Synthesis of brain-targeted 1-(2-deoxy-2-fluoro-beta-D-ribofuranosyl)-(E)-5-(2-iodovinyl)uracil coupled to a dihydropyridine <---> pyridinium salt redox chemical-delivery system.
1-(2-Deoxy-2-fluoro-beta-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-beta-D-ribofuranosyl)uracil with Bu(t)Me(2)SiCl 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-pyridylcarbony  l )-beta-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(3)Sn-CH = CH-SiMe(3) in the presence of (Ph3P)2Pd2(II)Cl2 in THF gave 1-[2-deoxy-2-fluoro-3-O-(3-pyridylcarbonyl)-beta-D-ribofuranosyl]- (E)-5-(2-trimethylsilylvinyl)uracil. Quaternization with iodomethane in acetone yielded the N-methylpyridinium iodide salt. Ionation of the reactive (E)-trimethylsilylvinyl moiety with iodine monochloride in acetonitrile and reduction of the quaternary pyridinium iodide salt with sodium dithionite in the presence of sodium hydrogen 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)-b eta-D-ribofuranosyl]-(E)-5-(2-iodovinyl)uracil (IVFRU-CDS). This synthetic strategy is readily amenable to the high specific-activity radioiodination of IVFRU.
Morin
K W
KW
University of Alberta, Edmonton.
Wiebe
L I
LI
Knaus
E E
EE
D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D001692:Biological Transport; D001921:Brain / Q000378:metabolism*; D005467:Floxuridine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D015394:Molecular Structure; D010084:Oxidation-Reduction; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism
C084792:1-(2-deoxy-2-fluoro-3-O-(1-methyl-1,4-dihydropyridyl-3-carbonyl)ribofuranosyl)-5-(2-iodovinyl)uracil; D000998:Antiviral Agents; D011725:Pyridines; D005467:Floxuridine; C060868:5-(2-iodovinyl)-1-(2'-fluoro-2'-deoxyuridine)