Abstract
2-Amino-5-(p-bromoacetamidophenoxypropyl)-6-phenyl-4-pyrimidinol (II), when incubated with dihydrofolic reductase at 37°, inactivated the enzyme with a half-life of about 45 min. In contrast, iodoacetamide and p-bromoacetamidophenylbutyric acid at the same concentration showed no inactivation of the enzyme in the same time. An interesting contrast to II was the 6-methyl analog (III) of II which inactivated the enzyme at about one-seventh the rate of II. This result gives unequivocal support for a previous suggestion that 6-methylpyrimidines and 6-phenylpyrimidines do not reversibly complex with dihydrofolic reductase in the same manner, else II and III should have inactivated the enzyme at the same rate at equal concentrations of reversible complex. These experiments are best explained on the basis of active-site-directed irreversible inhibition of dihydrofolic reductase. 2-Amino-5-(p-bromoacetamidophenoxypropyl)-6-phenyl-4-pyrimidinol (II), when incubated with dihydrofolic reductase at 37°, inactivated the enzyme with a half-life of about 45 min. In contrast, iodoacetamide and p-bromoacetamidophenylbutyric acid at the same concentration showed no inactivation of the enzyme in the same time. An interesting contrast to II was the 6-methyl analog (III) of II which inactivated the enzyme at about one-seventh the rate of II. This result gives unequivocal support for a previous suggestion that 6-methylpyrimidines and 6-phenylpyrimidines do not reversibly complex with dihydrofolic reductase in the same manner, else II and III should have inactivated the enzyme at the same rate at equal concentrations of reversible complex. These experiments are best explained on the basis of active-site-directed irreversible inhibition of dihydrofolic reductase.
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