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5-Azaorotic Acid and Related Inhibitors of the Synthesis de Novo of Pyrimidine Nucleotides^*

R. E. Handschumacher

( Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut)

The pyrimidine analogs, 5-azaorotic acid (6 x 10^-7 M) and 5-azauracil (2 x 10^-4 M), caused approximately 50 per cent inhibition of the metabolism of orotic acid by cell-free extracts from mouse liver or L5178Y leukemia cells. Seven other compounds of a total of 42 tested also caused at least 50 per cent inhibition at concentrations less than 2 x 10^-3 M. The primary site of action of the two symmetrical triazine derivatives appeared to be orotidylic acid pyrophosphorylase. However, 5-azaorotate was a much more effective inhibitor of the utilization of exogenous orotic acid by liver slices than by intact leukemia cells. Conversely, 5-azauracil was nearly inactive in liver slices but was much more effective with leukemia cells. Intraperitoneal injection of 5-azaorotate (0.3 µmole/gm) into mice caused an 80 per cent inhibition of the utilization of orotic acid but did not affect the incorporation of uridine into the liver.

^* Presented in part at the annual meeting (April, 1962) of the American Association for Cancer Research. Supported by grants from the American Cancer Society (T-112B) and from the Public Health Service (CY-2817).

Formerly a Scholar in Cancer Research of the American Cancer Society.

Received 11/12/62.