Fluorinated pyrimidine nucleosides. 4. Synthesis and antitumor testing of a series of 2',5'-dideoxy- and 2',3',5'-trideoxynucleosides of 5-fluorouracil.
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 methyltriphenoxyphosponium iodide, followed by catalytic reduction. 1-(2',5'-Dideoxy-beta-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 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, as well as the trideoxy compound 13, were tested against sarcoma 180 in mice in comparison with 5-flourouracil, FUDR (1), and Ftorafur (17).
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis*; D003857:Deoxyuridine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D005467:Floxuridine / Q000627:therapeutic use; D005472:Fluorouracil / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D051379:Mice; D012510:Sarcoma 180 / Q000188:drug therapy; D005641:Tegafur / Q000627:therapeutic use
D000970:Antineoplastic Agents; D005467:Floxuridine; D005641:Tegafur; D005472:Fluorouracil; D003857:Deoxyuridine