Studies on antitumor agents, 2. Syntheses and antitumor activities of 1-(tetrahydro-2-furanyl)-5-fluorouracil and 1,3-bis(tetrahydro-2-furanyl)-5-fluorouracil.
Convenient and efficient methods were developed for preparing 1-(tetrahydro-2-furanyl)-5-fluorouracil (Thf-FU, 3) [trade name, Futraful (Ftorafur) or FT-207], which is used clinically as an antitumor agent, and 1,3-bis(tetrahydro-2-furanyl)-5-fluorouracil (Thf2-FU, 4). For the syntheses, 2,4-bis(trimethylsily)-5-fluorouracil (Me3Si-FU, 1) and 2-acetoxytetrahydrofuran (Thf-OAc, 2) were condensed in the presence of Friedel-Crafts catalysts, such as SnCl4 and BF3-Et2O in dichloromethane, or in the presence of NaI in acetonitrile to give Thf-Fu or Thf2-FU depending on the reaction conditions and workup procedure. A trace of 3-(tetrahydro-2-furanyl)-5-fluorouracil (3-Thf-FU, 5) was formed in these reactions. Thf2-FU was easily hydrolyzed to Thf-FU. 2-Methoxytetrahydrofuran can be used instead of Thf-OAc for preparation of Thf-FU under similar conditions. The optimal ratios of Me3Si-FU, Thf-OAc, and SnCl4 or NaI for preparation of Thf-FU and Thf2-FU were determined. In all cases, 2-2.5 equiv of Thf-OAc with respect to Me3Si-FU gave the best results. The yields of Thf-FU and more especially of Thf2-FU were greatly dependent on the relative amount of SnCl4, and 0.01-0.1 equiv of the catalyst with respect to Me3Si-FU gave the best results. Thf2-FU was found to be effective against murine solid tumors and it was less toxic than Thf-FU when given orally. The antitumor activity of 3-Thf-FU is also reported.
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000627:therapeutic use / Q000633:toxicity; D002279:Carcinoma 256, Walker / Q000188:drug therapy; D002286:Carcinoma, Ehrlich Tumor / Q000188:drug therapy; D005472:Fluorouracil / Q000031:analogs & derivatives*; D007928:Lethal Dose 50; D051379:Mice; D009374:Neoplasms, Experimental / Q000188:drug therapy; D051381:Rats; D012510:Sarcoma 180 / Q000188:drug therapy; D012517:Sarcoma, Yoshida / Q000188:drug therapy; D005641:Tegafur / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000627:therapeutic use / Q000633:toxicity
D000970:Antineoplastic Agents; D005641:Tegafur; C016882:FD 1; D005472:Fluorouracil