The liposome eatrapping CO₂ gas inside the vesicle, which is called the echogenic liposome, has been made and characterized in vitro as an ultrasound contrast agent. The small unilamellar vesicle (SUV), large unilamellar vesicle (LUV) and multilamellar vesicle (MLV) as echogenic liposomes were compared in their echogenic efficiency and stability, and the effect of size and acoustic property was tested. The acoustic reflectivity increased with the increase in size of the vesicle, largest for the gas filled MLV among the three liposome suspensions. The acoustic reflectivity obtained with the echogenic MLV was larger than that of the gas bubbles enclosed within a surfactant mixture.A half-lifetime of 39 min was observed for the MLV prepared from egg-yolk phosphatidylcholine liposomes. The duration of reflectivity was prolonged drastically to a half-lifetime of 866 min by incorporating cholesterol into the MLV, although the echogenicity was decreased by such incorporation. The stabilizing effect of cholesterol for the ordinary liposomal membrane was thus ascertained in the present case of the gas-entrapping liposome.Our findings encourage the future development of improved gas-entrapping liposomes for the clinical trials of ultrasound ocntrast agents.

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The reactions of sec-aminodienyl esters 3 in the presence of propargylaldehyde diethylacetal afforded 1, 4-dihydropyridines. This provides a new self-heterocyclic annelation reaction.

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Anacardic acids, 6-pentadecylsalicylic acid (1) and 6-[8(Z)-pentadecenyl]salicylic acid (2) were synthesized from isoxazoles by annelation reactions with ethyl acetoacetate.

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Two known naturally-occurring constituents, 1, 7-dihydroxy-3-methylxanthone and emodin, were isolated from as Ascomycete Anixiella micropertusa as inhibitors of mouse monoamine oxidase (MAO), together with four non-MAO inhibitory components, including two novel compounds, 1, 7-Dihydroxy-3-methylxanthone and emodin inhibited MAO moderately, and IC₅₀ value were calculated to be 2.06×10^-5 and 3.70×10^-5 M, respectively.

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From the air-dried roots of Glycyrrhiza aspera PALL. (Leguminosae) collected in Xinjiang province, China (known as a kind of "Shinkyo-Kanzo"), five new flavonoid compounds named glucoisoliquiritin apioside (1) (a chalcone bisdesmosidic triglycoside), 7-O-apioglucosyl-7, 4'-dihydroxyflavone (5) (a flavone diglycoside), dehydroglyasperin C (7) (a prenylated isoflav-3-ene derivative), asperopterocarpin (9) and 1-methoxyphaseollidin (12) (an O-prenylpterocarpan and a C-prenylpterocarpan, respectively), were isolated together with four known saponins, one known flavonoid O-glycoside, two known flavonoid C-glycosides, and seven flavonoids. The structures of the new compounds have been elucidated on the basis of their chemical and physicochemical properties. Some pterocarpan compounds showed moderate cytotoxic activity against KB and L1210 cells.

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Four new acridone-coumarin dimers, neoacrimarines-H (1), -I (2), -J (3) and -K (4), were isolated from the roots of Marsh grapefruit (Citrus paradisi MACF.). The structures of these new compounds were elucidated by spectral analysis especially using heteronuclear multiple-bond correlation (HMBC) and nuclear Overhauser effect experiments.

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Photoreaction of arenecarbothioamides (1) with 2-vinylfuran analogues (2, 6) in benzene aolution gave tetracyclic indole systems (3, 8) via photogenerated diarylethylene intermediates. In the case of reaction of furan- or thiophenecarbothioamide (1c, 1d) with 2-furanacrylic acid (2-i), 2, 3-diaryl-2-pyrrolin-5-ones (5c-i, 5d-i) were obtained.

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Martefragin A (1), a novel indole alkaloid, was isolated from a red alga, Martensia fragilis, by repeated column chromatography. The structure of 1 was elucidated on the basis of spectral analysis of its methyl ester (2), including ¹H- and ¹³C-NMR, ¹H-¹H correlation spectroscopy (COSY), and ¹³-¹H COSY. A single crystal X-ray analysis of the hydrochloride of 1 confirmed the assignment. Martefragin A (1) showed inhibitory activity on NADPH-dependent lipid peroxidation in rat liver microsomes. The IC₅₀ values of 1, α-tocopherol and ascorbic acid were 2.8, 87 and 200 μM, respectively.

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Arginine-vasopressin (AVP) was acylated with various acyl azides (2a-j) in pH 9.1 buffer to give AVP derivatives (11a-j) modified at the tyrosine side chain with a carbohydrate via a spacer arm. Glycoconjugates of AVP modified at the N-terminal amide (12a-e) were also synthesized from AVP and carboxylic acids (3a-e) using dicyclohexylcarbodiimide and 1-hydroxybenzotriazole as coupling agent. Analogues (11a-j) exhibited greater in vivo antidiuretic activity than AVP. AVP and glycoconjugates (12a-e) were stable in rat plasma. On the other hand, glycoconjugates (11a-i) were found to readily convert to AVP according to first order kinetics. Hence, 11a-j are considered to be prodrugs of AVP.

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To discover a novel NK₁-NK₂ dual antagonist, we have synthesized a series of spiro-substituted piperidines utilizing YM-35375 as a lead compound, and evaluated affinities for NK₁ and NK₂ receptors. In the N-methylbenzamide moiety, introduction of methoxy groups increased affinity for the NK₁ receptor without a significant loss of affinity for the NK₂ receptor. We also found that a conformation in which the phenyl groups of the N-methylbenzamide and 3, 4-dichlorophenyl moieties are close to each other through a cis-amide bond, may be favorable for showing high affinity for the NK₁ receptor and that a hydrogen bond-accepting group in the spiro-substituted piperidine moiety may be crucial for exhibiting high affinity for the NK₂ receptor. Among the compounds prepared, YM-44778 (31) showed high and well-balanced affinity for NK₁ and NK₂ receptors (IC₅₀ values of 18 and 16 nM, respectively). This compound also exhibited potent antagonistic activities against both NK₁ and NK₂ receptors (IC₅₀ values of 82 and 62 nM, respectively) in isolated tissues.

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To overcome hydrolysis by β-glucosidase persent in the digestive tract, the OH groups on the glucose moiety of the 4'-dehydroxyphlorizin derivatives (1, 2, 3) were modified with various kinds of patterns, and then the effects of the modified compounds on urinary glucose excretion were evaluated in rats. Among them, triacetyl (9), , 2, 3-O-diacetyl (17), 6-O-methoxycarbonyl (34), 4-O-methoxycarbonyl (38), and 2-O-acetyl (41) derivatives showed more potent effect than the parent compound 2 by oral administration (p.o.). The stabilities of the compounds 34, 38, and 41 against β-glucosidase were higher than that of 2. The increase in oral activity was found to correlate with the enhancement of the stability against β-glucosidase.

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A novel series of 2, 2-dialkyl-5-(2-quinolylmethoxy)-1, 2, 3, 4-tetrahydro-1-naphthols was synthesized and evaluated as 5-lipoxygenase (5-LO) inhibitors. Systematic optimization led to identification of several highly potent non-redox type 5-LO inhibitors with nanomolar IC₅₀s as racemic mixtures. Optical resolution of racemate 50 indicated that its 5-LO inhibitory activity was enantiospecific and due to the (+)-enantiomer. An efficient synthetic route to the (+)-enantiomers via asymmetric reduction of tetralone intermediates was established. The best compound, (+)-2, 2-dibutyl-5-(2-quinolylmethoxy)-1, 2, 3, 4-tetrahydro-1-naphthol (FR110302, (+)-50), showed potent inhibitory activity against leukotriene (LT) biosynthesis by intact neutrophiles in rats (IC₅₀ 4.9nM) and in humans (IC₅₀ 40 nM). Furthermore oral administration of FR110302 significantly inhibited neutrophil migration in the rat air pouch model at 1 mg/kg.

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A series of compounds structurally related to 2-phenyl-4'-(2, 3, 4, 5-tetrahydro-1H-1, 5-benzodiazepine-1-carbonyl)benzanilide was synthesized and demonstrated to have arginine vasopressin (AVP) antagonist activity for both V_1A and V₂ receptors. The introduction of a hydrophilic substituent group into the 5-position of the benzodiazepine ring resulted in an increase in oral availability. Especially, the (3-pyridyl)methyl (31b), the 2-(4-methyl-1, 4-diazepan-1-yl)-2-oxoethyl (32i), and the 2-(4-methylpiperazin-1-yl)ethyl (33g) derivatives exhibited high antagonist activities and high oral availability. Details of the synthesis and pharmacological properties of this series are presented.

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Five new monoterpenoid polyols were obtained from the fruits of Cnidium monnieri CUSSON (Umbelliferae). They were characterized as distereomers of 3, 7-dimethyloctane-1, 2, 6, 7-tetrols (3 and 4), (6, 7-threo)- and (6, 7-erythro)-3, 7-dimethyloct-3(10)-ene-1, 2, 6, 7, 8-pentols (5 and 6) and trans-p-menthane-1β, 2α, 8, 9-tetrol (7), respectively.

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From the water-soluble portion of Torillis japonica D.C. fruit, a new hemiterpenoid pentol, (3R)-2-hydroxymethylbutane-1, 2, 3, 4-tetrol (1) and a new monoterpenoid apiosyl-glucoside (4) have been isolated together with known (2S, 3R)-2-methylbutane-1, 2, 3, 4-tetrol (2) and hemiterpenoid glucoside (3).As 2 is a commonly existing constituent in Umbellierous plants, and considered to be the first putative precursor of isoprenoid derived from glucose, we assumed that apiose and these hemiterpenoids may be biosynthesized from glucose by a mevalonate-independent route of isoprenoid.

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From the water-soluble portion of the methanol extract of the herbal medicine fennel, the fruit of Foeniculum vulgare MILLER (Umbelliferae), four new phenylpropanoid glycosides, three new benzyl alcohol derivative glycosides, one new phenylethanoid and its glycoside were obtained. They were characterized by spectral investigation.

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Four erythro-anethole glycol monoglucosides were isolated from the methanolic extract of fennel, the fruit of Foeniculum vulgare MILLER (Umbelliferae). From chemical and spectroscopic evidence, they were characterized as (1'S, 2'R)-erythro-anethole glycol 1'-O-β-D-glucopyranoside, (1'R, 2'S)-erythro-anethole glycol 1'-O-β-D-glucopyranoside, (1'S, 2'R)-erythro-anethole glycol 2'-O-β-D-glucopyranoside, (1'R, 2'S)-erythro-anethole glycol 2'-O-β-D-glucopyranoside, respectively. Along with these glycosides, two new glycosides of p-hydroxyphenylpropylene glycol were obtained and characterized as threo-1'-(4-hydroxyphenyl)propane-1', 2'-diol 4-O-β-D-glucopyranoside (a mixture of two stereoisomeric forms) and 1'-(4-hydroxyphenyl)propane-2', 3'-diol 4-O-β-D-glucopyranoside (an epimeric mixture at C-2') from spectral evidence.This is the first report of the isolation of all four O-β-D-glucopyranosides which have the glucosyl unit attached to the hydroxy group of the erythro-glycol function of individual stereoisomeric aglycones.

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From the methanolic extract of the root and rhizoma of Glehnia littoralis FR. SCHMIDT ex MIQ. (Umbelliferae, Hamabofu in Japanese), five new monoterpenoid glycosides were isolated together with (+)- and (-)-angelicoidenol 2-O-β-D-glucopyranoside. Based on the results of spectral investigation, they were characterized as (-)-angelicoidenol 2-O-β-D-apiofuranosyl-(1→6)-β-D-glucopyranoside, (2R, 6S)-bornane-2, 6-diol 2-O-β-D-apiofuranosyl-(1→6)-β-D-glucopyranoside, (2R)-bornane-2, 9-diol 2-O-β-D-apiofuranosyl-(1→6)-β-D-glucopyranoside, and (4R)- and (4S)-p-menth-1-ene-7, 8-diol 8-O-β-D-apiofuranosyl-(1→6)-β-D-glucopyranosides, respectively.

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From the water-soluble portion of the methanolic extract of fennel, the fruit of Foeniculum vulgare MILLER (Umbelliferae), nine fenchane-type monoterpenoid glycosides were isolated.Based on the spectral evidence, they were characterized as (1R, 4R, 5S)-5-hydroxyfenchone β-D-glucopyranoside, (1R, 4S, 6R)-6-hydroxyfenchone β-D-glucopyranoside, (1R, 3S, 4S, 6R)-6, 9-dihydroxyfenchone 6-O-β-D-glucopyranoside, (1S, 4R)-10-hydroxyfenchone β-D-glucopyranoside, (1S, 3S, 4R)-9, 10-dihydroxyfenchone 10-O-β-D-glucopyranoside, (1S, 3R, 4R)-8, 10-dihydroxyfenchone 10-O-β-D-glucopyranoside, (1R, 2R, 4S, 6R)-2, 6-dihydroxyfenchane 2-O-β-D-glucopyranoside, (1R, 2S, 4R, 5S)-2, 5-dihydroxyfenchane 2-O-β-D-glucopyranoside and (1S, 2S, 4S, 6R, 7S)-2, 6, 7-trihydroxyfenchane 2-O-β-D-glucopyranoside. The latter seven glycosides were new, and this is the first report of the isolation of fenchane-type glucosides from plant sources.

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Two free forms and five glycosyl forms of menthane-type monoterpenoids were isolated from the water-soluble portion of the methanolic extract of fennel. From the spectral evidences, these were characterized as cis-p-menthane-1, 7, 8-triol, trans-p-menthane-1, 7, 8-triol, cis-p-menthane-1, 7, 8-triol 8-O-β-D-glucopyranoside. trans-p-menthane-1, 7, 8-triol 8-O-β-D-glucopyranoside, trans-p-menthane-7, 8-diol 7-O-β-D-glucopyranoside, trans-p-menthane-7, 8-diol 8-O-β-D-glucopyranoside and (4R)-p-menth-1-ene-7, 8-diol 8-O-β-D-glucopyranoside.

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Two new lanostane-type triterpenes, lucidumol A and ganoderic acid β, were isolated from the spores of Ganoderma (G.) lucidum, together with a new natural one and seven that were known. The structures of the new triterpenes were determined as (24S)-24, 25-dihydroxylanost-8-ene-3, 7-dione and 3β, 7β-dihydroxy-11, 15-dioxolanosta-8, 24(E)-dien-26-oic acid, respectively, by chemical and spectroscopic means. The quantitative analyses of 5 fruiting bodies, antlered form and spores of G. lucidum were performed by high performance liquid chromatography and demonstrated that ganoderic alcohol and acid contents were quite high in the spore. Of the compound isolated, ganoderic acid β, (24S)-lanosta-7, 9(11)-diene-3β, 24, 25-triol (called lucidumol B), ganodermanondiol, ganodermanontriol and ganolucidic acid A showed significant anti-human immunodeficiency virus (anti-HIV)-1 protease activity with IC₅₀ values of 20-90 μM.

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The objective of this study was to produce enteric microspheres containing bovine insulin as a model drug using a water-in-oil-in-water (w/o/w) emulstion solvent evaporation method, and the preparative conditions were optimized.When hydroxypropylmethylcellulose acetate succinate (AS-HG type; high content of succinyl group) was employed as an enteric wall material, optimized microspheres showed almost 90% of the loading efficiency of insulin and 30.8 μm of mean volume diameter. The mixture of methylene chloride and acetone (4 : 1) as an oleaginous phase, 400 μl of bovine insulin solution (dissolved in 30% of acetic acid) as an internal aqueous phase, and 1.0% of polyvinylalcohol dissolved in pH 3.0 citrate buffer as an external aqueous phase, were employed in the experiment. In relation to other enteric cellulose derivatives (AS-MG type, AS-LG type; medium and low content of succinyl group, respectively), the microencapsulation using a simultaneous preparation method also resulted in quite high loading efficiencies, whereas the choice of poly(methyl methacrylate) as a wall material caused aggregation or flocculation in the preparative process of every batch.The AS-HG microspheres showed very fast release profile in pH 6.8 buffer, but no released fraction was observed in pH 1.2 buffer. This phenomenon suggested enteric characteristics of prepared microspheres. Finally AS-HG microspheres containing 4% lauric acid and 9% insulin were prepared, suspended in 0.1% of carboxymethyl cellulose solution, and administered to the rat rectum (corresponding to 50 I.U./kg insulin). The plasma glucose level reached minimum level at 0.5 h after administration then gradually rose to normal.

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Cationomycin, isolated from Actinomadura azurea belongs to a large family of carboxylic polyehter antibiotics, transporting monovalent cations through membranes by a mobile carrier mechanism, leading globally to an H⁺, M⁺ exchange.In this report the cation transporting properties of cationomycin were characterized in large unilamellar vesicles (LUVs) by ²³Na- and ³⁹K-NMR. Kinetic studies showed that cationomycin transported potassium more rapidly than sodium, and the more stable complex was formed with potassium at the water/membrane interface. The transport rate constants measured for cationomycin were compared with those obtained for monensin. Cationomycin transports Na⁺ more slowly than monensin and has a lower stability complex with Na⁺ because of the lower formation rate for the complex on the membrane surface. Our results show that transport selectivity of cationomycin is in favour of K⁺ versus Na⁺ while the reverse situation is observed for monensin.The relationships between the ionophore properties of cationomycin and monensin with their biological activities are discussed.

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The crystal structures of o-xylene picrate (1) and p-xylene picrate (2) have been elucidated by X-ray analysis. In the structure of 1, o-xylene and picric acid are arranged alternately along the α-axis, making their molecular planes parallel to each other. Two crystallographically independent o-xylene : picric acid complexes exist in an asymmetric unit, which are formed through both π-π interaction and hydrogen bonding between neighboring molecules. The p-xylene molecule forms a picrate with one of three crystallographically independent picric acid moleties through π-π interaction, but not with the two other picric acid molecules.

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Two new phenanthrene derivatives, aristoliukine-A, -B, and a benzenoid, sodium (2R)-(p-hydroxyphenyl)-lactate, together with thirty-three known compounds were isolated from the fresh leaves of Aristolochia kaempferi. Structures were elucidated by spectral analysis. Among the new compounds, sodium (2R)-(p-hydroxyphenyl)lactate was determined to be in the salt form by IR and ¹H-NMR methods.

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Three new lupane derivatives, 3-(E)-feruloyl-28-palmitoylbetulin (1), 3-(Z)-coumaroyl-28-palmitoylbetulin (2), and 3-(Z)-coumaroyllupeol (3) have been isolated from the stem of Diospyros maritima. Their structures were determined by using spectral and chemical methods.

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A new compound, 6'-(stigmast-5-en-7-one-3-O-β-glucopyranosidyl) hexadecanoate, together with 3β-hydroxystigmast-5-en-7-one, oleanolic acid, 6, 8-dimethylchrysin, and chrysin were isolated from the bark of Bauhinia purpurea LINN. Their structures were elucidated by spectral and chemical evidence.

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The treatment of 2H-pyrano[2, 3-b]indolizin-2-imines and 2H-thiino[3, 2-a]indolizin-2-imines with acetic acid at reflux temperature smoothy afforded the corresponding 2H-pyrano[2, 3-b]indolizin-2-one and 2H-thiino[3, 2a]indolizin-2-one derivatives in moderate to good yields. An X-ray analysis of a 2H-thiino[3, 2-a]indolizin-2-one derivative was also performed.

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A Fe complex of a novel bleomycin model compound bearing a diaminopropionamide (DAPA) moiety as the axial ligand and a long alkyl chain as the steric factor around the 6th coordination site promoted reversible redox reaction and exhibited high oxygen activating ability. Kinetic analysis of the redox reaction in the presence of dioxygen and a reducing agent revealed that the presence of the carbamoyl group on the DAPA moiety facilitates the oxygenation-activation process of the Fe(II) complex, and the reduction process of the resulting Fe(III) complex.

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The conventional method of identifying individuals by DNA in the field of forensic medicine is slab gel electrophoresis, which is time-consuming, labor-intensive, and nonquantitative. Accordingly, the use of capilary electrophoresis with a laser-induced fluorescence detector (CE-LIF), human genome D1S80 locus, a DNA marker which has a variable number of tandem repeats (VNTR) on chromosome 1, was examined to improve DNA analysis for identification. Using an internal standard, fragment size of VNTR was accurately and rapidly determined.

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From the water-soluble portion of the methanol extract of the herbal medicine fennel [fruit of Foeniculum vulgare MILLER (Umbelliferae)], one ethyl, two propyl, two butyl and four isopentyl (hemiterpenoid) glycosides were obtained. Of these glycosides, six were new.

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From a methanolic extract of fresh leaves of Ficus pumila LINN (Moraceae), a new tocopherol-related compound has been isolated together with α-tocopherol, and its structure determined by spectral methods. Along with these compounds, two known sterols, fifteen known triterpenoids and five known flavonoid glycosides were identified as constituents.

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Two new naphthopyrones, cassiasides B₂ (1) and C₂ (2), were isolated from the seeds (Cassiae Semen) of Cassia obtusifolia L. The structures of the two new compounds 1 and 2 were established as rubrofusarin 6-O-β-D-glucopyranosyl-(1→6)-O-β-D-glucopyranosyl-(1→3)-O-β-D-glucopyranosyl-(1→6)-O-β-D-glucopyranoside and toralactone 9-O-β-D-glucopyranosyl-(1→6)-O-β-D-glucopyranosyl-(1→3)-O-β-D-glucopyranosyl-(1→6)-O-β-D-glucopyranoside, respectively, on the basis of spectral and chemical evidence.Compound 2 was found to inhibit the histamine release from rat peritoneal exudate mast cells induced by antigen-antibody reaction.

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The first direct separation of Fel Ursi using octadecyl sillica (ODS) open column chromatography has been accomplished and provided to provide several pure, free and conjugated bile acids, the structures of which were substantiated by spectroscopic methods.

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A new convenient method of deoxygenation of heteroaromatic N-oxides is described. Ruthenium prophyrin was used as a catalyst and this method expressed high yields for o-substituted pyridine N-oxides, quinoline N-oxide derivatives, acridine N-oxide, etc. under mild conditions. Moreover, nitro-, benzyloxy-, and ketone carbonyl groups, which can be affected by the usual deoxygenation methods such as catalytic hydrogenation or borane reduction, were retained.

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A water-soluble complex of C₇₀ with δ-cyclodextrin (δ-CD) which was isolated and purified from cyclodextrin powder in our laboratory was investigated. The complex was characterized by its UV-VIS spectrum, which had higher aqueous solubility than that of the complex between C₇₀ and γ-cyclodextrin (γ-CD). the aqueous solution had a red-brown color and resembled the color of C₇₀ in toluence solution.

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The first total synthesis of plumbazeylanone (1), which is a trimer of naphthoquinone, was carried out successfully utilizing the unsymmetrical methylene-bridged dimer with the naphthoquinone unit and the naphthol unit, 11b as a key intermediate in 11 steps. This synthesis features a regioselective nucleophilic 1, 2-addition reaction and dinone-phenol-type rearrangement.

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