Abstract

Cyclo-(3-methylsaligenyl)-5-O-[1-(2,4-difluoro-5-[125I]iodophenyl)-2-deoxy-β-D-ribofuranosyl]phosphate (cycloSal- dRF[125I]IB) was radioiodinated with sodium [125I]iodide via copper-catalyzed isotope exchange in 48% radiochemical yield. cycloSal-dRF[125I]IB was found to be incorporated into the cytoplasmic nucleic acid and mitochondrial fractions of murine KBALB and K-STK (engineered to express HSV-1 thymidine kinase) cells in cell culture. Uptake was greater than that for either the corresponding nucleoside dRF[125I]IB or [125I]IUdR. These in vitro studies support a mechanism of metabolic activation to the free nucleotide, thereby effecting TK-bypass. Pharmacokinetic studies in rats reflect a complex interplay of tissue depot effects, hepatobiliary recycling, and metabolism. Biodistribution studies in tumor- bearing mice provide further evidence for lipophilic depot effects and hepatobiliary recirculation, with no evidence for active (metabolic) accumulation in any tissue.

Keywords: Iododeoxyuridine, difluorophenyldeoxyribosides, prodrugs, thymidine kinase (TK) by-pass, pharmacokinetics, biodistribution, mitochondrial uptake, CycloSal-dRFIB, Thymidine, Thymidine Kinase by-Pass, Murine Models, cycloSal-dRF[I]IB, HSV-1 thymidine kinase, dRF[I]IB, [I]IUdR, pyrimidine nucleosides, phosphorylation, nucleoside kinases, nucleotides, monophosphate, cyclosaligenyl phosphodiester pronucleotides, Xenopus oocytes, fluorodeoxyuridine, cycloSal-dRFIB, Tris-acetate-EDTA buffer, Coomassie blue G250 reagent, ELISA, BSA, bovine plasma albumin, radioassay, EMT6 tumour cells, (CO asphyxiation), gamma scintillation counter, Cell Culture