Synthesis and biological activity of 5-fluoro- and 5-methyl-1,3-oxazine-2,6(3H)-dione

Abstract

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.

Fluorinated azines and benzazines containing oxygen or sulfur atoms

“…These compounds have been tested as inhibitors of the tumor cell growth and have exhibited the activity comparable with that for some natural pyrimidines (Scheme 8) [29,30].…”

1,3‐Oxazine as a Promising Scaffold for the Development of Biologically Active Lead Molecules

“…[18] Synthesis of 5-methyl-3H-1,3oxazine-2,6-dione was catalysed by ring closure of β-(N-ethoxycarbonylamino)-α-methacrylic acid at 75-80 °C. [21]…”

A Convenient and Concise Metal-Free Approach to Functionalized Bicyclic Pyrimidinones from Oxazine-2,6-diones

“…Compound 20 was prepared according to the literature report. 9 To a mixture of NaOCl solution (4.99%, 10 mL) and NaOH (1.6 g, 40 mmol) cooled at 0 °C was added dropwise a precooled (0 °C) solution of 3-methylpyrrole-2,5-dione (3.55 g, 32 mmol) in H 2 O (14 mL). The reaction mixture was then stirred at the same temperature for 4 h to obtain a clear solution.…”