Potential Folic Acid Antagonists. III. The Antitumor and Folate Reductase Inhibitory Properties of Some Irreversibly Acting 6-N-Substituted 2,4,6-Triamino-5-(4-carbethoxyphenylazo)pyrimidines

The synthesis of some irreversibly acting inhibitors of folic acid reductase is described. These compounds, the 6-N-ω-(N-ethyl-N-2-chloroethyl)alkyl-2,4,6-triamino-5-(4-carbethoxyphenylazo)pyrimidines (XVI-XX), were tested for antitumor activity against the Ehrlich ascites system. Their ability to reduce the in vivo levels of folic acid reductase in mouse tissues was also determined. Only a partial correlation between the in vitro effectiveness of these compounds as folate reductase inhibitors and their ability to reduce folate reductase levels in vivo in mouse tissues and to inhibit the growth of the Ehrlich ascites tumor was discovered. Some reasons for this discrepancy are discussed. The possible mechanism of action of these compounds at the enzyme level is discussed in terms of Baker's extensive work on pyrimidine binding to folic and dihydrofolic acid reductase.