Synthesis, transportability and hypoxiaselective binding of 1-beta-D-(5-Deoxy-5-fluororibofuranosyl)-2-nitroimidazole (beta-5-FAZR), a configurational isomer of the clinical hypoxia marker, FAZA.
OBJECTIVE
Cellular uptake of most azomycin-based radiosensitizers depends on perfusion and diffusion, rather than on active transport. In medical imaging using radioisotopically labeled azomycin nucleosides, image contrast depends on rapid diffusion from normoxic tissues and rapid renal clearance from the central compartment. [18F]FAZA [1-alpha-D-(5-deoxy-18F]fluoroarabinofuranosyl)-2-nitroimidazole], an azomycin nucleoside currently under clinical evaluation as a marker of tissue hypoxia in medical centers world wide, provides high contrast but its uptake is diffusion dependent and therefore low. 1-D-(5-Fluoro-5-deoxyribofuranosyl)-2-nitroimidazole 6 (beta-5-FAZR), a Beta-ribose analog of FAZA, has now been developed to exploit transport across cell membranes to improve absolute uptake in hypoxic regions and high contrast.


METHODS
Beta-5-FAZR was synthesized by classical sugar base coupling followed by regioselective fluorination. In radiosensitization of hypoxic and normoxic to 60Co x-rays was determined relative to known radiosensitizers. The relative abilities of five human nucleoside transporters (hENT1/2, hCNT1/2/3 to bind the radiosensitizers were determined by quantifying their inhibition of uridine transport by recombinant transporters produced in yeast.


RESULTS
Beta-5-FAZR was synthesized in 44 percent yield. Beta-5-FAZR had moderate radiosensitization effect on human HCT116/100 colorectal carcinoma (OER 1.8). Beta-5-FAZR was a weak inhibitor of uridine transport relative to nonfluorinated 1-beta-D-(ribofuranosyl)-2-nitroimidazole (beta-AZR).


CONCLUSIONS
Facile synthesis of beta-5-FAZR was achieved and its activity as a radiosensitizer was confirmed. Substitution of C-5 hydroxyl by fluorine in the ribose moiety greatly reduced interaction with hENT1/2 and hCNT1/2 and moderately reduced interaction with hCNT3 relative to thymidine and beta-AZR.
Emami
Saeed
S
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada.
Kumar
Piyush
P
Yang
Jennifer
J
Kresolic
Zbigniew
Z
Paproski
Robert
R
Cass
Carol
C
McEwan
Alexander Jb
AJ
Wiebe
Leonard I
LI
D015687:Cell Hypoxia; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000532:radiotherapy; D033721:Equilibrative Nucleoside Transporter 1 / Q000378:metabolism; D033722:Equilibrative-Nucleoside Transporter 2 / Q000378:metabolism; D005720:Gamma Rays; D045325:HCT116 Cells; D006801:Humans; D007536:Isomerism; D026901:Membrane Transport Proteins / Q000378:metabolism; D009593:Nitroimidazoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D011838:Radiation-Sensitizing Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D014529:Uridine / Q000378:metabolism
D033721:Equilibrative Nucleoside Transporter 1; D033722:Equilibrative-Nucleoside Transporter 2; D026901:Membrane Transport Proteins; D009593:Nitroimidazoles; D011838:Radiation-Sensitizing Agents; C438649:SLC29A1 protein, human; C065171:cif nucleoside transporter; D014529:Uridine