varying functionality at C-3 was prepared. Compounds with hydrogen bond donor groups at C-3 were recognized selectively by fructose transporter GLUT5, whereas those with hydrogen bond acceptor groups at C-3 were recognized by glucose transporter GLUT1.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1002/chem.201701329