Synthesis and biological activity of 5-fluoro- and 5-methyl-1,3-oxazine-2,6(3H)-dione.
5-Fluoro-1,3-oxazine-2,6(3H)-dione (3-oxa-FU) was synthesized by reacting 3-oxauracil with fluoroxytrifluoromethane and decomposing the adduct in the presence of a catalytic amount of Et3N. 5-Methyl-1,3-oxazine-2,6(3H)-dione (3-oxathymine) was prepared by polyphosphoric acid catalyzed ring closure of beta-(N-ethoxycarbonylamino)-2-methacrylic acid and by treatment of citraconimide with sodium hypochlorite. As determined in vitro, 3-oxa-FU was markedly inhibitory to S. faecium (ID50 = 9 X 10(-8) M) and E. coli (ID50 = 1 X 10(-7) M) but was less active against leukemia L-1210 cells (ID50 = 1 X 10(-5) M). At 1 x 10(-4) M, 3-oxathymine was inactive in these cell systems. Inhibition of the growth of S. faecium by 3-oxa-FU was reversed competitively by the natural pyrimidines. The relatively rapid hydrolysis of the compounds in the growth media is a major factor in determining their biological effectiveness.
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D003470:Culture Media; D004355:Drug Stability; D004926:Escherichia coli / Q000187:drug effects / Q000254:growth & development; D005472:Fluorouracil / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D066298:In Vitro Techniques; D007939:Leukemia L1210 / Q000188:drug therapy; D051379:Mice; D010078:Oxazines / Q000138:chemical synthesis / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D013056:Spectrophotometry, Ultraviolet; D013291:Streptococcus / Q000187:drug effects / Q000254:growth & development; D013941:Thymine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology
D003470:Culture Media; D010078:Oxazines; D011743:Pyrimidines; D013941:Thymine; D005472:Fluorouracil