Synthesis of brain-targeted 1-(2-deoxy-2-fluoro-β- D-ribofuranosyl)-( E)-5-(2-iodovinyl)uracil coupled to a dihydropyridine ⇋ pyridinium salt redox chemical-delivery system

1-(2-Deoxy-2-fluoro-β- d-ribofuranosyl-( E)-5-(2-iodovinyl)uracil (IVFRU) was coupled to a dihydropyridine ⇋ pyridinium salt redox chemical-delivery system (CDS) via a cleavable sugar-ester linkage as a site-directed approach to increase diffusion of the parent nucleoside into the central nervous sy...

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Bibliographic Details
Published in:Carbohydrate research 1993-10, Vol.249 (1), p.109-116
Main Authors: Morin, Kevin W., Wiebe, Leonard I., Knaus, Edward E.
Format: Article
Language:English
Subjects:
Animals
Antiviral Agents - chemical synthesis
Antiviral Agents - chemistry
Antiviral Agents - metabolism
Biological Transport
Brain - metabolism
Floxuridine - analogs & derivatives
Floxuridine - chemical synthesis
Floxuridine - chemistry
Floxuridine - metabolism
Molecular Structure
Oxidation-Reduction
Pyridines - chemical synthesis
Pyridines - chemistry
Pyridines - metabolism
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Summary:1-(2-Deoxy-2-fluoro-β- d-ribofuranosyl-( E)-5-(2-iodovinyl)uracil (IVFRU) was coupled to a dihydropyridine ⇋ pyridinium salt redox chemical-delivery system (CDS) via a cleavable sugar-ester linkage as a site-directed approach to increase diffusion of the parent nucleoside into the central nervous system. Treatment of 1-(2-deoxy-2-fluoro-β- d-ribofuranosyl)uracil with Bu tMe 2SiCl in the presence of imidazole in DMF yielded the protected 5- O- tert-butyldimethylsilyl derivative. Subsequent reaction with nicotinoyl chloride hydrochloride in pyridine afforded 1-[5- O-tert-butyldimethylsilyl-2-deoxy-2-fluoro-3- O-(3-pyridylcarbonyl)-β- d- ribofuranosyl]uracil. Reaction with iodine monochloride in methanol simultaneously cleaved the silyl ether moiety and iodinated the uracil ring at the 5-position. Coupling with ( E)-Bu 3Sn-CHCH-SiMe 3 in the presence of (Ph 3P) 2Pd 2(II)Cl 2 in THF gave 1-[2-deoxy-2-fluoro-3- O- (3-pyridylcarbonyl)-β- d-ribofuranosyl]-( E)-5-(2-trimethylsilylvinyl)uracil. Quaternization with iodomethane in acetone yielded the N-methylpyridinium iodide salt. Iodination of the reactive ( E)-trimethylsilylvinyl moiety with iodine monchloride in acetonitrile and reduction of the quaternary pyridinium iodide salt with sodium dithionite in the presence of sodium bydrogen carbonate was carried out as a one-pot procedure to afford 1-[2-deoxy-2-fluoro-3- O-(1-methyl-1,4-dihydropyridyl-3-carbonyl)-β- d- ribofuransyl]-( E)-5-(2-iodovinyl)uracil (IVFRU-CDS). This synthetic strategy is readily amenable to the high specfi-activity radioiodination of IVFRU.
ISSN:0008-6215
1873-426X
DOI:10.1016/0008-6215(93)84064-D