5-azaorotic acid and related inhibitors of the synthesis de novo of pyrimidine nucleotides.

The pyrimidine analogs, 5-azaorotic acid (6 X 10@ M) and 5-azauracil (2 X 10@ 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@ M. The primary site of action of the two symmetrical triazine derivatives ap peared 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 @mole/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.