Fluorinated Pyrimidine Nucleosides. 4. Synthesis and Antitumor Testing of a Series 2',5'-Dideoxy- and 2',3',5'-Trideoxynucleosides of 5-Fluorouracil

Article abstract of DOI:10.1021/jm00182a008

Dideoxy- and trideoxynucleosides of 5-fluorouracil have been 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-β-D-threo-pentofuranosyl)-5-fluorouracil (4) was prepared from 3 by mesylation, followed by alkaline hydrolysis. 2',3',5'-Trideoxy-5-fluorouridine (13), a methyl homologue of Ftorafur (17), was synthesized by two routes: Treatment of the 3'-mesylate 8 with potassium tert-butoxide yieldedthe 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-β-D-threo-pentofuranosyl)-5-fluorouracil (5), presumably produced by rearrangement of the corresponding 1-isomer 9.The dideoxy compounds 3 and 4, as well as the trideoxy compound 13, were tested against sarcoma 180 in mice in comparison with 5-fluorouracil, FUDR (1), and Ftorafur (17).