Synthesis and Antitumor Activity of a Series of Ftorafur Analogues: The Effect of Varying Electronegativity at the 1'-Position

Article abstract of DOI:10.1021/jm00380a016

To test the effect of changes in electronegativity within the alicyclic N-1 substituent of substituted 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 (84.5percent and 92.0percent, 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.