Pteroic Acid Research Articles

The Effect of Gamma Radiation on a Number of Water Soluble Vitamins.

Solutions of thiamin hydrochloride, riboflavin, niacinamide, biotin, pteroyiglutamic acid, and N/sub 5/-formyltetrahydropteroylglutamic acid were irradiated with gamma rays from a Co/sup 60/ source. Residual activity as well as the formation of biologically active breakdown products was studied using microbiological test systems. No microbial growth factors other than the vitamins themselves were detected in irradiated solutions of thiamin, riboflavin and niacinamide. Biotin-L-suifoxide was formed on irradiation of biotin and pteroic acid on irradiation of pteroylglutamic acid. A great number of biologically active breakdown fragments were observed in irradiated solutions of N/sub 5/-formyltetrahydropteroylglutamic acid, amongst them pteroylglutamic acid, N/sub 10/-formylpteroic acid, pteroic acid, and N/sub 10/-formylpteroylglutamic acid as well as three chemically unidentified growth factors. It was noted that the degree of destruction as determined spectrophotometrically appeared to be considerably lower than found on microbiological estimation. (auth)

Enzymic synthesis of folic acid-like compounds by cell-free extracts of Lactobacillus arabinosus

2-Amino-4-hydroxy-6-hydroxymethyltetrahydropterine (THP) replaces the naturally occurring pteridine in extracts of Lactobacillus arabinosus in the enzymic synthesis of folic acid-like compounds. Folic acid was detected when p-aminobenzoylglutamic acid was added to a system containing dialyzed extracts, THP, adenosine triphosphate, and magnesium. Pteroic acid was identified when p-aminobenzoic acid was present.

Polyazanaphthalenes. Part II. Attempted synthesis of some analogues of pteroic acid

The first page of this article is displayed as the abstract.

Factors affecting the requirement of Tetrahymena pyriformis (geleii) for folic acid.

SUMMARY: In the use of an organism for assay of folic acid those compounds which affect the utilization of folic acid should be determined. With Tetrahymena pyriformis (geleii), it is shown that thymine (or thymidine), glycine, p-amino-benzoic acid, creatin and vitamin B12 diminish the requirement for folic acid. Pteroic acid, p-aminobenzoylglutamic acid, 5-methylcytosine, p-hydroxybenzoic acid, carbamylaspartic acid and ribonucleic acid have no effect on the requirement, while cholesterol and cortisone increase the requirement.

Some effects of 2-deaminopteroylglutamic acid upon bacterial growth.

SUMMARY: Four analogues of pteroic acid and one of pteroylglutamic acid were tested for their ability to stimulate growth of Streptococmfaecalis R in the absence of pteroic acid or to inhibit growth in its presence. The four analogues of pteroic acid were inactive in either respect, but 2-deamhopteroylglutamk acid was inhibitory. Inhibition of the or anism wasmost marked in the presence of pteroic acid, and became relatively more efficient as the concentrations of inhibitor and growth factor were increased. Inhibition was much less marked in the presence of rhizopterin or Leucovorin, the relative efficiency decreasing in comparable conditions. Pteroylglutamic acid had an intermediate position and showed a competitive relationship. Lactobacillus cmei was similarly inhibited when growth was supported by either pteroylglutamic acid or Leucovorin, but was less pronounced in the presence of the latter. On the other hand, the analogue could substitute for pteroylglutamic acid in stimulating the suboptimal growth supported by a mixture of thymine and a purine in the absence of added folic acid. Several other organisms whose growth is independent of exogenous folic acid were unaffected by the analogue.

398. The use of nitro- and halogeno-ketones in the synthesis of pteridines, including pteroic acid, from 2 : 4 : 5-triamino-6-hydroxypyrimidine

398. The use of nitro- and halogeno-ketones in the synthesis of pteridines, including pteroic acid, from 2 : 4 : 5-triamino-6-hydroxypyrimidine

Application of Halogeno-Ketones to the Synthesis of Pteridines, Including Pteroic Acid

PTEROIC and pteroylglutamic acids were first synthesized from 2 : 4 : 5-triamino-6-hydroxypyrim-idine (I), 1 : 2-dibromopropionaldehyde and p-amino-benzoic or p-aminobenzoylglutamic acids1. The action of an α-halogenocarbonyl compound on a 4 : 5-diaminopyrimidine introduces a new variation of the general method of pteridine synthesis remarkable for the spontaneous oxidation of the dihydro-pteridine initially obtained during the course of the reaction. It has been observed, however, that the formation of an intermediate dihydro derivative can sometimes be troublesome in that the hydrogen eliminated may effect the reduction of substituents2. The use of 1 : 1-dihalogeno-aldehyde or -ketone would, if successful, avoid this difficulty; but apart from Purrmann's somewhat analogous synthesis of xanthopterin from dichloracetic acid and the pyrimidine (I)3, it is a modification not hitherto investigated.

Pteroic Acid Derivatives. V. Pteroyl-α-glutamyl-α-glutamylglutamic Acid, Pteroyl-γ-glutamyl-α-glutamylglutamic Acid, Pteroyl-α-glutamyl-γ-glutamylglutamic Acid

Pteroic Acid Derivatives. V. Pteroyl-α-glutamyl-α-glutamylglutamic Acid, Pteroyl-γ-glutamyl-α-glutamylglutamic Acid, Pteroyl-α-glutamyl-γ-glutamylglutamic Acid

Pteroic Acid Derivatives. III. Pteroyl-γ-glutamylglutamic Acid and Pteroyl-γ-glutamyl-γ-glutamylglutamic Acid

Pteroic Acid Derivatives. III. Pteroyl-γ-glutamylglutamic Acid and Pteroyl-γ-glutamyl-γ-glutamylglutamic Acid

General Discussion

The idea of a drug interfering with the utilization of an essential metabolite is older than the subject of chemotherapy itself, and probably celebrated its fiftieth birthday about a month ago. In 1898 Ehrlich, in a letter to his cousin Carl Weigert, indicated clearly the conception which has attracted so much attention in recent years. In his example Ehrlich pictured, for the sake of argument, an aldehyde group protruding from a cell having the particular function of fixing a specific nutritional factor for that cell. He then pictured a harmless compound, circulating in the blood, having the property of combining with this aldehyde group and so rendering the latter unavailable for its normal role. He goes on to say that the cell in this specific way must go hungry and can only survive if it can throw out another side-chain carrying an aldehyde group (Heymann 1928). In modern nomenclature, a drug may occupy the site on an enzyme normally utilized by an essential metabolite and, as Fildes pointed out in 1940, if the drug is similar to the metabolite in general structure, yet not sufficiently similar to have the same biological action, it has a good chance of interfering with that metabolite by competing with it for its enzyme. I do not know if any writers on this subject go beyond this and enquire what happens to the drug, but it was suggested by Andrewes, King & Walker (1946) in discussing the action of p -sulphonamidobenzamidine and related compounds in experimental typhus that these drugs were incorporated into functionally useless structures by the organism with consequent squandering of its synthetic resources. Such a view may sound heretical to many enzymologists but we have a good analogy in the work described from the Lilly Research Laboratories (1945), where unnatural phenylacetic acids were presented to Penicillium notatum , either as ethanolamides or as amides with DL-valine, with consequent production of analogues of penicillin G in which the phenylacetyl group of the latter has been replaced by the corresponding acyl radicals from the unnatural phenylacetic acids; incidentally, it would be a great convenience in the nomenclature of the penicillins if a trivial name could be adopted for the amine of which penicillin G is the phenylacetyl derivative. Similarly, with the knowledge that p -aminobenzoic acid turns up in the folic acid molecule, it seems likely that sulphonamides may be built up into functionally useless structures and that they do not merely compete with p -aminobenzoic acid for a site on the enzyme utilizing p-aminobenzoic acid in the fashion of a game of musical chairs. Forrest & Walker (1948) have suggested that the three carbon atoms of pteroic acid indicated in heavy type may be derived from a triose, and the suggestion by O’Meara, McNally & Nelson (1947) that the strongly-reducing non-sulphydryl substance found in bacterial cultures during the logarithmic phase of growth might be reductone, CHO. C(OH):CH(OH), seemed to us to be significant in that connexion.

STUDIES ON THE RELATIONSHIP OF PTEROYLGLUTAMIC ACID TO THE GROWTH OF PSITTACOSIS VIRUS (STRAIN 6BC)

p-Aminobenzoic and pteroic acids antagonize the inhibition of the growth of psittacosis virus (strain 6BC) by sulfadiazine in a competitive manner. Pteroylglutamic acid exerts a non-competitive type sulfonamide antagonism. The effects of certain analogues of pteroylglutamic acid and of pteroic acid on the growth of psittacosis virus and its inhibition by sulfadiazine are reported. The implications of these findings with regard to the possible synthesis of pteroylglutamic acid by psittacosis virus and its suggested rôle as an essential factor for growth of this virus are discussed.

Benziminazole Analogues of Pteroic and Pteroylglutamic Acids

IN the course of experiments on the relationship of structure to biological activity in the folic acid series of growth factors, we have examined the benziminazole analogues of pteroic acid and of pteroylglutamic acid1.

Reductone and the Synthesis of Pteridines

As we have pointed out1 that the 3-carbon atom unit comprising the ring atoms 6 and 7 and the exocyclic carbon atom (indicated in heavy type) in pteroic acid (I) might be derived from a triose, 3-phosphoglyceraldehyde and phosphodihydroxyacetone being specifically mentioned, the suggestion by O‘Meara, McNally and Nelson2 that the strongly reducing non-sulphydryl substance found in bacterial cultures during the logarithmic phase of growth might be reductone, CHO.C(OH) : CH(OH), seemed to us to have considerable significance in that connexion. O‘Meara and his colleagues suggested that p-aminobenzoic acid acts as a stabilizing agent for reductone in bacterial metabolism, enabling the cell to store reductone and to utilize it as required, presumably, from the context, after hydrolysis of the reductone – p-aminobenzoic acid condensation product to free reductone. They also showed that the reductone – p-aminobenzoic acid compound was capable of being utilized by streptococci as a source of energy for growth, and suggested that sulphonamides interfere with bacterial growth by combining with reductone and preventing it from becoming available for the use of the cell.

Pteroic Acid Derivatives. I. Pteroyl-α-glutamylglutamic Acid and Pteroyl-α,γ-glutamyldiglutamic Acid

Pteroic Acid Derivatives. I. Pteroyl-α-glutamylglutamic Acid and Pteroyl-α,γ-glutamyldiglutamic Acid

Pteroic Acid Derivatives. II. Pteroyl-γ-glutamylglutamic Acid and Pteroyl-γ-glutamyl-γ-glutamylglutamic Acid

Pteroic Acid Derivatives. II. Pteroyl-γ-glutamylglutamic Acid and Pteroyl-γ-glutamyl-γ-glutamylglutamic Acid

Pteroylglutamic acid displacing agents

7-Methyl pteroylglutamic, 7-methyl pteroic, pteroyl-aspartic and 7-methyl pteroylaspartic acids are effective displacing agents for pteroylglugtamic acid. Oxypteroylglutamic and oxypteroic acids are inactive in the system studied.

Synthesis of Pteroylglutamic Acid (Liver L. casei Factor) and Pteroic Acid. II

Synthesis of Pteroylglutamic Acid (Liver L. casei Factor) and Pteroic Acid. II

Synthesis of Pteroylglutamic Acid (Liver L. casei Factor) and Pteroic Acid. I

Synthesis of Pteroylglutamic Acid (Liver L. casei Factor) and Pteroic Acid. I

FURTHER OBSERVATIONS ON THE SPECIFICITY OF THE FOLIC ACID MOLECULE

Abstract Methyl folic acid,2 N-(4-(4-quinazoline) amino) benzoyl)-glutamic acid, the Mg salt of formyl pteroyl glutamic acid, the Mg salt of formyl pteroic acid, pteroyl aspartic acid, oxyfolic acid and oxypteroic acid have been studied as to their effect on blood regeneration in selected cases of Addisonian pernicious anemia, nutritional macrocytic anemia and tropical sprue. In the amounts administered, only the Mg salt of formyl pteroyl glutamic acid was effective in producing reticulocytosis and an increase in red blood cells, hemoglobin, white blood cells and platelets, and it was not as effective per unit of weight as was folic acid per se. Presumably this compound is slowly changed into folic acid in the body. It is of special interest that the Mg salt of formyl pteroic acid (Streptococcus lactis factor) was negative in producing hemopoiesis. These observations show the very great specificity of the folic acid molecule.

Urinary Excretion Studies Following the Administration of Pteroic Acid

1. Pteroic acid was administered to normal adult human males and the urine was assayed for “folic acid” with S. faecalis R and for pteroylglutamic acid with L. easel. On the basis of the relative response of these organisms to pteroic acid and pteroylglutamic acid, the apparent concentration of these compound's in the urine was determined.