Fluorinated pyrimidine nucleosides. 4. Synthesis and antitumor testing of a series of 2',5'-dideoxy- and 2',3',5'-trideoxynucleosides of 5-fluorouracil

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Abstract
Dideoxy- and trideoxynucleosides of 5-fluorouracil were synthesized for antitumor evaluation. 2'',5''Dideoxy-5-fluorouridine (3) was prepared from 2''-deoxy-5-fluorouridine (1) by iodination using methyltriphenoxyphosphonium iodide, followed by catalytic reduction. 1-(2'',5''-Dideoxy-.beta.-D-threo-pentofuranosyl)-5-fluorouracil (4) was prepared from 3 by mesylaton, followed by alkaline hydrolysis. 2'',3'',5''-Trideoxy-5-fluorouridine (13), a methyl homologue of Ftorafur (17), was synthesized by 2 routes. Treatment of the 3''-mesylate 8 with potassium tert-butoxide yielded the 2'',3''-unsaturated derivative 12, which on hydrogenation yielded 13. Alternatively, treatment of 1 with a large excess of methyltriphenoxyphosphonium iodide produced several products, including two 3''-epimeric diiodo compounds (14 and 15), each of which could be hydrogenated to 13. The major product from this iodination reaction was characterized 3-(2,3''-anhydro-2'',5''-dideoxy-5''-iodo-.beta.-D-threo-pentofuranosyl)-5-fluorouracil (5), presumably produced by rearrangement of the corresponding 1-isomer 9. The dideoxy compounds 3 and 4, and the trideoxy compound 13, were tested against sarcoma 180 in mice in comparison with 5-fluorouracil, FUDR (1) and Ftorafur (17).

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