Amino-5, 8-quinolinequinone derivatives were easily obtained by the reaction of 5, 8-quinolinequinones with hydrazoic acid. 7-Amino-5, 8-quinolinequinone was prepared by the reduction of 7-azido-5, 8-quinolinequinone with Na2S2O4. The reaction of azidomethyl-5, 8-quinolinequinones with aliphatic secondary amines (pyrrolidine, piperidine, and morphorine) in benzene afforded substituted aminomethyl-5, 8-quinolinequinone derivatives. The reaction of azido-5, 8-quinolinequinones with aliphatic secondary amines in benzene was examined.
A series of phenylacetic acid and phenethyl alcohol derivatives with a bicyclic heteroaromatic ring were synthesized. The bicyclic heteroaromatic rings were imidazo [1, 2-a]-pyridine, imidazo [2, 1-b] thiazole, imidazo [1, 2-a] pyrimidine, and indolizine. These compounds were tested for both analgesic and anti-inflammatory activity in the phenylquinone writhing and carrageenin paw edema assays, and the relationship between their structure and activity was discussed. It was thereby found that 2-[4-(imidazo[1, 2-a]-pyridin-2-yl) phenyl] propionic acid (XII-2) had the most potent activity among the compounds tested.
Sodium 35S-cyclamate (35S-Cy-Na) with a specific radioactivity of 0.10 mCi/mmol was synthesized from cyclohexyl isocyanate and H235SO4. Radiochemical and chemical purities of the 35S-Cy-Na were confirmed, and the radiochemical and chemical yields from H235SO4 were 24.4% and 48.5%, respectively. The fundamental conditions for isotope dilution analysis were examined for the quantitative determination of sodium cyclamate (Cy-Na) by the use of the 35S-Cy-Na. Three kinds of methods were compared with regard to measurement of the radioactivity of sulfur-35. In the radioactivity measurement of Ba35SO4, which was derived quantitatively from 35S-Cy-Na by means of sodium nitrite in an acidic solution, a gas-flow counter for the solid phase and a liquid scintillation counter for the heterogeneous system in a toluene type scintillator with the aid of Cab-O-Sil were compared. In the third method, analysis through the combination of the radioactivity measurement of 35S-Cy-Na and absorptiometric analysis of Cy-Na at 550 nm showed 0.1 mg as the determination limit. In this isotope dilution analysis, the coloration of Cy-Na was made by means of chloranil and hydrogen peroxide, and the radioactivity of 35S-Cy-Na diluted was measured simultaneously using an aliquot of the colored solution. This isotope dilution method was applied to determine Cy-Na in three kinds of canned seafoods which were manufactured before prohibition against Cy-Na as a food additive. The Cy-Na content in canned foods was 0.26% for ark-shell fish, 0.21% for squid, and 0.35% for tuna.
Eggs of Rana catesbiana were found to contain two agglutinins showing specific reactivities, one with human blood group A erythrocytes and the other with mouse Ehrlich ascites carcinoma cells and rat ascites hepatoma cells (AH-109A). These agglutinins were purified by chromatography over Sephadex G-75, DEAE- and CM-cellulose, and finally hydroxylapatite column. The purified anti-A agglutinin contained about 1.6% carbohydrate and the molecular weight estimated by polyacrylamide gel electrophoresis in sodium dodecyl sulfate was 17000. The purified cancer cell agglutinin contained about 0.6% carbohydrate and the molecular weight was 15000. Its electrophoretic mobility on cellulose acetate membrane was similar to that of basic proteins such as protamine and histone. Two agglutinins had similar amino acid compositions, and showed a relatively large amount of glutamic acid and aspartic acid but a small amount of lysine, arginine, and histidine. The agglutinating activity of anti-A agglutinin is inhibited by oligosaccharides such as lactose and N-acetyllactosamine, whereas that of cancer cell agglutinin is specifically inhibited only by ganglioside obtained from human blood group A erythrocytes. The remarkable difference in the biological properties of these agglutinins are discussed.
Three new eremophilenolide derivatives, 3β-angeloyloxyeremophilenolide (I), 3β-angeloyloxy-8β-hydroxyeremophilenolide (II), and 3β-angeloyloxy-6β-hydroxyeremophilenolide (III), were isolated from the rhizome of Ligularia tussilaginea MAKINO. I, II, and III were identified in the original ethereal extract by thin-layerchromatography, but it is presumed that secondary oxidation of 3β-angeloyloxyfuranoeremophilane contained in this plant would also afford I and II.
Pharmacological response and diameter of a pupil in the rat were examined after oral administration of isopropamide iodide when given in combination with 50-fold molar excess of trichloroacetate in solution and compared with those after single administration of isopropamide iodide. However, the increased pharmacological activity, as reported by Irwin and others in 1969 using male albino mice, was not observed and the decrease in the response was seen in the presence of trichloroacetate. This fact could better be related to the inhibition behavior in stomach emptying of trichloroacetate through the direct effect on the stomach wall. Absorption study using the rat small intestine in situ and in vivo indicated that trichloroacetate (50-fold molar excess) enhanced the absorption rate of isopropamide iodide but unfortunately the above result could not explain the pharmacological response in this study. A great care should be taken for explanation and presumption of pharmacological response by applying the data of in situ and in vivo studies using a part of the animal body.
The crude drug "Zhu" has been classified empirically into two groups ; Changzhu and Baizhu, and this classification has recently been examined on the basis of their morphological characteristics and chemical constituents. In order to clarify the pharmacological significance of these two groups, some biological activities of Atractylodes lancea and A. lancea var. chinensis (Changzhu) and A. ovata and A. japonica (Baizhu) were examined, using their essential oil constituents. (a) Changzhu had a central nerve system (CNS) depressant action in terms of general behavior, spontaneous movement, anti-electroshock convulsion, and potentiation of hypnotic action of hexobarbital sodium. The active entities existed chiefly in β-eudesmol and hinesol. (b) Other pharmacological actions, such as anti-ulcer action, carbon transport action, and stimulation of gastric juice secretion, which are all regarded as actions on the gastrointestinal functions, and effect on normal body temperature, diuretic action, analgesic action, and anti-inflammatory action were examined. Responses of experimental animals (mice and rats) to the rhizome extracts and constituents were not significantly different from those of the control animals. (c) Changzhu and Baizhu could be classified by evaluation of their CNS depressant action.
Two kinds of known ellagic acid derivatives, 3, 3', 4-tri-O-methylellagic acid and 3-O-methylellagic acid, were isolated from the leaves of Lagerstroemia subcostata KOEHNE. and from the leaves of L. speciosa (L.) PERS. respectively. From the latter, 3, 4-di-O-methylellagic acid, previously reported as the aglycon of lagertannin, was synthesized. In addition to 3, 3', 4-tri-O-methylellagic acid, β-sitosterol, campesterol, and stigmasterol were identified by gas chromatography from the leaves of L. subcostata.
D(-)-α-[4-Substituted 1-piperazinecarboxamido] benzylpenicillin (I), D(-)-α-[4-substituted 2-oxo-1-piperazinecarboxamido] benzylpenicillin (II), and D(-)-α-[4-substituted 3-oxo-1-piperazinecarboxamido] benzylpenicillin (III) were prepared. In vitro antibacterial activity of these compounds against S. aureus, E. coli, P. aeruginosa, P. vulgaris, and K. pneumoniae was examined and the activity decreased in the order of II, I, and III. These compounds were found to have a stronger antibacterial activity against P. aeruginosa and K. pneumoniae than aminobenzylpenicillin or carbenicillin.
The chemical constituents of the bark of Xanthoxylum arnottianum MAXIM. (Japanese name : Iwa-Zansho) were examined. Six known alkaloids ; chelerythrine (1) chloride, des-N-methylchelerythrine (2), oxychelerythrine (4), and decarine (12), arnottianamide (9), skimmianine (23), and a new alkaloid, iwamide (13), mp 271-273°, were isolated. Two lignans, l-asarinin (5) and l-sesamin (22), two coumarins, marmesin (6) and columbianetin (24), and eight neutral compounds, arnottin I (7), arnottin II (8), β-amyrin (15), acid X-I (17), sesquiterpene mixture I (11), compound I (10), compound II (14), and compound III (21), were also isolated.
Methanolysis of diphenic anhydrides (Va-c) obtained from diphenic acids (VIa-c) gave monomethyl diphenates (VIIa-c and VIIIa-c). The structures of these diphenates were confirmed by direct comparison of these compounds with authentic samples of VIIa-c and VIIIa-c prepared by oxidation of methyl 2'-formyl-2-biphenylcarboxylate derivatives (IXa-c and Xa-c) with potassium permanganate. The two directions of methanolysis of V to form VII and VIII are discussed.
6-Amino-4-oxo-2-thioxo-1, 2, 3, 4-tetrahydropyrimidine and its N- or S-substituted derivatives are hydrolyzed by p-toluenesulfonic acid or hydrochloric acid to the corresponding barbiturates. These barbiturates condense with the Ehrlich reagent in the presence of an acid catalyst to afford stable benzylidene compounds. These reactions were found to be almost quantitative. The optimal experimental conditions were also established for using the above reactions for the quantitative colorimetric determination of 6-amino-4-oxo-2-thioxo-1, 2, 3, 4-tetrahydropyrimidine derivatives.
Pharmacological effect of crude extracts, CS1 and CS4 to CS6, obtained from the Chinese crude drug Shoma (rhizome of Cimicifuga simplex WORMSK.), was examined in small animals. Weak toxic effect was found in CS1, CS4 and CS6 showed a significant hypothermic, analgesic, and anti-edematous effect, but CS5 showed only a potent antiedematous effect. An anti-analulcerative effect was found in CS5 and CS6. Caffeic acid, isoferulic acid, and ferulic acid were detected in Cimicifuga plants. Isoferulic acid and ferulic acid showed a significant decrease of writhing responses. Caffeic acid was approximately as effective as isoferulic acid in lowering the rectal temperature. The significance of these pharmacological results was discussed.
A new method for the determination of paeoniflorin and albiflorin in crude drug Shaoyao ( ?? ??, peony root) was established by the use of a rod-thin-layer chromatograph equipped with a flame ionization detector (rod-TLC-FID). The test solution was submitted to rod-TLC-FID method using a mixture of chloroform-methanol (5 : 1) as a developing solvent. The content of paeoniflorin and albiflorin was calculated from their calibration curves previously prepared using guaiacol glyceryl ether as an internal standard. The recovery rate of paeoniflorin and albiflorin was more than 95%. This method is considered to be useful for the chemical evaluation of Shaoyao.
As a part of systematic studies on 5, 8-quinolinequinone derivatives, reaction of 6-methyl-5, 8-quinolinequinone (I) with primary and cyclic secondary amines was carried out. The reaction of I with aziridine in benzene afforded 7-aziridino-6-methyl-5, 8-quinolinequinone (II) and that of I with hexamethyleneimine, piperidine, or pyrrolidine afforded-6-(substituted aminomethyl)-5, 8-dihydroxyquinolines (III-V). Reactions of I with primary amines (p-toluidine, p-anisidine, aniline, and cyclohexylamine) afforded 8-(N-substituted amino)-6-(N-substituted amino) methylidenequinolin-5-ones (VI, VIII-X).
Ketenethioacetal derivatives, 1-[2, 2-bis (methylthio) vinyl] pyridinium iodides, were synthesized by alkylation with methyl iodide of sulfur-containing pyridinium ylides, which were prepared by the reaction of pyridinium ylides with carbon disulfide in the presence of sodium hydroxide.
Metal complexes of 8-aminoquinoline with bivalent transition metals, Cu, Pt, and Pd, were prepared, and mixed ligand complexes of 8-aminoquinoline-copper complex with oxalate and malonate were also prepared. Antitumor activity of these complexes were tested against either leukemia L-1210 or P-388 in CDF1 mice. Screening results showed these complexes to be not effective, except the Pt-complex.
Experiments were undertaken to examine the effect of adenyl compounds (adenosine or adenosine 3'-monophosphate) on the accumulation of thiopental (free base) in the tissues of mice, and following results were obtained. 1) In mouse liver and blood, there was no difference in the accumulation of thiopental between the groups pretreated with adenyl compounds (subcutaneous injection) and those treated with a vehicle. 2) Immediatly after the administration of thiopental sodium (intraperitoneal injection), accumulation of thiopental in the brain did not differ between these two groups. However, the concentration of brain thiopental in the groups pretreated with adenyl compounds showed a 2-fold increase after 2 hr and a 10-fold change after 4 hr compared with that in the vehicle-treated groups. From these results, a better correlation was found between the prolongation effect of thiopental accumulation time in the brain and that of thiopental sodium sleeping time by the use of adenyl compounds.
A rapid estimation procedure using a high-speed liquid chromatography is described for determination of berberine in crude drugs (phellodendron cortex, coptis rhizome, and phellodendron extract). Separation can be achieved within 10 min employing a 1 m column packed with Zipax SCX, using 0.1 M NaClO4 (CH3CN-H2O 6 : 4), and 0.2M H3BO3-0.002 M NaClO4 (pH 8.5) (7 : 3) solution as an eluant in a Du Pont LC 830 liquid chromatograph. Berberine in crude drugs was extracted with citric acid-methanol solution and injected into the column. Accuracy in this method was found to be less than ±1% with the relation Y=13.806X+0.0025, where X=quantity of berberine (μg) and Y=peak height of berberine (cm), and a relative coefficient of 0.999.
Methylenomycin A methyl ester (II) was synthesized from methylenomycin (I) in a high yield, and reaction of the resulting ester with several amines as a nucleophile afforded the adducts of 2-substituted 5, 6-epoxy-5, 6-dimethylperhydrocyclopenta [c] pyrrole-1, 4-diones (IIIa-VIIa) or s-substituted 2, 3-epoxy-2, 3-dimethyl-4-oxocyclopentane-1-carboxylates (VIIIa, IXa).