Mono-and di-bromination of 2-oxo-5β-santanolide (I), and dehydrobromination of the bromoketones were carried out. Monobromides (II, III, IV, and V) and dibromides (VII and VIII) were obtained. The stereoformulae of these bromides (II-V, and VII-VIII) were determined by infrared, ultraviolet, nuclear magnetic resonance, and circular dichroism spectroscopy. The C-4 axial epimer of I was obtained by hydrogenation of the enone (IX), which was prepared from II. Dehydrobromination of dibromoketones (VII and VIII) under several conditions gave a mixture of XII to XVIII. These structures were confirmed from spectroscopic data. A mechanism of dehydrobromination of VII and VIII is discussed.

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Bromination of 2-oxo-5α-santanolide (I) gave a bromide (II) together with III as a minor bromide. This equatorial bromide (III) epimerized into the axial bromide (II). Dibromination of I gave dibromoketones (IV and V). Configuration and conformation of the bromoketones (II-V) were assigned from their infrared, ultraviolet proton magnetic resonance, and circular dichroism spectra. Dehydrobromination of II gave an enone (VI), whose treatment with ethanolic hydrochloric acid afforded an equilibrium mixture of VI and VII. Hydrogenation of VI gave a C-4 axial epimer of I. Dehydrobromination of dibromoketones (IV and V) under several conditions gave a mixture of IX-XII, and XIV-XV, and their structures were confirmed from their spectroscopic data. A mechanism of the bromination of I, and dehydrobromination of IV and V are discussed.

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In oxidation of 2-methyl-3-o-tolyl-4 (3H)-quinazolinone (I) with hydrogen peroxide, five products in addition to unreacted I were obtained from reaction mixture and identified as N-(o-tolyl)-2-nitrobenzamide (II), 2-methyl-3-o-tolyl-4 (3H)-quinazolinone 1-N-oxide (III), N-acetyl-o-toluidide (IV), (2-carboxyphenyl) (2-methylphenyl) diazene (V), and N-(acetyl) (o-tolyl)-2-nitrobenzimide (VI), respectively, and a reaction mechanism of I to II was proposed.

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Equilibrium and rate constants have been determined for the reactions of amphetamine with pyridine-4-carboxaldehyde, pyridoxal and pyridoxal-5-phosphate to give the corresponding Schiff bases. The reactions were found to be dependent on amphetamine concentration and pH of the solution. The overall equilibrium constants are 5.97×10², 13.7×10³ and 8.2×10³ for amphetamine with pyridine-4-carboxaldehyde, pyridoxal and pyridoxal-5-phosphate, respectively.

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The regional differences in the capacities of absorption and lymphatic transport for lipid-soluble dyes, Sudan Blue and Oil Red XO, from oil-in-water emulsions were investigated in rat's whole gastrointestinal tract. The absorptive capacity was the highest in duodenum, followed by jejunum, ileum, large intestine, and the lowest in stomach. This was well compatible with the regional absorption of vehicle oil, triolein. Lymphatic transport of Sudan Blue was recognized only in duodenal and jejunal regions. This fact was supported by the observation of lymphatic staining, which also suggested the defect of usual lymphatic experiments dealed only the drained lymph fluids. It is also documented in this paper that lipid-soluble dyes are taken up into the intestinal epithelial cells from emulsions by an energy-independent process, since little or no inhibition was observed in various pretreated duodenum except the decrease of lymphatic transport in acetone washed intestine. However, severe damage in the villi was observed light microscopically when pretreated with high concentration (80%) of acetone, the absorption of Sudan Blue was significantly decreased in the case. These results suggest that the normality of macromorphological structure of mucosal surface is important for the absorption of lipid-soluble drugs from oil-in-water emulsions.

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The properties of testosterone glucuronyltransferase of rat liver microsomes were studied. The conjugate which was formed from testosterone was identified as the 17β-glucuronide by thin-layer chromatography, hydrolysis with β-glucuronidase, and reverse isotope dilution analysis of the acetate-methyl ester derivative. The microsomal testosterone glucuronyltransferase of liver was shown to increase with age of the animals up to 15-16 weeks. Treatment of the isolated microsomes with Triton X-100 or with deoxycholate enhanced apparent glucuronyltransferase activity 5-and 2-fold at maximum, respectively. This increase of the enzyme activity was due to the elevation of the V max value. Pretreatment of the animals with phenobarbital, 3-methylcholanthrene, diphenylhydantoin, phenylbutazone, or with 1, 1, 1-trichloro-2, 2-bis (p-chlorophenyl) ethane (DDT) increased the liver glucuronyltransferase activity by 130-230%. The microsomes obtained from 3-methylcholanthrene-treated rats showed the glucuronyltransferase activity with smaller Km value for testosterone. The kinetic studies also demonstrated that p-nitrophenol inhibited glucuronidation of testosterone competitively, whereas both bilirubin and estradiol inhibited the reaction noncompetitively.

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The new method employed to organic anions was applied to investigate the active excretory process of organic cations from liver cells to bile canaliculi. Biliary excretion of acetyl procaineamide ethobromide (APAEB) and quinine in rats was studied after infusing retrogradely a solution of various reagents from the cannulated common bile duct into the biliary trees. Among the tested reagents, surfactants, sulfhydryl reagents and aminoreactive agents remarkably inhibited the active biliary excretion of organic cations. The concentrations in bile, the amounts excreted for 30 minutes and the bile/plasma ratios of APAEB were decreased to about 1/2-1/3 of their values at the sham operation by the treatment with these reagents. Because of the intensive decrease in the B/L ratios compared to the L/P ratios, the reagents are supposed to act locally on the bile canalicular site of the liver plasma membrane and to inhibit the active excretory process of organic cations. As compared with organic anions, the biliary excretion of organic cations was more sensitive to the treatment with sulfhydryl reagents and less sensitive to the solubilizing effect of surfactants and organic solvents.

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The significance of vehicle oil metabolism in the absorption of lipid-soluble compounds from oil-in-water emulsions was investigated in rat small intestine using lipidsoluble dyes, Sudan Blue and Oil Red XO, and vitamin A acetate as model compounds. Although little difference was observed among their initial uptake rates, negligible amount of lipid-soluble compounds was absorbed from oleic acid emulsions during the first hour whereas an obvious amount of them was absorbed from triolein emulsions. From oleic acid-triolein mixed emulsions their absorption were decreased as oleic acid-triolein ratio was increased. These results suggested that in the presence of oleic acid lipid-soluble compounds were pooled in some components of epithelial cells. This was well supported by the distribution experiments of Sudan Blue and Oil Red OX into the brush border fraction of the epithelial cells. In the case of oleic acid emulsions, about three to five times as much of dyes were bound to the brush border fraction as compared with triolein emulsions. This phenomenon was considered to be the reflection of the affinity of lipid-soluble compounds to oils, which was partly indicated by the solubilities of the former in the later. It seems probable that the saturation of absorption of lipid-soluble dyes from triolein emulsions, described in our previous paper, is mainly due to the strong affinity of dyes to the membrane components in the presence of oleic acid which was produced from the hydrolysis of triolein.

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l-Epinephrine administered intraperitoneally in rats caused a hyperuricemia, which can be inhibited by the pretreatments with alpha-adrenergic blockers, but not with betaadrenergic blockers. This was also inhibited by the pretreatments with ouabain, adrenochrome and allopurinol. The mechanism of the epinephrine-induced hyperuricemia was, therefore, considered to be due to the stimulation of ATP-degradation by epinephrine via alpha-adrenergic receptor.

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The experiments, using rat blood, were carried out on increase of uric acid in plasma by preincubation of blood and degradation of adenine nucleotides in erythrocyte and in plasma, by chromatographic separation on a Sephadex G-10 column, and also on existence and characteristics of xanthine oxidase in plasma. A system for the production of uric acid from adenine nucleotides and the existence of xanthine oxidase were demonstrated in rat plasma from these experimental results. Xanthine oxidase found in plasma has different characteristics from the enzyme present in liver, and rather resembles the enzyme isolated from milk (EC 1.2.3.2).

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The origin of increased plasma uric acid in l-epinephrine-induced hyperuricemia was studied. It was shown that uric acid is increased by an extra-hepatic process, in particular by reduction in the intestinal adenosine-tri-phosphate level. Further, from evidence for the existence of plasma xanthine oxidase, it was shown that production of uric acid by an extra-hepatic process is very likely in many mammals, even in man.

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The title new reducing trisaccharides were synthesized starting from 1, 6-anhydro-β-maltose. Reflux of 2, 2', 3, 3', 4'-penta-O-acetyl-1, 6-anhydro-β-maltose with 2, 3, 4, 6-tetra-O-benzyl-α-D-galactopyranosyl chloride in benzene in the presence of mercuric cyanide and Drierite stereospecifically afforded the corresponding trisaccharide derivative having α-D-(1→6) galactosidic linkage (yield 63%). After debenzylation with subsequent acetylation, acetolysis of the β-1, 6-anhydro linkage, and deacetylation, the former title trisaccharide was obtained. Stirring of 2, 2', 3, 3', 4'-penta-O-acetyl-1, 6-anhydro-6'-O-trityl-β-maltose with 2, 3, 4, 6-tetra-O-acetyl-α-D-galactopyranosyl bromide in nitromethane in the presence of silver perchlorate and Drierite, followed by acetylation stereospecifically yielded the corresponding trisaccharide derivative having β-D-(1→6) galactosidic linkage (yield 56%). Acetolysis of the β-1, 6-anhydro linkage, followed by deacetylation gave the latter title trisaccharide.

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When phenylalanine was treated with ascorbic acid and Cu⁺⁺ in acetate buffer (pH 6.0), the decomposition of phenylalanine was observed. Cu⁺⁺ accelerated remarkably the decomposition of phenylalanine as compared with other transition metal ions. In contrast, nitrogen gas, other reducing agents and radical scavengers prevented the decomposition. The results indicate that a transient free radical intermediate, formed during the autoxidation of ascorbic acid, is responsible for the decomposition. The ascorbic acid-Cu⁺⁺ system was found to decompose phenylalanine giving hydroxy-phenylalanines such as dihydroxyphenylalanine, m-tyrosine, p-tyrosine and o-tyrosine.

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Hydrolysis of sulpyrine was investigated in neutral and alkaline solution. 4-Methylaminoantipyrine (MAA), 4, 4'-[methylenebis (methylimino)] diantipyrine (Bis), and 4-(N-hydroxymethyl-N-methyl) aminoantipyrine (HMA) were identified as hydrolyzed products by nuclear magnetic resonance spectroscopy and spectrophotometry, and the determination methods of them were proposed. Sulpyrine was in an equilibrium with these products and the percent composition of each species at equilibrium was affected by the initial concentration of sulpyrine. The ratios of the equilibrated amounts of Bis and HMA to that of MAA increased with an increase in the initial concentration of sulpyrine. The apparent rate constants of hydrolysis and formation of sulpyrine were determined in the moderately diluted solution (below 4.5 mg/ml) where Bis was negligible. The results suggest that the apparent rate of hydrolysis is independent of pH, whereas that of formation apparently decreases with an increase in pH values, which is ascribed to an increase in the dissociation of hydroxymethanesulfonate into formaldehyde and bisulfite.

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Hydrolysis of sulpyrine was studied in acid region. Sulpyrine and the hydrolyzed products were directly determined by NMR spectroscopy. In the pH range between 3 and 7, sulpyrine was found to be in an equilibrium with the hydrolyzed products, mainly 4-methylaminoantipyrine (MAA). A decreases in the rate of hydrolysis and formation of sulpyrine was observed with a decrease in pH value. In the pH range below 3, 4-(N-hydroxymethyl-N-methyl) aminoantipyrine (HMA) was detected as a hydrolyzed product in addition to MAA. An equilibrium was attained between supyrine and HMA immediately after sulpyrine was dissolved, and the ratio of the equilibrated amount of HMA to that of sulpyrine was found to increase with a decrease in pH value. Successively the first order hydrolysis of sulpyrine and/or HMA was observed and no equilibrium was attained between sulpyrine and the hydrolyzed products, which indicated that the reverse reaction was negligible.

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In a previous paper, we described the reaction of some aromatic carboxylates with 2, 4-diamino-5-hydroxy-6-methylpyrimidine. In continuation with this work, this paper deals with the synthesis of oxazolo [4, 5-d] pyrimidines, pyrimido [5, 4-b] [1, 4] oxazines and pyrimido-[5, 4-b] [1, 4] oxazepines by the reaction of 2, 4-diamino-5-hydroxy-6-methylpyrimidine with aliphatic carboxylates.

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A convenient synthetic method of 8-substituted theophyllines, which consists of the oxidative cyclization of 6-amino-5-benzylideneamino-1, 3-dimethyluracils with thionyl chloride, is described.

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The present study was undertaken to reconfirm the previous conclusion that morphine-6-conjugates cause potent analgesia by themselves in mice. For this purpose, inhibitory effect of morphine and its three pairs of 3-and 6-conjugates (glucuronides, ethereal sulfates and phosphates) to nicotine-induced contraction of the isolated guinea-pig ileum was examined. The potency of these conjugates was found to decrease in the following order, morphine-6-sulfate>morphine-6-glucuronide>morphine, morphine-3-and 6-phosphate>morphine-3-glucuronide, morphine-3-sulfate, indicating fairly good accordance with order in their analgesic effects in mice. The present experiment again provided strong suggestion that the above biological effect was attributable to the conjugates themselves.

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Uterotropic and anti-uterotropic activities of 16β-ethylestradiol-17β and their derivatives were examined in immature female rats. By subcutaneous administration, 16β-ethylestradiol-17β demonstrated a high potency in the anti-uterotropic activity but a low potency in the uterotropic activity which was approximately 0.01% of the activity of estradiol-17β in the four-day test.

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Antitumor activity of 4-nitropyridazine 1-oxides and related compounds was tested with AH-13 system. Among these nitro compounds, 3, 6-dimethoxy-4-nitropyridazine 1-oxide (III) and 4-nitrocinnoline 1-oxide (XIII) were the most effective. 4-Nitropyridazine 1-oxide (I), 3, 6-dimethyl-4-nitropyridazine 1-oxide (II) and 3-alkoxy-4-nitro-6-chloropyridazine 1-oxides (VI, VII) were effective to some extent.

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Various tricyclic diterpenoid derivatives of totarol, abietane and pimarane groups were found to have serum cholesterol lowering action in rats. Inhibition of intestinal cholesterol absorption was suggested to be involved in the main mechanism of hypocholesterolemic action of totarol and abietic acid.

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Methyl substituted bis-oxido-bridged [15] annulenones III and VIII, n=3 members of [4n+3] annulenone, were prepared starting from 2, 15-dimethoxycarbonyl-[15] annulenone I. Annulenones III and VIII have no appreciable amount of a diamagnetic ring current due to the nonplanar conformations. On the contrary, VI and XI sustain a strong diamagnetic ring current as a consequence of the delocalized14π electron system, whose planarity is enforced by ring formation. On protonation, annulenone III and VIII were converted into stable annulenium ions IIIa and VIIIa, respectively.

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A new chalcone, xanthoangelol was isolated from the roots of Angelica keiskei KOIDZUMI (Umbelliferae), and was elucidated as 2', 4', 4-trihydroxy-3'-[(E)-3, 7-dimethyl-2, 6-octadienyl] chalcone.

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The synthesis of 2, 5 : 14, 17-diepoxy-8, 10-bisdehydro [17] annulenone (III) is described The paratropicity of III is discussed in terms of 1, 4 : 13, 16-diepoxycycloheptadeca-1, 3, 5, -11, 13, 15-hexa-ene-7, 9-di-yne (VII), as a model system.

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Lupinic acid (III), a metabolite of the phytohormone zeatin (I), was synthesized from O-acetyl-L-serine (II) and zeatin by an enzyme in higher plants. Some properties of the enzyme are described.

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From the flowers of Pieris japonica (Ericaceae), three new diterpenoids, now designated as asebotoxin VI, VIII, and IX (A-VI, A-VIII, and A-IX), have been isolated. Chemical and spectroscopic examinations have led to the conclusion that A-VI, A-VIII, and A-IX are represented by formulas I, II, and III, respectively.

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Anodic oxidations of benzenesulfenanilides (4'-OMe (I), 4'-Me (II), 4'-Cl (III), 4'-H (IV) ) and 2-nitrobenzenesulfenanilides (4'-OMe (V), 4'-Me (VI), 4'-Cl (VII), 4'-H (VIII) ) were carried out in acetonitrile containing 0.1 M NaClO₄. electrolyses of I, II, V, VI, and VII gave the corresponding 2, 7-disubstituted phenazines, whereas those of III, IV, and VIII did not. The R-N. intermediates are suggested for the formation of the phenazines.

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(-)-(trans-4'-Hydroxycinnamoyl) lupinine (III) was found to be synthesized from (-)-lupinine (I) and trans-4-hydroxycinnamic acid (II) by enzymes in Lupinus seedlings in the presence of adenosine triphosphate and co-enzyme A as cofactors. The conversion of trans-cinnamic acid (IV) to (-)-(trans-cinnamoyl) lupinine (V) by the enzyme systems was negligible although the cinnamoyl-CoA ligase activity was clearly observed.

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The structures of four new flavone derivatives, kuwanon A, B, C and oxydihydromorusin, which were isolated from the root bark of the cultivated mulberry tree (a variety of Morus alba L.), were shown to be I, II, III and IV, respectively.

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A new Erythrina alkaloid designated as dihydroerysovine was isolated from Cocculus trilobus DC. (Menispermaceae). From chemical and spectroscopic studies, especially INDOR and NOE techniquse, the structure (III) was assigned to this alkaloid. The utility of INDOR and NOE methodes for the determination of substituent pattern on an aromatic ring of Erythrina alkaloids was ascertained.

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