Studies on the syntheses of heterocyclic compounds. 845. Studies on the synthesis of chemotherapeutics. 10. Synthesis and antitumor activity of N-acyl- and N-(alkoxycarbonyl)-5-fluorouracil derivatives

Abstract

A number of N-acel and N-(alkoxycarbonyl)-5-fluorouracil derivatives possessing, for example, benzoyl, o-toluyl, acetyl, propionyl, heptanoyl, ethoxycarbonyl, phenoxycarbonyl and benzyloxycarbonyl groups as N1 and/or N3 substituents were synthesized; their antitumor activities were evaluated [using mouse leukemia L-1210 and P-388 cells, mouse fibrosarcoma Meth A cells and mouse hepatoma MH-134 cells]. The synthesis was achieved by a direct and 2-step acylation of 5-fluorouracil (1) and by selective N1-deacetylation of N1-acetyl-N3-substituted-5-fluorouracil under appropriate reaction conditions. Several N3-benzoyl- and N3-o-toluyl-5-fluorouracil derivatives showed significant activity against experimental tumor; N1-acetyl-N3-o-toluyl-5-fluorouracil (12) was most promising among them. Further investigation revealed 12 to retain higher activity toward various tumors, with lower toxicity and good blood level, than 1 of FT-207 [N1-(2-tetrahydrofuryl)-5-fluorouracil], even for oral administration.