Expecting an antagonistic activity upon nucleic acid metabolism, several kinds of pyrimidine derivatives were synthesized, of which 5-phenylazopyrimidines were found to have growth-inhibitory activity against some microorganisms. With consideration for their biological activities, 31 kinds of 5-phenylazopyrimidine derivatives were synthesized by either of two methods according to the kind of substituents to be introduced into the pyrimidine ring ; benzenediazonium salts were coupled with pyrimidine derivatives at the 5-position in one method, and phenylazo-β-dicarbonyl compounds were condensed with guanidine or acetamidine in the other.

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Among the 5-phenylazopyrimidine derivatives reported in the preceding paper, some members showed a remarkable inhibitory effect upon the growth of Lactobacillus casei, Tetrahymena geleii, as well as chick embyro fibroblast. Others which were only slightly effective, had anti-tumor activity against Yoshida sarcoma and Ehrlich carcinoma. As a result of study on the structure-activity relationships in these compounds, it was found that 2, 4, 6-triamino-5-phenylazopyrimidines, in which the para-position of the benzene ring of the 5-phenylazogroup was substituted with sulfonic acid, sulfonamide, carboxylic acid, or phosphonic acid group, were effective upon several transplantable tumors in experimental animals and their anti-tumor activity increased by a combined administration with other nucleic acid antagonists such as 6-mercaptopurine.

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Results of growth inhibition tests and of the reversal experiments on the growth of Str. faecalis by 5-phenylazopyrimidine derivatives were described. The 5-phenylazopyrimidine derivatives were classified into following two groups on the basis of their antagonistic pattern. The first group consists of those compounds whose growth inhibitory activity is reversed by thymine or leucovorin but not by folic acid, and the second group, those compounds whose inhibitory activity is reversed by thymine or leucovorin, as well as by folic acid.

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Examinations were made on the inhibitory action of two groups of 5-phenylazopyrimidines, which were classified on the basis of their antagonistic pattern on Str. faecalis, on enzymatic conversion of folic acid to the citrovorum factor by supernatant solutions of chickliver homogenates. It was demonstrated that the compounds which belong to the first group inhibited the enzymatic conversion of folic acid to the citrovorum factor by interfering in the enzymatic formation of FAH₄, but the compounds of the second group exerted no influence on CF conversion.

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A new method for the separatory determination of glycosamine present in polysaccharides was established. Glycosamine generates nitrogen gas by reaction with nitrous acid, but it no longer produces nitrogen gas after reaction with acetylacetone, because the reaction converts it into the corresponding pyrrole derivative. Combination of the two reactions can determine the amount of glycosamine present in the hydrolyzate of polysaccharides. The values of nitrogen gas generated by the reaction of a sample with nitrous acid before and after treatment with acetylacetone are measured by Iwasaki's amino-N Azotometry, and the quantity of glycosamine in the sample is calculated from the difference between the two values. In this method the presence of amino acids is not obstructive.

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The second component, Naramycin-B, was isolated from the fermentation broth of Streptomyces naraensis novo sp. This antibiotic was also active against microorganisms sensitive to cycloheximide. The physical and chemical properties of Naramycin-B indicated that this antibiotic was one of the stereoisomers of cycloheximide.

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The fluorescence produced by 5-hydroxy-1-tetralone and hexose in sulfuric acid had the maximum intensity at 532 mμ. The fluorescence intensity of glucose obeyed the Beer's law in a concentration of 1∼40 γ/cc. of the sugar and a standard procedure of the estimation was established. The other hexoses and oligosaccharides which contained hexose units in their molecule gave individual intensities. This method was not interfered by pentoses.

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Ethyleneacetal of nicotinaldehyde was quaternized with 3, 4-dimethoxyphenethyl bromide and the product (I) was oxidized with alkaline potassium ferricyanide, yielding 1-(3, 4-dimethoxyphenethyl)-5-(1, 3-dioxolan-2-yl)-2 (1H)-pyridone (II) in a fair yield, from which the aldehyde (III) was recovered in an excellent yield. (III) will serve as a starting material for various syntheses and in this paper a synthesis of rac-c-noremetine-Pyman was described as such an example.

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A new synthesis of rac-c-bisnoremetine was described, in which 4-acetylpyridine was one of the starting materials. Ethyleneketal of this compound was quaternized with 3, 4-dimethoxy-phenethyl bromide and the product (II) was subjected to oxidation with alkaline potassium ferricyanide to furnish 1-(3, 4-dimethoxyphenethyl)-4-acetyl-2 (1H)-pyridone in a good yield after acid hydrolysis. The latter ketone (IV) underwent a smooth Willgerodt reaction to give the corresponding acetic acid (VI) from which the key intermediate (XIII) was prepared by several different routes. The structure of the final product (XV) was proved by converting the penultimate compound (XIV) into a well defined crystalline rac-c-bisnorrubremetinium bromide (XVI).

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Kobusine, C₂₀H₂₇O₂N, m.p. 267∼267.5°, was hydrogenated over palladium-carbon in methanol, and α-dihydrokobusinone, C₂₀H₂₇O₂N, m. p. 230∼232°, β-dihydrokobusinone, C₂₀H₂₇O₂N, m.p. 240∼241°, and dihydrokobusine, C₂₀H₂₉O₂N, m.p. 229∼231°, were obtained as the product. α-and β-Dihydrokobusinones were proved to be a ketone in six-membered ring. The β-isomer was also obtained from α-isomer or directly from kobusine on heating with 5% hydrochloric acid. Oxidation of kobusine with chromium trioxide in pyridine gave ketokobusinone, C₂₀H₂₃O₂N, m.p. 189∼191°, and kobusinone, C₂₀H₂₅O₂N, m.p. 273∼275°, both products showed the bands for α, β-unsaturated ketone in their infrared spectra. On catalytic hydrogenation, the former gave a saturated diketone, C₂₀H₂₅O₂N, m.p. 173∼175, which was identified with the oxidation product of β-dihydrokobusinone. The latter gave α-dihydrokobusinone. Diacetylkobusine, C₂₄H₃₁O₄N, m.p. 139∼141°, and also dibenzoylkobusine (hydrochloride, C₃₄H₃₅O₄N·HCl·H₂O, m.p. 290∼292°) were prepared. Allyl alcohol of the type of HO-C^^1-C^^1=CH₂ and secondary hydroxyl group were thus confirmed as the functional groups in kobusine.

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Hypognavinon, C₂₇H₂₉O₅N, eine α, β-ungesattigtes Keton, wurde durch Oxydation des Hypognavins hergestellt. Das letztere ergab bei der katalytischen Reduktion mit Pd-Kohle ein Dihydroderivat, welches mit dem Dihydrohypognavinon³⁾ identisch ist. Dihydrohypognavinon ergab bei der weiteren Oxydation eine Diketoesterbase C₂₇H₂₉O₅N, welche violettrote Zimmermann'sche Farbreaktion zeigt. Durch Verseifen der letzteren wurden zwei isomere Diketoalkamine C₂₀H₂₅O₄N erhalten, die sowohl die Fehling'sche Losung wie die ammoniakalische AgNO₃-Losung reduzierten, sich mit Triphenyltetrazoliumchlorid rotlich farbten und im Gegensatz zur Diketoesterbase 1 Mol HJO₄ verbrauchten. Die vier Sauerstoffatome des Hypognavinols sind als Hydroxylgruppe vorhanden und zwar drei davon acylbar. Die vierte Hydroxylgruppe stellt hochstwahrscheinlich eine tertiare Hydroxylgruppe dar. Eine dieser acylbaren Hydroxylgruppen ist im Hypognavin benzoyliert vorhanden und eine andere bildet mit einer Vinylgruppe ein Allylalkohol-Skelett. Die Benzoyloxygruppe des Hypognavinols bildet mit der anderen acylbaren Hydroxylgruppe einen α-Glykolester. Der Hofmann'sche Abbau des Hypognavinols wurde ausgefuhrt und Des-N-methylhypognavinol und Des-N-athylhypognavinol wurden hergestellt. Des-N-methylhypognavinol-Methylhydroxyd widersteht dem zweiten Hofmann'schen Abbau und regeneriert Des-N-methylhypognavinol.

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Durch Selen-Dehydrierung des Des-N-methylhypognavinols wurde eine schwach basische aromatische Fraktion in sehr kleiner Menge erhalten, deren UV-Spektrum demjenigen des 3-Azaphenanthrens ahnlich ist. Durch Oxydation des Tribenzoyl-des-N-athylhypognavinols und darauffolgende Verseifung wurde ein 6-gliedriges Laktam C₂₂H₂₉O₅N erhalten. Anhydrohydroxy-des-N-methylhypognavinol C₂₁H₂₇O₄N, ein Carbinolaminather, wurde durch Oxydation des Des-N-methylhypognavinol mit Kaliumferricyanid erhalten. Fur die Konstitution des Hypognavinols wurde die Formel (VIII) oder (IX) und fur Hypognavin die Formel (X) oder (XI) aufgestellt.

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The β-hydroxy-DL-glutamic and L-glutamic acid decarboxylases in Escherichia coli were investigated. It was concluded that the two enzymes are different and presumed that these enzymes are induced by glutamic acid simultaneously.

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Effect of volatile amines such as methylamine, dimethylamine, and trimethylamine on the determination of ammonia with the Conway microdiffusion method using colorimetry by the so-called Van Slyke-Hiller and Akamatsu-Katsumata methods was examined. Among these amines, methylamine shows the same color reaction as ammonia, trimethylamine inhibits the color development, and dimethylamine does not show any effect.

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Spectrophotometric investigations of copper chelates of 1, 4-and 1, 9-dihydroxyphenazines, which are isomers of the already reported compound having two oxine-like functional groups, have been carried out. The copper chelates of 1, 2- and 1, 7-dihydroxyphenazine, which have only one functional group, though they are dihydroxyl compounds and the other hydroxyl group located at the β-position, have been studied by spectrophotometric method on their properties, compositions, and dissociation constants. It was learned that all of the compounds formed a normal complex, with a five-membered chelate ring.

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Properties and compositions, as well as the dissociation constants of the copper chelates of α-hydroxyphenazine derivatives, which possess CH₃ or COOH group at the α- or β-position, have been investigated by spectrophotometric method. The COOH group peri to a ring-nitrogen is also capable of forming a chelate, and copper chelate of pherazine-1-carboxylic acid has also been studied. In concluding this study of the series of copper chelates of α-hydroxyphenazine derivatives, some findings on the mode of action were made from the standpoint of chelate chemistry. 1) The fortifying effect by copper is caused by the formation of chelate compounds, which are required to possess at least one oxine-like functional group at the α-position. 2) Di-N-oxide derivatives are fairly effective. 3) Introduction of lipophilic radical strengthens the effect. 4) The antibacterial effects depend upon the degree of the binding power between phenazine derivatives and copper.

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Spectrophotometric studies of copper complexes of oxine and its N-oxide were carried out in ethanol solutions. At pH 8.0, the chelates of both oxine and its N-oxide indicated the normal complex and, when the measurements were carried out in an acid medium, the formation of a cation complex was taken into consideration.

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By oxidation with chromium trioxide in the presence of conc. sulfuric acid at about 5∼15°, 6-hydroxyphenazine-1- and 9-hydroxyphenazine-2-carboxylic acids were obtained from their respective methylphenazine derivatives.

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Alkali salts of some aromatic hydroxycarboxylic acids are effective in increasing the solubility of pyrazinamide in water and the use of sodium p-aminosalicylate (PAS-Na) results in the formation of a yellow solution of pyrazinamide-PAS-Na complex. It has been found from examination of absorption spectrum in the visible range that the coloration is due to the formation of a 1 : 1 molecular compound of pyrazinamide and PAS-Na in aqueous solution. It was also found that sodium o-, m-, and p-hydroxybenzoates also form 1 : 1 molecular compound with pyrazinamide. There is a linear relationship between increased solubility of pyrazinamide per mole of aromatic hydroxycarboxylic acid added and equilibrium constant of the molecular compound thereby formed. The equilibrium constants obtained in the present series of work were larger than the values calculated from the solubility increase and some considerations were made on the reason for this difference.

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Several amino acids were synthesized from variousl alkylmalonic acids by reacting with a little excess of hydrazoic acid in chloroform at 50∼60°, catalyzed by 100% sulfuric acid. Reaction products were treated with Amberlite IR-120 or Amberlite IR-4B and the expected amino acids were readily obtained in a considerably pure state. In this reaction it seemed that a large alkyl group in alkylmalonic acid tended to lessen the yield of amino acids. This method is excellent in some points, namely, the starting mateial, alkylmalonic acid, is easily obtainable, the procedure is simple, the yield is high, and there is no fear of inorganic salts contaminated in the products.

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A new method was found for synthesis of ω-amino acids in a good yield by the Schmidt reaction, reacting basic acids with calculated amount of hydrazoic acid. In this case, the use of monoalkyl ester of dibasic acid as the starting material gave still better yield. In addition, DL-2, 8-diaminooctanoic acid and DL-2, 9-diaminononanoic acid were obtained in a high yield as their monohydrochlorides from 8-aminooctanoic acid and 9-aminononanoic acid, respectively, which were prepared by the above-mentioned reaction.

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L-threo-1, 2-Dimethyl-3-phenylaziridine (threo-III) was, for the first time, isolated in the form of picrate either partly by action of KOH on the supposed L (+)-⩛-ephedrine O-sulfate (threo-V) or wholly by action of NaOH on L (+)-threo-1-chloro-1-phenyl-2-methylamino-propane (threo-II). These observations revised the previous claim that the reaction in the latter case would not initially pass into the aziridine, but into others, e.g. β-methylstyrene derivative, which could not be identified because it polymerized rapidly. The aziridine polymerizes very easily in the free state and more or less easily even in the salt form. It was also discussed that the steric requirement for the aziridine formation favored L-threo-aziridine more than the L-erythro-diastereomer in the transition state of the reaction. The conclusion was supported by the formation ratio of both aziridines roughly calculated on the ground of optical rotatory power.

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The urinary metabolites of p-dimethylaminoazobenzene (DAB) in dog were studied, and in this connection, the metabolites of p-aminoazobenzene (AB) and 4'-hydroxy-4-aminoazobenzene (4'-OH-AB) were also examined. From the hydrolyzed 24-hr. urine after administration of DAB, o-aminophenol, p-aminophenol, aniline, p-phenylenediamine, AB, and p-methylaminoazobenzene (MAB) were detected. The amount of o-aminophenol was larger than that of the other amines. By paper chromatography 5-phenylazo-2-aminophenyl hydrogen sulfate (3-HSO₃O-AB), 3-HSO₃O-MAB, and 4'-HSO₃O-AB were respectively identified from the 3- to 7-hr. DAB-urine. The presence of 3-HSO₃O-AB N-glucosiduronic acid in the DAB- and AB-urine was assumed from their paper chromatographic behavior.

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The reaction of 2, 5-dialkylhydroquinones, 2-methyl-5-ethylhydroquinone (II), 2, 5-diethyl-hydroquinone (III), 2-methyl-5-propylhydroquinone (IV), and 2, 5-dipropylhydroquinone (V), with maleic anhydride was investigated. Of these hydroquinone homologs, (II) and (III) gave the maleic anhydride adducts, (VIIa) or (VIIb) and (VIII), respectively. The effect of alkyl groups on the reactivity of the hydroquinone homologs is discussed.

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The enzyme system that decomposes ethanolamine into ammonia and acetaldehyde was found in Proteus morganii and it was named ethanolamine dehydrase. The acetaldehyde formed during the course of this decomposition was also found to undergo concurrent dismutation to be changed into ethanol and acetic acid.

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Spermine was found to be the powerful activator of bovine testicular hyaluronidase at 10^-4M concentration. The enzyme activity was determined either in vitro by viscometric and reductometric methods or in vivo by intracutaneous diffusion method. Oxidation of spermine oxidase originating in goat serum resulted in the loss of activation of the enzyme activity. Several amines, especially polymethylenediamines related to spermine, were also found to exhibit similar activating effect on hyaluronidase, although the effect is less than that of spermine. The activity of these amines at 10^-3M concentration decreases in the following order : Spermine, spermidine, trimethylenediamine, histamine, hexamethylenediamine, putrescine, cadaverine and ethylenediamine.

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