Fine particles of calcium phosphate were obtained by mixing K₂HPO₄ and CaCl₂ in 154mM NaCl in the presence of condensed phosphate. The effects of condensed phosphate on the particle formation of amorphous calcium phosphate (ACP), on the transformation of ACP to hydroxyapatite (HAP), and on the dispersibility of ripened HAP particles were studied by means of a Coulter counter, a calcium-ion specific electrode, X-ray powder diffraction analysis, and so on. The effective concentration of the condensed phosphate to retard the transformation of ACP to HAP was found to be between 10^-4 and 10^-3mM ; that to disperse the particles sufficiently was between 10^-3 and 10^-2 mM ; and that to disaggregate ripened HAP particles was between 3 and 10² mM. The order of effectiveness of the condensed phosphate was common irrespective of the measuring method : hexametaphosphate>triphosphate>diphosphate. Adsorption and/or competitive adsorption of condensed phosphate and orthophosphate, which is the lattice ion of calcium phosphate, was taken into account to explain the above results. The physiological significance of the present work is briefly discussed.

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In this study, the effect of cross-linking time on the adsorption characteristics of microcapsules containing activated charcoal (ACMC) was investigated. The microcapsules were prepared by the gelatin-acacia coacervation procedure. Activated charcoal powder was used as an adsorbent, and creatinine as a model adsorbate. The following results were obtained. The adsorption rate on ACMC could be controlled by changing the cross-linking time of the coacervate. A stable semipermeable membrane was formed by gelatin-acacia coacervation at cross-linking times greater than 60 min. Accordingly, the oral administration of ACMC should be available as a supporting technique in the treatment of patients with renal failure.

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Racemic 2-phenylpropionic acid ((±)-1) and 2-benzyloxypropionic acid ((±)-4) were subjected to microbial reduction and simultaneous resolution with several molds, i.e., Malus and Prunus strains of Glomerella cingulata, Gloeosporium olivarum and Gloeosporium laeticolor, yielding (R)-2-phenylpropanol ((R)-2) and (S)-2-benzyloxypropanol ((S)-5), and leaving (R)-2-phenylpropionic acid ((R)-1) and (R)-2-benzyloxypropionic acid ((R)-4), respectively. The microbial reduction of racemic 2-(2-furfuryl) propionic acid ((±)-8) gave optically inactive (±)-2-(2-furfuryl) propanol ((±)-9).

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Chiral N-methyl-4-phenyl-1, 3-oxazolidines (2a-e) having a methyl, ethyl, benzyl, isopropyl, and cyclohexyl group at the 2-position of the 1, 3-oxazolidine ring were synthesized. Reactions of 2a-e with Grignard reagents gave (1R, 1'R)- and (1S, 1'R)-1-alkyl-and 1-cycloalkyl-N-2'-hydroxy-1'-phenylethyl-2-phenylethylamines (3a, 3b, 3d, 3e). The absolute configurations of (1R, 1'R)-3a and-3e were determined. (R)-1-Methyl-and (R)-1-cyclohexyl-2-phenylethylamines (4a, 4e) were obtained in high yield by hydrogenolysis of (1R, 1'R)-3a and -3e.

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Reactions of aromatic and aliphatic hydrocarbons with a new reagent system, Fe (CH₃CN)²⁺₆-H₂O₂-Ac₂O in CH₃CN, gave oxygenation products with fairly high reaction efficiency (Tables I and II) compared to known reagent systems used as enzyme models for mono-oxygenases. Investigations of the mechanism of these reactions indicated the involvement of either complex C, Fe^IV (OH) (OAc)²⁺, or complex D, Fe^IV (OAc)²⁺₂, depending on the organic substrate.

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Combined oxidizing reagent systems of Fe (AN)₆ (ClO₄)₃ (AN=acetonitrile) with halogen oxyacids were investigated. In particular, reactions of paraffin hydrocarbons with a combined reagent system of Fe (AN)³⁺₆-IO^-₄ were explored because of the high reactivity of this system in the oxidation of adamantane (Table I). Oxidations of bornane, norbornane, cyclohexane, and n-hexane gave the corresponding acetamides and acetates (Table II). These results show that the title reagent system can efficiently oxidize organic substrates which have onset potentials of anodic current of ca. 2.7V vs. saturated calomel electrode.

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Two new minor triterpenoid saponins, rotundioside D (1) and rotundioside G (2), isolated from the leaves of Bupleurum rotundifolium L., were characterized as 16α, 28-dihydroxyolean-12-en-3β-yl α-L-rhamnopyranosyl-(1→2)-β-D-glucopyranosyl-(1→2)-β-D-glucopyranoside (1) and 13β, 28-epoxy-16α-hydroxyolean-11-en-3β-D-xylopyranosyl-(1→2)-β-D-glucopyranosyl-(1→2)-β-D-fucopyranoside (2), respectively, on the basis of chemical and spectroscopic evidence.

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Stereochemical studies were performed on asymmetric [2, 3] sigmatropic rearrangements of sulfur ylides derived from chiral ketenimines possessing various kinds of substituents and prochiral sulfur ylides. A mechanistic pathway for these rearrangements is proposed on the basis of the stereochemical results obtained. New asymmetric centers are induced on the sulfur atoms of the ylides during the reactions.

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Six compounds were isolated from the roots of Tetrapanax papyriferum K. KOCH. and characterized as β-D-glucopyranosyl oleanate-(3)-[α-L-arabinofuranosyl-(1→4)]-[β-D-galactopyranosyl-(1→2)]-methyl-(β-D-glucopyranosid) uronate (1), α-L-rhamnopyranosyl-(1→4)-β-D-glucopyranosyl-(1→6)-β-D-glucopyranosyl oleanate-(3)-α-L-arabinofuranosyl-(1→4)-methyl-(β-D-glucopyranosid) uronate (2), β-D-glucopyranosyl oleanate-(3)-β-D-galactopyranosyl-(1→2)-methyl-(β-D-glucopyranosid) uronate (3), methyl oleanate-(3)-[α-L-arabinofuranosyl-(1→4)]-[β-D-galactopyranosyl-(1→2)]-methyl-(β-D-glucopyranosid) uronate (4), β-sitosterol β-D-glucopyranoside (5) and oleanolic acid-(3)-β-D-galactopyranosyl-(1→2)-β-D-fucopyranoside (6) on the bases of chemical and spectroscopic evidence.

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Ethyl indole-2-carboxylate (1a) and its derivatives were reacted with various carboxylic acids by using trifluoroacetic anhydride and phosphoric acid (or polyphosphoric acid) to yield effectively the corresponding ethyl 3-acylindole-2-carboxylates (3). However, strongly acidic carboxylic acids and nitrogen-containing carboxylic acids were poor acylating agents. Ethyl 3-acylindole-2-carboxylate (3) could easily be converted to 3-acylindole (5)

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Two new alkaloids, aljesaconitine A and aljesaconitine B, and six known alkaloids, aconitine, jesaconitine, mesaconitine, neoline, hokbusine A, and delcosine, were isolated from the roots of Aconitum japonicum THUNB. (formerly known as Aconitum subcuneatum NAKAI). The structures of aljesaconitines A and B were determined on the basis of spectral data and derivation from jesaconitine. An acetoxy group at C-8 of an aconitine-type alkaloid was found to be easily changed to an alkoxy group by the use of alcohols such as methanol and ethanol in the extraction procedure. Quantitative determination and the LD₅₀ values of these 8-O-alkyl derivatives are also described.

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The reactions of heterohomophthalic anhydrides, 3-carboxy-1-methylindole-2-acetic anhydride (4), 2-carboxybenzo [b] furan-3-acetic anhydride (5), 2-carboxythiophene-3-acetic anhydride (6), and 3-carboxy-1, 4-dimethylpyrrole-2-acetic anhydride (23) with carbon-carbon multiple bonds (C=C and C≡C), acylating agents, and cyclic imines are described. Treatment of the anhydrides (4-6) with various compounds containing carbon-carbon multiple bonds (7-10) in the presence of a strong base caused cycloaddition with spontaneous extrusion of carbon dioxide to give the corresponding linearly condensed peri-hydroxy heteroaromatic compounds (11-19), regioselectively. Base-catalyzed acylation of 4 with acetic anhydride and β, β-dimethylacryloyl chloride gave 3, 5-dimethylpyrano [4, 3-b] indol-1 (5H)-one (21) and 3, 3, 11-trimethyl-3, 4-dihydropyrano [4', 3' : 2, 3]-pyrano [4, 5-b] indole-1, 6 (11H)-dione (22), respectively. Reaction of the anhydrides (4, 6, and 23) with 3, 4-dihydroisoquinoline (24) gave the corresponding condensation products, 14-carboxy-13-methyl-5, 6, 14, 14a-tetrahydrobenz [a] indolo [3, 2-g] quinolizin-8 (13H)-one (25), 12-carboxy-5, 6, 12, -12a-tetrahydrobenzo [a] thieno [2, 3-g] quinolizin-8-one (26) and 12-carboxy-11-methyl-5, 6, 12, 12a-tetrahydrobenzo [a] pyrrolo [3, 2-g] quinolizin-8 (11H)-one (27), in high yields.

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A new triterpene saponin, gymnocladus saponin D (5), having a glycosyl monoterpene carboxylate and a monoterpene carboxylate group, was isolated and its structure was characterized as the (6S)-2-trans-2, 6-dimethyl-6-hydroxy-2, 7-octadienoate of 2β, 23-dihydroxy-3-O-α-L-rhamno-pyranosyl-21-O-[(6S)-2-trans-2, 6-dimethyl-6-α-L-arabinopyranosyloxy-2, 7-octadienoyl]-acacic acid 28-O-β-D-xylopyranosyl-(1→3)-β-D-xylopyranosyl-(1→2)-[L-rhamnopyranosyl-(1→6)]-β-D-glucopyranosyl-(1→2)-β-D-glucopyranoside, on the basis of chemical and physicochemical evidence.

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Simple and efficient syntheses of 7-deazacaffeines, 9-deazatheophyllines, furo [2, 3-d] pyrimidines and furo [3, 2-d] pyrimidines from 5- or 6-substituted pyrimidines by means of intramolecular cyclization reactions are described.

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Epoxidation of cholesteryl acetate by a nonradical reagent system such as m-chloroperbenzoic acid, Mo (CO)₆-'BuOOH, or Fe (ClO₄)₃-H₂O₂ was highly α-stereoselective. In contrast, a radical reagent system such as Fe (acac)₃-'BuOOH, KO₂-'BuBr, or biacetyl-O₂-hv, showed high β-selectivity. The stereoselectivity in the epoxidation of cholesteryl acetate seems, therefore, to be a useful indication of the mode of reaction. On this basis, epoxidation may occur through a radical process in the tetraphenylporphinatoiron (III) chloride-iodosylbenzene system. Earlier studies with stilbene had failed to clarify the mechanism in this system.

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A convenient method for the preparation of 4-aryl- and 4-heteroarylpyridines by the palladium-catalyzed cross-coupling reaction of diethyl (4-pyridyl) borane with aryl and heteroaryl halides is described.

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The reaction of aminohalopyridines with ethyl acrylate in the presence of palladium (II) acetate and triarylphosphine gave ethyl aminopyridineacrylates. The cyclization of the resulting acrylates under basic conditions gave naphthyridinones having a carbostyril-type moiety.

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The title compounds are obtained by intramolecular cyclization of 2-hydrazino 3-(1-pyrrolyl) pyridine. Proton nuclear magnetic resonance (¹H-NMR) spectra are described.

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The infrared carbonyl absorptions of protopine and α-allocryptopine in dilute carbon tetrachloride solution and nuclear Overhauser effect experiments in the proton nuclear magnetic resonance spectra have shown that these alkaloids each interconvert between two major conformations of the ten-membered ring. These conformations are discussed on the basis of the observed spectral data.

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Two diastereomers (6 and 7) of the cyclic tautomer of cyclo-L-propyl-L-tryptophyl (5) have been prepared by dissolving 5 in 85% phosphoric acid or trifluoroacetic acid. The stable isomer (6) was obtained in 89% yield on the acid treatment of 5 at room temperature. Cyclic tautomers (15 and 17) of the related 2, 5-piperazinediones (14 and 16) have also been prepared. Hydroxylation of the N-acetyl cyclic tautomers (8 and 9) with lead tetraacetate in trifluoroacetic acid followed by methylation gave the 8- and 9-methoxy derivatives (18, 19, 21, and 22) in moderate yields. The 9-methoxy derivative (22) was the major product of the oxidation of 9. On the other hand, oxidation of 5 in trifluoroacetic acid with lead tetraacetate followed by reduction with zinc gave the 8-hydroxy derivative (28) selectively in good yield via the cyclic tautomer (26) and the quinoneimine (27).

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Four new furanoeremophilane-type sesquiterpenes, adenostylol (1a), adenostin A (2a), adenostin B (3a) and adenostylide (4a), were isolated from Cacalia adenostyloides MATSUM., along with eight known sesquiterpenes, cacalol (5), cacalolide (6), cacalone (7), epicacalone (8), adenostylone (9), neoadenostylone (10), 6β-propionyloxy-1, 10-dehydrofuranoeremophil-9-one (11) and tetrahydromaturinone (12). Of these compounds, 2a and 3a are novel-type dimers.

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Electrochemical oxidation of olefins using N-hydroxyphthalimide as a mediator was studied. Allylic methylene and allylic methine groups were oxidized to give the corresponding enones, while allylic methyl groups were not readily oxidized except for those of 2, 3-dimethyl-2-butene. The product distribution was similar to that observed in free radical autoxidation of olefins. A possible mechanism of the oxidation is proposed.

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A new 4-hydroxycoumarin glycoside (V), named 5-methyl-4-rutinosyloxycoumarin, C₂₂H₂₈O₁₂, mp 240-241°C (dec.), [α]²²_D-79.4° (pyridine), was isolated from the underground parts of Gerbera jamesonii hybrida (Compositae), in addition to three cyanogenic glycosides (prunasin (I), amygdalin (II) and vicianin (III)) and a coumarin glycoside (4-β-D-glucopyranosyloxy-5-methylcoumarin (IV)). The chemical structure of V was determined to be 5-methyl-4-[α-L-rhamnopyranopyranosyl-(1→6)-β-D-glucopyranosyloxy] coumarin on the basis of chemical and spectral evidence.

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Two glycosides named cynafoside-A (1) and -B (2) were isolated from Cynanchum africanum R. BR. (Asclepiadaceae) which is toxic to stock in South Africa. Their structures were determined on the basis of spectral and chemical evidence, and are unusual in that they include both D-and L-cymaroses in the sugar chain.

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Two new vitamin D₃ analogues, 1α-hydroxy-24, 24-dimethyl-22E-dehydrovitamin D₃ (13) and 1α, 25-dihydroxy-24, 24-dimethyl-22E-dehydrovitamin D₃ (17), which are blocked for 24-hydroxylation by the methyl groups, were synthesized from 1α, 3β-bismethoxymethoxypregn-5-ene-20Scarbaldehyde (6) by using the orthoester Claisen rearrangement for construction of the carbon skeleton of their side chains. These compounds (13 and 17) elicited a rise in serum calcium, but not in serum inorganic phosphorus in rats. In a bioassay for alkaline phosphatase, they were found to show much weaker activity than 1α-hydroxy vitamin D₃ (5).

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(-)-α-Cuparenone, (17) was synthesized from the olefinic aldehyde (9) by utilizing a rhodium-catalyzed cyclization as a key step. The optically active aldehyde (7) was prepared by employing an asymmetric [2, 3] sigmatropic rearrangement of a quaternary L-prolinol derivative. The aldehyde (7) was also converted into its antipodal form (24) in several steps.

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Eight new terpenoid constituents named ganoderenic acids A (1), B (2), C (3) and D (4), ganoderic acids E (5), F (6), and G (7), and lucidenic acid D (8) were isolated from dried fruiting bodies of the fungus, Ganoderma lucidum (Fr.) KARST (Polyporaceae) and their structures were determined on the basis of spectral data and some chemical interconversions.

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The (2S, 5R)-(+)- or (2R, 5S)-(-)-thiol (4a or 4b) was synthesized by catalytic hydrogenation of the corresponding (S)-(-)- or (R)-(+)-pyrrolinecarboxylic acid (8a or 8b) resolved with (R)-(-)-1, 2-diphenylethylamine, followed by acylation with 3-(benzoylthio) propionyl chloride and ammonolysis. The thiols were converted into the corresponding O, S-diacetates (16a and 16b), which were transformed into (2R, 5R)-(+)- and (2S, 5S)-(-)-thiols (18a and 18b) via their O, S-diacetates (17a and 17b) by epimerization and then ammonolysis. The stereochemistry of these thiols was elucidated on the basis of synthesis from tert-butoxycarbonyl-L-glutamic acid γ-benzylester (9) and proton nuclear magnetic resonance (¹H-NMR) analysis. The thiols were tested for inhibitory activity against angiotensin-converting enzyme in vitro. (2S, 5R)-5-(2-Hydroxyphenyl)-1-(3-mercaptopropionyl)-2-pyrrolidinecarboxylic acid (4a) showed the most potent activity among them.

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In an attempt to inhibit uptake sites for biogenic amines, the following "rigid" and "flexible" bifunctional analogues of amitriptyline of various topologies have been synthesized and evaluated as antidepressants : 5, 7-bis (3-dimethylaminopropylidene)-12, 13, 15, 16-tetrahydrobisbenzo-cyclohepta [7, 6-a ; 6', 7'-d] bezene (7), 5, 13-bis (3-dimethylaminopropylidene)-7, 8, 15, 16-tetrahy-drobisbenzocyclohepta [6, 7-a ; 6', 7'-d] benzene (8), 9, 18-bis (3-dimethylaminopropylidene)-4b, 4c, 13b, 13c-tetrahydrotetrabenzo [a, d, h, k] dicycloheptacyclobutene (9), and 1, 2-bis [3, 3'-(5-N, N-dimethylaminopropylidene [5H] dibenzo [a, d] cyclohepten)] ethane (12). All were active as measured by the uptake inhibition of ³H-serotonin into human blood platelets. Their structure-activity relationships revealed somewhat lower activity as compared with amitriptyline (1) but indicated the bifunctional amitriptylines can still interact with the uptake site. The synthesis and molecular structures including stereochemistry of the chiral pentacyclic aminoalcohol precursors (R, R and S, S)-4 and (R, S)-5 are reported. Strong intramolecular O-H···N bonding in 4 and 5 are noted.

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An examination of structural similarities between gastrins (3-5) and antigastric 5, 1-benzothiazocines (2) suggested the presence of common functional groups and atoms, i. e., a benzene ring, a nonbasic nitrogen and a sulfur atom. A working hypothesis presuming these to be essential binding moieties is presented. A molecular mechanics calculation study of Ac-Trp-Met-NHMe (14) as.a model peptide bearing the receptor binding sites was carried out in an attempt to find a stereochemical correlation with a representative 5, 1-benzothiazocine, RS-2039 (1), a derivative of which had been structurally elucidated by X-ray crystallographic analysis. Several stable conformers of Ac-Trp-Met-NHMe were discovered to have a close approximation of the 3-dimensional array of binding sites to that of 1. It has thus been theoretically demonstrated that gastrins and 5, 1-benzothiazocines could bind with an identical receptor.

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Des-Tyr¹-dermorphin, des-Tyr¹-[D-Arg²] dermorphin, and the N-terminal di-, tri-, tetra- and hexapeptide amides of [D-Arg²] dermorphin were synthesized by a conventional solution method and their analgesic activities were assayed by means of the tail pressure test after subcutaneous administration (s. c.) to mice. The des-Tyr¹ analogs of both dermorphin and [D-Arg²] dermorphin did not show analgesic activity even at a dose of up to 50 mg/kg, s. c. The N-terminal tetrapeptide amide, H-Tyr-D-Arg-Phe-Gly-NH₂, showed extremely potent activity, being 31 times more active than morphine on a molar basis, whereas the N-terminal tri- and dipeptide amides showed no activity even at a dose of up to 40 mg/kg, s. c.

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As a new type of norfloxacin (NFLX) prodrug, N-(5-substituted 2-oxo-1, 3-dioxol-4-yl) methyl NFLXs were designed. These N-masked NFLXs were prepared and confirmed to produce higher NFLX levels in blood than NFLX itself after oral administration to mice. N-(5-Methyl-2-oxo-1, 3-dioxol-4-yl) methyl NFLX was found to be smoothly hydrolyzed in mouse blood in vitro, and when administered orally, gave about 5-fold higher blood levels of NFLX than NFLX itself. Thus, the (5-methyl-2-oxo-1, 3-dioxol-4-yl) methyl group was confirmed to function as an amine-type promoiety.

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Malonamate, malonic acid and malonamide derivatives of heterocyclic compounds were synthesized as part of a search for new biologically active compounds, e. g., those having antiinflammatory activity. Malonamates (1-17) were prepared by the reaction of amines containing heterocycles with malonic acid monoethyl ester. Hydrolysis of the malonamates gave the malonamic acids (18-24) in good yields. Malonamides (25-43) were synthesized by condensing amines with N-substituted malonamic acids. The antiinflammatory activity of these compounds was examined against carrageenin-induced rat paw edema. N-[2-(6-Methoxy) benzothiazolyl] malonamic acid (23) and its ethyl ester (7) showed significant activity.

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Six diarylheptanoids, including three new compounds, were isolated from the rhizomes of Alpinia officinarum HANCE (Zingiberaceae). The structures of the new compounds were determined to be 7-(4"-hydroxyphenyl)-1-phenyl-4-hepten-3-one (I), 5-methoxy-7-(4"-hydroxyphenyl)-1-phenyl-3-heptanone (II), and 5-methoxy-1, 7-diphenyl-3-heptanone (III) on the basis of the spectroscopic data. This is the first time that compound IV, in which both phenyl rings are substituted, has been isolated from Alpinia spp.

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Histochemical studies were performed on the distribution of bioactive flavones, baicalein, baincalin, wogonin and wogonin 7-O-glucuronide, in various parts and tissues of Scutellariae Radix and cultivated Scutellaria baicalensis (Labiatae) root. By means of high-performance liquid chromatography, it has been clarified that the flavone glucuronides are mainly distributed in the cortex, phloem and xylem of the root, and the aglycones are present in the outer periderm at high concentrations. It has been found that Scutellariae Radix from China is morphologically different from the drugs from Japan, Korea and North Korea.

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Three new alkaloids, picrasidines N (I), O (II), and Q (III), have been isolated from the root wood of Picrasma quassioides BENNET (Simaroubaceae). The structures were determined on the basis of spectral analysis and chemical evidence.

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Five new guaiane-type sesquiterpene glycosides have been isolated from Crepidiastrum keiskeanum NAKAI (Compositae). Their structures were elucidated on the basis of spectral data and several chemical transformations.

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Two new naphtho-α-pyrones, 8-methyltoralactone (1) and 8-methyltoralactone 10-methylether (2), were isolated from the roots of Cassia torosa CAV. along with chrysophanol, chrysophanol-10, 10'-bianthrone, physcion, physcion-9-anthrone, emodin and phytosterols (a mixture of stigmasterol, campesterol, and sitosterol). The structures of the two new compounds 1 and 2 were established as 9, 10-dihydroxy-7-methoxy-3, 8-dimethyl-1H-naphtho [2, 3-c] pyran-1-one and 9-hydroxy-7, 10-dimethoxy-3, 8-dimethyl-1H-naphtho [2, 3-c] pyran-1-one, respectively, on the basis of spectral and chemical evidence.

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The role of the solvent in the partition of procaine (PC) and its hydrolysis product, p-aminobenzoic acid (PABA), into various organic solvents was investigated from the viewpoints of the solvent polarity, the proton-donating and/or -accepting properties, and the solvation of the solute. The partition coefficients of PC and PABA in a pentanol (PeOH)-cyclohexane (CyH) mixture/water system gradually increased with increase of the mixing ratio of PeOH, but the change with the mixing ratio was not linearly correlated with the change of solvent polarity. The electrophilicity and/or nucleophilicity of the solvents did not greatly influence the partition of PC, whereas the partition of PABA varied with different solvent systems as follows ; nucleophilic solvents> amphiprotic solvents»electrophilic solvents»inert solvent. Furthermore, although it was ascertained that an appropriate solvating agent is required for the partition of a polar solute, the specificity was not always high due to the amphiprotic properties of PC and PABA. The solvation number and the extraction constant were obtained for PeOH, ethyl acetate, and chloroform as solvating agents for PC and PABA, and the nature of the solute-solvent interaction is discussed.

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The reactions of sulbactam (I) with pyrazole, 1, 2, 4-triazole and imidazole in weakly alkaline solutions yielded 1-(5-carboxy-6-methyl-6-sulfino-4-aza-2-heptenoyl)-pyrazole (III), -1, 2, 4-triazole (IV), and -imidazole (V), respectively. The proton nuclear magnetic resonance spectra and high-performance liquid chromatographic (HPLC) behavior indicate that III, IV and V each exist as a mixture of E- and Z-isomers in a ratio of about 2 : 1 in aqueous solutions at low temperature, and that rapid interconversion between the E- and Z-isomers occurs at high temperature. Compounds III, IV and V were converted to methyl 5-carboxy-6-methyl-6-sulfino-4-aza-2-heptenoate (II) in methanol.

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A sensitive fluorometric method for the determination of primary aromatic amines was developed. The procedure requires diazotization of the amino group followed by coupling with 2, 4, 6-triaminopyrimidine (TAP), and the resulting azo compound is oxidized to a fluorescent triazole. Substituted triazoles were synthesized by using various pyrimidines and their fluorescence characteristics were evaluated. TAP was selected as the most sensitive reagent. None of the pyrimidines substituted at the 2-position was fluorescent. A method for the determination of sulfamethoxazole (SMX) was established (quantitation limit : 40 ng/ml). This method is more practical and simple than that reported before : the final solution for measurement was obtained in one flask through a one-pot reaction. The effects of substituents of the triazole ring on the fluorescence are discussed.

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Pd (II) chelates of 1, 1-dimethyl-3-(4-methyl-2-thiazolyl) thiourea and related N-(2-thiazolyl)-thioureas were prepared and their molecular structures were determined by means of spectroscopic, thermochemical, and X-ray crystallographic measurements, in order to establish the identity of the colored substances in the spectrophotometric determination of Pd (II) with the thiazolyl-thioureas. The results indicated that Pd (II) formed 1 : 2 chelates with the thiazolylthioureas and that the ligands were bidentate and coordinated through the thiourea sulfur and thiazole nitrogen atoms. The geometry of Pd (II) coordination was roughly square-planar and the configuration of the two thiazolylthiourea molecules was cis.

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Human plasma vitamin D binding proteins (DBP, also denoted as group-specific components ; Gc) were highly purified from commercial human α-globulin (also denoted as Cohn Fraction IV ; HαG). Chromatofocusing separated the partially purified HαG into three DBPs which had the same molecular size in gel permeation high-performance liquid chromatography. They each exhibited binding affinity with 25-hydroxyvitamin D₃ [25 (OH) D₃] and cross-immunoreactivity against antihuman plasma group-specific components (Gc) antiserum. However, the three DBPs were completely different in charge on chromatofocusing, and gave distinct peaks having apparent isoelectric points of 4.64, 4.59 and 4.54. It is well known that the Gc has three phenotypes separable only by isoelectric focusing. The relationship between the three purified DBPs and the three phenotypes of Gc has not been clarified. However, we suggest that the chromatofocusing method may provide a convenient procedure for the purification of DBP from human plasma and commercial HαG.

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The structure-function relationship of the antitumor 6-branched β-1, 3-glucan (grifolan NMF-5N) extracted from the matted mycelium of Grifola frondosa was examined by using various chemical modification procedures (periodate oxidation, Smith degradation, and enzymic hydrolysis). The antitumor activity of grifolan NMF-5N was not lowered by periodate oxidation. Partial removal of branches by mild hydrolysis did not affect the activity. However, the linear β-1, 3-glucan obtained by Smith degradation lacked antitumor activity. From the results of enzymic hydrolysis of grifolan NMF-5N, this glucan contains a β-1, 3-glucanase-resistant core structure. The core structure is present randomly in this glucan, and does not itself show antitumor activity. These results suggest that some of the branches at C-6 in grifolan NMF-5N are important for the antitumor activity, and that the activity requires a relatively high molecular weight.

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Amine oxidase (AO) activity was assayed in 51 species of plants. Among these plants, high AO activity was observed in Lyophyllum aggregatum KUHNEN ("Hon-shimeji") ; some of its properties were investigated. It was found that 96% of the AO activity was localized in the soluble fraction (100000×g sup.). When β-phenylethylamine (PEA) was used as a substrate, the AO activities in mitochondrial (15000×g ppt.) and microsomal fractions (100000×g ppt.) had similar kinetic constants, but that in the soluble fraction was different. Based on inhibition studies, AO in Honshimeji could be classified into two forms. One is a metallo enzyme (containing cupric copper and pyridoxal phosphate) which is inhibited by semicarbazide and cuprizone, and the other is a flavin enzyme which is inhibited by clorgyline.

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Carboxypeptidase C_N from Citrus natsudaidai HAYATA is an acidic protease (M, 93000). The enzyme was inactivated by the incorporation of 1.0 mol of ³²P-labeled diisopropylphosphofluoridate, 1.3 mol of ²⁰³HgCl₂, or 2.2 mol of ^110mAgNO₃ per mol of enzyme at pH 5.5. Four or five radioactive peptides were isolated from a partial acid hydrolysate of the ³²P-labeled enzyme. These peptides provided evidence indicating the amino acid sequence Glx-Gly-Asx-Ser-Gly-Gly-Glu-Leu-Val around the reactive serine residue. The enzyme reacted with 0.4 mol of ²⁰³Hg-labeled p-chloromercuribenzoate without appreciable loss of enzymatic activity. On the other hand, 1 mol of ²⁰³Hg-labeled p-chloromercuribenzoate was incorporated into the enzyme which had been denatured with 6 M guanidine hydrochloride and 8 M urea at pH 7.0 in the absence of dithiothreitol. Thus, the enzyme has one sulfhydryl group which possesses only poor reactivity. Photooxidation using methylene blue as a sensitizer caused a loss of enzymatic activity and specific destruction of approximately 1 mol of histidine residue per mol of enzyme. The photooxidized, p-bromophenacyl bromide-treated and HgCl₂-treated enzyme failed to react with ³²P-labeled diisopropylphosphofluoridate. From these findings, we inferred that one serine, one histidine, and the carboxyl groups are essential for catalytic activity.

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The hepatic transport of amaranth (AM) was investigated in normal rats and rats with hepatic intoxication induced by subcutaneous or oral administration of carbon tetrachloride (CCl_{4s. c.} or CCl_{4p. o.}) or by oral administration of α-naphthylisothiocyanate (ANIT). The kinetics of the disappearance of AM from plasma as well as the kinetics of its appearance in the bile were studied in rats under pentobarbital anesthesia and the binding activities of plasma and hepatic cytoplasmic proteins to AM were also investigated. A retarded plasma disappearance of AM was observed in CCl₄-or ANIT-intoxicated rats and biliary excretion of AM was decreased in CCl₄-intoxicated rats. Bile flow and biliary excretion of AM were not observed in ANIT-intoxicated rats. The total amount of AM bound to the plasma protein was decreased in ANIT-intoxicated rats, but was not affected in CCl₄-intoxicated groups. The pharmacokinetic parameters were calculated with a three-compartment model, and a decrease in k₁₂ (transfer rate constant from plasma to liver) and k₂₃ (transfer rate constant from liver to bile) were observed in CCl_{4p. o.}-intoxicated rats. In CCl_{4s. c.}-intoxicated rats, only k₁₂ was decreased. In ANIT-intoxicated rats, significant decreases in k₁₂ and increases in k₂₄ (rate constant of metabolism) were observed. AM was bound preferentially to X-and Y-fraction rather than to Z-fraction in cytoplasmic proteins. Although the protein concentration in the 110000g supernatant and in the Y-fraction was decreased in CCl_{4p. o.}-intoxicated rats, the total protein content of whole liver was not affected. It was considered that changes in the hepatic plasma flow may be a main cause of the retarded disappearance of AM from plasma in the intoxicated rats.

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The relationship between the bioavailability of various phenytoin (DPH) suspensions and the physicochemical properties of the vehicle as well as the physiological factors influencing the bioavailabllity were studied in rats. The vehicles used were aqueous solutions of methylcellulose (0.1, 0.5 and 1%), 1% polysorbate 80 aqueous solution, sesame oil and sesame oil emulsion. The gastric emptying time was determined from the amount of phenol red remaining in the stomach after oral administration. As the gastric emptying time increased, the area under the blood concentration-time curve, the maximum blood concentration and the time required to reach the maximum blood concentration increased. The gastric emptying time became smaller as the fluidity of the vehicle increased. Clearly, the viscosity is an important factor affecting the bioavailability of DPH. As the gastric emptying and the dissolution rate slowed down, the apparent absorption rate constant (k_a) became small. However, k_a obtained from an oily suspension was only one-third of the value obtained from an aqueous suspension. Thus, the mechanism by which DPH is absorbed from the digestive tract after administration as an oily suspension appears to be considerably different from that after administration as an oily suspension appears to be considerably different from that after administration as an aqueous suspension. The value of k_a obtained from the in vivo absorption study was about half of that found in situ. These results suggest that k_a obtained from the in vivo absorption study includes the transit rate of suspension from the stomach to the intestinal tract.

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The bioavailabilities of phenytoin (DPH) from oil suspensions (sesame oil and oleic acid) were studied in rats in relation to the physicochemical properties and gastric emptying time of the vehicles. The maximum blood concentration (C_max) of DPH after oral administration of sesame oil suspension was about twice that from the oleic acid suspension. DPH in oleic acid suspension was absorbed more slowly ; this was consistent with the dissolution rate data. Oleic acid delayed gastric emptying to a significant degree in comparison with sesame oil. The area under the blood concentration-time curve (AUC) for the oleic acid suspension was significantly higher than that for the sesame oil suspension. On the other hand, AUC and blood concentrations of DPH after intraduodenal administration of oleic acid suspension were approximately twice those obtained with the sesame oil suspension up to one hour after administration. It was concluded that the lower C_max of DPH, the higher AUC and the longer T_max (the time required to reach the maximum blood concentration) after oral administration of oleic acid suspension as compared with those in the case of sesame oil suspension could be attributed to the delayed gastric emptying.

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The reaction of 2, 4-dinitrophenyl diethyl phosphate (DDP) with human serum albumin (HSA) was investigated kinetically at various pHs and 25°C. The pH profile of the catalytic rate constant indicated the involvement of an ionizable group with pK_a 7.5 in the reaction. Ethoxycarbonylation of about two histidine residues (imidazole groups) per mol of HSA by diethylpyrocarbonate inactivated the reaction of DDP with HSA by about 70%, suggesting the existence of more than two reactive histidine residues towards DDP. Among these residues, one has higher activity than the others and it appears to be located near the tyrosine-411 residue (R site), because the reaction with DDP was inhibited most strongly by drugs which bind to the R site of HSA.

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