Synthesis and antitumor activity of a series of ftorafur analogues: the effect of varying electronegativity at the 1'-position.
To test the effect of changes in electronegativity within the alicyclic N-1 substituent 5-fluorouracil analogues on cytotoxic activity, a series of derivatives of ftorafur, 1-(2'-tetrahydrofuranyl)-5-fluorouracil, was synthesized and tested for antitumor activity in the P388 lymphocytic leukemia screen and cytotoxic activity in the L1210 cell culture screen. Two compounds of N-1 substituent with high electronegativity, the 2'-tetrahydrothiophene 1'-oxide and the 2'-tetrahydrothiophene 1',1'-dioxide derivatives, demonstrated the highest in vitro L1210 cell inhibition (84.5% and 92.0%, respectively). Furthermore, against P388 lymphocytic leukemia in vivo, the 2'-tetrahydrothiophene 1'-oxide derivative showed significant activity (T/C = 143). Other compounds of similar or lower electronegativity within the N-1 cyclic substituent were inactive against P388 lymphocytic leukemia and less active against L1210 cells.
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis*; D002478:Cells, Cultured; D005260:Female; D005472:Fluorouracil / Q000031:analogs & derivatives*; D007939:Leukemia L1210 / Q000188:drug therapy; D007941:Leukemia P388 / Q000188:drug therapy; D051379:Mice; D005641:Tegafur / Q000031:analogs & derivatives* / Q000627:therapeutic use
D000970:Antineoplastic Agents; D005641:Tegafur; D005472:Fluorouracil