Antagonists of Nucleic Acid Derivatives

Inhibition of the growth of Lactobadlus casei with folic acid as the nutrilite is a general property of 2,4-diaminopyrimidines, 2-aminopyrimidines, and condensed systems containing these groupings (1). These compounds comprise a spectrum of inhibitors. At one end lie the simpler diaminopyrimidines which are competitive antagonists of folic acid (1, 2). The center may be represented by 2-aminopurine (3), the action of which is reversible by either folic acid or a purine, while the inhibitory action of 2,6-diaminopurine (1, 3) is affected only slightly by the concentration of folic acid but is reversed by adenine. The microbiological studies (1, 2) and many of the biological effects on higher animals are suggestive of an interference with nucleic acid synthesis. Thus diaminopurine has a protective effect in mouse leucemia (4), inhibits the hematopoietic tissues of dogs (5), swine (6), and chick embryo (7), inhibits the multiplication of vaccinia virus in vitro (8), and has a differential toxicity on cells of sarcoma 180 in tissue culture (9). The appearance of N16, administered as 2,6-diaminopurine, in the guanine fraction of the nucleic acid of rats (10) indicates the ability of diaminopurine to participate in nucleic acid metabolism, although it affords no clear picture of the metabolic pathways which are involved. Studies on the specificity of the purine requirement of L. casei (11) have indicated that this organism possesses a mechanism for the interchangeable use of the physiological purines. Diaminopurine appears to interfere with this mechanism since at high concentrations its effects are reversed by adenine but not by guanine (1, 2), hypoxanthine, or xanthine. Reversal studies with free purines, nucleosides, and nucleotides reveal that the utilization of the ribose derivatives is inhibited more strongly than that of the free purines. The results of these studies, presented herein, suggest a number of inferences regarding the biochemical pathways in the nucleic acid metabolism of L . casei.