A possible role of parasympathetic nervous system in the development of fatty liver produced by the administration of carbon tetrachloride was investigated in rats. The fatty infiltration of liver and the increase in plasma-free fatty acids (FFA), which were observed after the administration of CCl4, were markedly potentiated by the pretreatment of rats with atropine. The treatment of rats with eserine or S-6 (1-methyl-5-chloroindoline methobromide), a parasympathomimetic drug, slightly inhibited the fatty liver prduced by CCl4. The mobilization of FFA induced by CCl4 was also enhanced by bilateral vagotomy. The potentiating effect of atropine on CCl4-induced fatty liver and mobilization of FFA was not observed in reserpinized or adrenalectomized rats. When adrenalectomized rats were treated previously with hydrocortisone, the potentiating effect of atropine on fatty liver was again observed. It is concluded from these results that atropine potentiates the fatty liver induced by CCl4 in rats only when their sympathetic nervous function in adipose tissues is intact. Furthermore, it is suggested that both sympathetic and parasympathetic nervous systems are intimately connected with the release of FFA induced by CCl4, and both nerves have mutually antagonistic functions.
Distribution of insect-moulting hormones in Achyranthes genus plants growing in various regions was examined. Ecdysterone (I) and inokosterone (II) were detected from A. japonica var. hachijoensis growing in Tanegashima, A. rubrofusca growing in Okinawa, and A. longifolia cultivated in Tokyo. I was detected from A. mollicula growing in Amamioshima and Formosa, A. obtusifolia growing in Yoronjima, A. ogatai growing in Formosa, A. bidentata growing in Bhutan, A. aspera growing in Nepal, and A. sp. growing in Kenya. Rubrosterone (III) was isolated with I from Formosan A. obtusifolia. A new substance (IV) of mp 278°, named epiecdysterone, was isolated from a Japanese A. fauriei, with I, II, and III. The structure of IV was concluded to be 5α-ecdysterone from its physicochemical properties. IV was identified with a crystalline product epimerized from I. Biological activity of IV was not so marked when tested with abdomen of Sarcophaga peregrina.
2-Amino-3-ethoxycarbonyl-6-benzyl-4, 5, 6, 7-tetrahydrothieno [2, 3-c] pyridine (Y-3642) hydrochloride showed 50% inhibition of histamine release from rat mast cells by polymixin B sulfate in vitro at a concentration of 40 μM. The activity was more potent than fulfenamic acid or phenylbutazone. At 50 μM, the compound inhibited histamine release from rat mast cells in vitro by dextran or lung thromboplastin of a rabbit. Y-3642 inhibited the delay of tissue clearance by polymixin B sulfate and protected the death by polymixin B shock in rats. These results may suggest that Y-3642 inhibits the release of mast cell histamine which plays a role as one of chemical mediators in the process of inflammation.
The stereochemistry of hydroxyl groups in sesquiterpene lactones of pseudoguaiane type was discussed from their infrared absorption spectra. It was considered that stereochemical relation of hydroxyls in unknown sesquiterpene lactones could be predicted from the relative measured values such as the inter-and intra-molecular hydrogen bonding of the hydroxyls.
Antibacterial tests against Bacillus saprogenes, which causes putrefaction of Sake, were carried out on 22 kinds of diphenyl ether series compounds, two kinds of dibenzofuran series compounds, and four kinds of biphenyl series compounds. In diphenyl ether series compounds, four compounds having a hydroxyl group in one benzene ring and a methyl in the other benzene ring, such as 2-hydroxy-2'-methyldiphenyl ether and 4-hydroxy-4'-methyldiphenyl ether, and a compound with a formyl and a hydroxyl in the same benzene ring, such as 4-formyl-2-hydroxydiphenyl ether, had antibacterial power 4-8 times that of salicylic acid and 2-4 times that of butyl p-hydroxybenzoate. Substitution of the methyl group with carboxyl lowered the antibacterial activity. In biphenyl derivatives, 2, 2'- and 4, 4'-dihydroxybiphenyl had antibacterial activity 8 times that of salicylic acid and 4 times that of butyl p-hydroxybenzoate. Increasing number of the hydroxyl group lowered the antibacterial activity. In dibenzofuran compounds, 3, 7-dihydroxydibenzofuran had twice the antibacterial activity of salicylic acid and about comparable to butyl p-hydroxybenzoate. 3, 7-Dihydroxy-1, 9-dimethyldibenzofuran increased the antibacterial activity to 8 times that of salicylic acid and 4 times that of butyl p-hydroxybenzoate, showing that increase of methyl groups resulted in stronger antibacterial activity.
Synthetic methods for α-pyridone, such as those of Thesing, et al. and Kronke, et al. were examined and (3-indolyl) pyridin-2 (1H)-one derivatives were synthesized by the reaction of indole compounds having α, β-unsaturated ketone in the 3-position of indole ring and N-carbamoylmethylpyridinium chloride (III), in the presence of sodium hydroxide or ammonium acetate. Reaction of 2-cinnamoylquinolines with III or with methyl- or quinolyl-carbonylmethylpyridinium chloride, in the presence of potassium carbonate or ammonium acetate, afforded (2-quinolyl) pyridine and (2-quinolyl) pyridin-2 (1H)-one derivatives.
Twenty-five para-substituted benzenesulfinamides were synthesized and their nuclear magnetic resonance spectra were investigated. The chemical shifts of aromatic protons attached to the sulfur atom were independent on the electronic character of the substituent R3, but that of NH proton was dependent on the substituent R1. This result indicated that the electronic structure of a molecule received insignificant contribution from the double bond structure between sulfur and nitrogen atoms, but it received some contribution from the double bond structure between sulfur atom and an aromatic ring. Sulfinamide group exerted an almost identical effect on the neighboring aromatic protons with that of sulfoxide group, and its substituent constant was estimated to be S0=-0.37. This fact was interpreted as a positive proof of the double bond character between sulfur and nitrogen atoms, even if the degree of its contribution is small.
Benzoylation of acetaldehyde o-methoxyphenylhydrazone (X) abnormally gave an enamine-type C-acylated product, 1-(2-benzoylvinyl)-2-(o-methoxyphenyl) hydrazine (XII), mp 106-107°. Treatment of this compound (XII) with acidic catalyst gave N2-benzoyl-o-methoxyphenylhydrazine (XIV), mp 148-149°, and acetaldehyde obtained as its 2, 4-dinitrophenylhydrazone. On the other hand, it was confirmed that benzoylation of acetaldehyde m-(XVI) and p-methoxyphenylhydrazone gave only the corresponding N1-benzoyl product.
The effect of osones, especially of D-arabinosone, on the growth of Escherichia coli (E. coli) was examined and the following results were obtained. 1) D-Arabinosone, D-xylosone, L-arabinosone, D-glucosone, and triosone showed an inhibitory effect on the growth. Pentosones showed bacteriostatic inhibition, but triosone showed bactericidal inhibition. D-Glucosone seemed to be utilized as a carbon source. 2) The inhibitory effect of D-arabinosone was apparent in resting cells. 3) The inhibition of growth by D-arabinosone was readily abolished by the addition of D-ribose, while the inhibition by D-xylosone and by L-arabinosone was readily abolished by the addition of sulfhydryl compounds. 4) D-Arabinosone had only a small effect on the growth of E. coli in the medium containing D-ribose as a carbon source. 5) The oxidation of D-glucose with intact cells was inhibited by D-arabinosone, but that with cell-free extract was not inhibited. 6) The utilization of D-glucose by intact cells was inhibited by D-arabinosone, but that of D-ribose was not inhibited. From these results, it is concluded that the inhibition of growth of E. coli by D-arabinosone is not the same as the inhibition by other osones studied, and a major factor in the inhibition by D-arabinosone is suggested to be an interference of the transport of D-glucose into the cells by D-arabinosone, though the transport of D-ribose is not interfered.
The substances preventing the autoxidation of D-arabinosone were extracted from swine liver and purified by ammonium sulfate fractionation, acetone fractionation, acid precipitation, DEAE-cellulose column chromatography, and carboxymethylcellulose column chromatography. One of them was obtained in homogeneous form as judged by polyacrylamide gel electrophoresis and was designated as "antioxidant II." It gave positive color reactions for protein, and its absorption spectrum was typical of protein. Its molecular weight as determined by gel filtration was in the range of 27000 to 29000. Antioxidant II is acid-and alkali-labile, and is inactivated above 60°. It also prevented the autoxidation of L-arabinosone, D-xylosone, D-glucosone, and L-ascorbic acid. Although yeast alcohol dehydrogenase and L-cysteine at relatively high concentrations prevented the autoxidation of D-arabinosone, other proteins, sulfhydryl compounds, amino acids, and α-tocopherol showed no preventing effect on the autoxidation. These results suggested that antioxidant II is quite specific in its antioxidative property.
In order to synthesize a compound having an E-ring of camptothecin, a Grignard reaction of 3-acetoxy-5-acetoxymethyl-4-cyano-2-methylpyridine (IX) with ethylmagnesium bromide was carried out and a mixture of a lactone (XI) and a lactam (XII) was obtained unexpectedly. The formation mechanism of these abnormal products was discussed. On the other hand, the reaction of 3-O-methyl-4-pyridoxic acid lactone with ethylmagnesium bromide gave 5-hydroxymethyl-3-methoxy-2-methyl-4-propionylpyridine (XVIII) in 48% yield as expected. However, the reaction of XVIII with hydrogen cyanide in hydrochloric acid gave a lactam (XIX), instead of a lactone (XX). Furthermore, the reaction of methyl 3-cyano-4-ethoxycarbonyl-1, 2-dihydro-2-oxo-6-pyridinecarboxylate (XXIV) with methyl acrylate under the above conditions gave XXVI instead of the desired compound (XXV).
In order to test their pharmacological properties, N-hydroxyalkyl-3, 3-diphenylpropylamines, their N-and/or O-acyl derivatives, N-chloroalkyl-3, 3-diphenylpropylamines and N-(3, 3-diphenylpropyl) piperazine derivatives were synthesized. Some of them were found to have a strong coronary vasodilating activity or anti-reserpine activity.
Examinations were made on the constituents of Lycopodium cernuum L. and Lycopodium inundatum L. From the former, a new triterpenoid, 16-oxo-21-episerratriol, and flavonoid, cernoside, together with the known alkaloids, lycocernuine (IV), cernuine (V), and triterpenoids, α-onocerin diacetate (VII), serratenediol diacetate (IIIa), serratriol triacetate (IX), 21-episerratriol triacetate (VIII) were isolated. From the latter, new alkaloids, anhydrolycocernuine (XXII) and LI Base A together with known alkaloids, lycocernuine (IV), lycopodine (XXI), and triterpenoids, α-onocerin diacetate (VII), serratenediol diacetate (IIIa), and acetyl p-cumaric acid (XV) were isolated. The structures of 16-oxo-21-episerratriol triacetate and anhydrolycocernuine were determined as XIII and XXII, respectively.
In order to find specific renin inhibitors, various kinds of oligopeptide derivatives were synthesized, which have amino acid sequences identical with or analogous to the partial structure of angiotensinogen around the renin attacking site, the Leu10-Leu11 bond. Among the 20 tetra-, penta-, and octa-peptide derivatives tested for the inhibitory activity on the renin-angiotensin system, eight compounds were found to be active, all of which have the Leu-Leu bond in their molecules. Some structure-activity relationship is discussed on the basis of the present work and the results of preceding work.
Some new alkaloids (gardneramine, gardnerine, gardnutine, and hydroxygardnutine) were isolated from a domestic plant, Gardneria nutans SIEB. et ZUCC. (Japanese name "Horai-kazura") and their structures were determined. The central nerve effect of gardneramine and gardnerine was examined in mice. Acute toxicity of gardneramine is lower than that of gardnerine. Depression of spontaneous motor activity, weak antagonistic effect on hypermotility induced by methamphetamine, motor incoordination, prolongation of sleeping duration induced by hexobarbital, and hypothermic effect were found in both alkaloids, gardneramine having a greater effect. Analgesic effect was found by the writhing test in acetic acid and tail pain test in both alkaloids but this effect may be very weak because of their low potency in the latter test. Anticonvulsive effect to seizure induced by maximal electroshock, pentetrazol, and strychnine was not found in either alkaloid but convulsion induced by nicotine was antagonized by them. In electrocorticographic examination in rabbits with chronically implanted electrodes, gardneramine produced slow waves and shortness of duration of arousal response to acoustic stimulation. From these results, it may be concluded that gardneramine has a mild central depressive effect and gardnerine has a weaker effect.
Three kinds of primary enaminic acid amide, 3-amino-4-methyl-2-pentenamide (VIII), 2-amino-1-cyclohexene-1-carboxamide (XIV), and 3-amino-2, 4-diphenyl-2-butenamide (XX) were synthesized. Acylation of VIII, XIV, and XX to the corresponding N-acylamino compounds (XXI, XXIII, and XXV) and their treatment with sodium ethoxide afforded 2-substituted 6-isopropyl-4 (3H)-pyrimidone (XXII), 2-substituted 5, 6, 7, 8-tetrahydro-4 (3H)-quinazolone (XXIV), and 2-substituted 6-benzyl-5-phenyl-4 (3H)-pyrimidone (XXVI), where the substituent R was CH3, CH2CH3, CH2CH2CH3, CH (CH3)2, or C6H5. Treatment of VIII with aromatic aldehyde, in the presence of sodium ethoxide, afforded 2-aryl-5-arylmethyl-6-isopropyl-4 (3H)-pyrimidone (XXVIII : R=C6H5, p-Cl-C6H4, p-CH3O-C6H4, 2-furyl).
Comparative examinations were made on the behavior of 2-(2-pyridyl) benzothiazoles (Ia-c) to various organic peracids. In their reaction with peracetic acid, N-oxygenation of the pyridine ring produced 2-(1-oxido-2-pyridyl) benzothiazoles (IIa-c) and cleavage of the thiazole ring gave 2-(1-oxido-2-picolinamido) benzenesulfonic acids (IIIa-c) and 2-(2-picolinamido) benzenesulfonic acids (IVa-c). Oxidation with monopermaleic acid gave IIa-c as the main products, but N-oxygenation of the thiazole ring occurred to give a minute amount of 2-(2-pyridyl) benzothiazole 3-oxides (Va-c) and the dioxides, 2-(1-oxido-2-pyridyl) benzothiazole 3-oxides (VIa-c). In oxidation with pertrifluoroacetic acid, Va-c were the main products, with a small amount of IIa-c and VIa-c. Relative quantity of the products IIa, IIIa, and IVa was examined by varying the amount of peracetic acid to be added to Ia. Furgher, treatment of IIIa with peracetic acid was found to produce partial dehydroxylation.
Three xanthones have been isolated from Swertia bimaculata. One of these was the known 1, 3-dihydroxy-4, 5-dimethoxyxanthone ; the others were proved to be 1- and 3-O-β-D-glucopyranosides of the xanthone, respectively. Biogenesis of these gentianaceous xanthones was also discussed.
It has been found that both griseophenone A and morphine can be oxidized on platinum anode, yielding a current-voltage curve similar to the conventional polarographic wave. Griseophenone A on the rotating platinum electrode at 0-+0.5 V vs. S.C.E. in MeOH-NaHCO3 solution gives an oxidation wave which shows the change of griseophenone A into dehydrogriseofulvin. Morphine gives an oxidation wave at +0.2-0.5 V vs. S.C.E. In controlled potential electrode oxidation, griseophenone A on the platinum anode (JIS H1201) at +0.5 V vs. S.C.E. gave dehydrogriseofulvin in 50% yield. Morphine at +0.5 V vs. S.C.E. gave pseudomorphine in 73% yield.
β-(2-Nitrobenzoyl)-2-nitrostyrene derivatives (VIII, IX, and X), obtained by the condensation of o-nitrobenzaldehyde derivatives and o-nitroacetophenone, when treated with triethyl phosphite afforded the corresponding indole compounds (XI, XII, and XIII) instead of the objective quindoline compound (XIV).