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.

K W Morin, L I Wiebe, E E Knaus

文献索引：Carbohydr. Res. 249(1) , 109-16, (1993)

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摘要

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.