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Methyl-5-fluoroorotate: Synthesis and Comparison with 5-Fluoroorotic Acid with Respect to Biological Activity and Cell Entry^*

V. H. Bono, Jr., C. C. Cheng, E. Frei, III and M. G. Kelly

( Medicine Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland; and Cancer Chemotherapy Section, Midwest Research Institute, Kansas City, Missouri)

The synthesis of methyl-5-fluoroorotate is described. Both methyl-5-fluoroorotate and 5-fluoroorotic acid behaved identically with respect to lethal toxic dose and optimal dose in the therapy of early and late L1210 leukemia in mice. Methyl-5-fluoroorotate is neither substrate for nor inhibitor of yeast orotidylic acid pyrophosphorylase. It is hydrolyzed spontaneously at pH 7.4 and 37° C. and enzymatically by incubation with isolated intact leukocytes. Evidence is presented, with human leukocyte suspensions in vitro, which may be interpreted as indicating that the ester does enter cells and produces a higher intracellular concentration of the free acid than the free acid itself is capable of establishing.

^* This investigation was supported in part by the Cancer Chemotherapy National Service Center, National Cancer Institute of the National Institutes of Health, Public Health Service, through contract SA 43-ph-3025.

Present address: Department of Biochemistry, Dartmouth Medical School, Hanover, New Hampshire.

Received 12/ 6/63.