In order to elucidate the action of chlorpromazine (CPZ) and imipramine (IMP) on nigericin-mediated Na⁺ transport across phosphatidylcholine vesicular membranes, ²³Na nuclear magnetic resonance was applied to the exchange system of Na⁺ ions present at the same concentration inside and outside unilamellar vesicles. CPZ and IMP added to the vesicles in micromolar concentrations produced an equal increase in the carrier-transport rate. The kinetic analysis, together with ¹H-NMR observations of the reduction in membrane fluidity produced by the drugs and on the direct interaction between drugs and nigericin, allowed us to conclude that the drug-induced promotion of transport occurred not from the formation step of the Na⁺-nigericin complex nor from its diffusion step, but from its dissociation step. The formation of an adduct between drug and nigericin could be the cause of the drug effect and this proceeded much more efficiently at a membrane-water interface (stability constant K_b; 3×10⁵M^-1) than in methanol (K_b; 5×10²M^-1). The reason for the difference is also discussed.

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Several (±)-dibenzocyclooctadiene lignans, (±)-schizandrin (1a) (±)-gomisin A (1b), and their stereoisomers 2a and 2b, were synthesized by the samarium-Grignard reaction of the phenylpropyl bromides 4 and the phenylacetone derivative 5 to give the erythro and threo-butanols 6 and 7 followed by oxidative aryl-aryl coupling reaction of each butanol.

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Several (±)-dibenzocyclooctadiene lignans, (±)-isoschizandrin (1a), 1b, 2a, and 2b, were synthesized by the samarium-Barbier reaction of the phenylpropenes 4 and the phenylacetone 5 to give the erythro- and threo-butanols 6 and 7, followed by oxidative aryl-aryl coupling reaction of each butanol.

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Ethyl acylindole-2-carboxylates were treated with thallium trinitrate (TTN) in methanol, methyl orthoformate, methyl orthoformate/sulfuric acid, and acetic acid. The reactions in the former three methanolic solvents gave methyl indoleacetate derivatives via the Favorskii-type rearrangement reaction at the acyl group, whereas the reaction in acetic acid gave oxindole derivative with rearrangement of the C₂-ethoxycarbonyl group. The TTN reaction was applied to a model compound leading to the synthesis of lysergic acid.

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The reaction of N-aminoimidazolium salts (4, 5) with polarized olefins (2a-d, 3a, b) in the presence of K₂CO₃ in EtOH gave the corresponding imidazolium N-vinylimino ylides (6, 7). Thermolyses of the N-vinylimino ylides (6c-f, 7a-c) afforded mesomeric betaines (8a-d, 9a, b, 10a, b). Treatment of the salt (5) with polarized olefins (2b-d, 3c) in the presence of K₂CO₃ in EtOH directly yielded mesomeric betaines (9c-d, 10c), while in EtOH, the reaction of the salt (5) with polarized olefins (2e, 3d) in the presence of K₂CO₃ gave pyrazoles (11a, b). The formation of mesomeric betaines is suggested to proceed via back-donated 1, 6-cyclization.

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A facile synthesis of 5α-fluorocholestan-3-one from 4-cholesten-3-one has been accomplished. Direct fluorination of the enone by molecular fluorine gave the cis-vicinal difluoride. Treatment of this adduct with triphenyltin hydride in the presence of azobisisobutyronitrile afforded the title compound.

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We designed several oxygenated steroids in which functional groups including a hydrophobic group are arranged analogously to those of phorbol ester (12-O-tetradecanoylphorbol-13-acetate, TPA), with the aim of finding compounds with TPA-like activity, but having a different skeleton and a rigid conformation. The designed steroids, 1β, 5α-dihydroxy-3β-hydroxymethylcholestan-6-one (4), 3β, 5α-dihydroxycholestan-6-one (5), 3β-hydroxymethylcholestan-5α-ol-6-one (6) and 1β, 3β, 5α-trihydroxycholestan-6-one (7), were synthesized. A related oxygenated steroid isolated from soft coral, cholestane-1β, 3β, 5α, 6β-tetrol (8), was also synthesized. Among these analogs, compound 7 showed weak TPA-like activities in three biological tests : inhibition of [³H]TPA binding to protein kinase C and to cytosolic-nuclear tumor promoter-binding protein (CN-TPBP), and induction of differentiation of human promyelocytic leukemia cells (HL-60) to monocyte-like cells. On the other hand, compound 5 was found to be a specific ligand for CN-TPBP, but lacked the other TPA-like activities.

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Asymmetric synthesis of a cyclopentene derivative was accomplished by transition metal-catalyzed vinylcyclopropane-cyclopentene rearrangements with chiral phosphine ligands. A dramatic solvent effect was observed on the nickel-catalyzed asymmetric rearrangement of a cyclopropane system into an optically active cyclopentene derivative with chiral phosphine ligands. The absolute configuration of the product was determined by chemical correlation to the compound of known absolute configuration. The stereochemistry of the product was readly controlled by selecting the catalyst, nickel or palladium, with extremely high enantioselectivity.

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For structure-activity relationship investigation of eudistomins 1, 12-carbaeudistomin 3, its 1, 10-trans isomer 4, and 11, 12-didehydro-12-carbaeudistomin 5 have been synthesized. The [2, 3]-Meisenheimer rearrangement of the corresponding N-oxide of the 2-vinylazetopyridoindole 12a bearing a benzenesulfonyl group as a protective group of the indole nitrogen atom afforded the oxazepino ester 14, which was easily isomerized to 20a. Compounds 3 and 4 were synthesized from 14 and 20a, respectively, according to the following reaction sequences [hydrogenation of the double bond (Pd-C/H₂), desulfonylation (Mg in MeOH), hydrolysis (AlBr₃-EtSH), and Curtius rearrangement (a mixed anhydride method using NaN₃), followed by debenzylation (Pd-C/H₂]. The Curtius reaction of the carboxylic acid 27 using DPPA gave the carbamate 29, which was subjected to debenzylation (AlBr₃-EtSH) followed by desulfonylation (LiAlH₄) to afford 5. Evaluation of anti-influenza virus activities of the amino compounds 3, 4, and 5 revealed that 12-carbaeudistomin 3 possesses a specific activity against influenza virus B.

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Chiral pyrrolidinebisphosphine ligands, (2S-cis)-BCPM and (2S-cis)-BCPP, bearing two different types of phosphino groups, a dicyclohexylphosphino group and a diphenylphosphino groups, were designed and prepared on the basis of our design concept for developing highly efficient ligands. The validity of the concept was confirmed experimentally in the asymmetric hydrogenation of ketopantolactone using neutral rhodium(I) complexes of BCPM, BCPP, BPPM, and BCCP. The rhodium(I) complex of (2S-cis)-BCPM was found to be the most effective catalyst (substrate/catalyst >ca. 10⁴, >90%ee (R)).

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Three new groups of peptaibols, trichodecenins, trichorovins and trichocellins, have been isolated from conidia of the fungus, Trichoderma viride. The structures of trichodecenins-I and -II were established by positive-ion fastatom bombardment, collision-induced dissociation mass spectrometry and two-dimensional NMR spectroscopy. Trichodecenins-I and -II have a (Z)-4-decenoyl group, six amino acid residues and a leucinol moiety in the molecules. Trichodecenin-II was synthesized by the solution-phase method.

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In an attempt to synthesize 2'-deoxy-7-methyladenosine (5b), 2'-deoxy-N⁶-methoxyadenosine (13b) was treated with MeI in AcNMe₂ at 0°C for 7h to give the 2'-deoxy-N⁶-methoxy-7-methyladenosine salt (14b), which was unstable and easily underwent glycosidic hydrolysis in H₂O at 16-18°C to form N⁶-methoxy-7-methyladenine (15). On account of such instability, hydrogenolysis of 14b in H₂O using hydrogen and Raney Ni catalyst failed to afford the desired nucleoside (5b). 2'-Deoxy-N⁶-methyladenosine (2b), 2'-deoxy-1-methyladenosine (3b), and 14b were found to undergo glycosdic hydrolysis in 0.1 N aqueous HCl at 25°C at rates of 7.92×10^-3 min^-1 (half-life 87.5 min), 5.02×10^-3 min^-1 (half-life 138 min), and 2.31×10^-2 min^-1 (half-life 30.0 min), respectively, while the rate in the case of 5b was roughly estimated to be ca. 2 min^-1 (half-life 0.35 min).

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The reaction of aromatic methylenedioxy compounds containing electron-withdrawing groups with sodium methoxide-thiols in dimethyl sulfoxide gave 3- and 4-hydroxybenzene derivatives in good yield by regioselective attack of the thiolate ions on the methylenedioxy ring. The formation mechanism and the reactivity of thiolate ions in the cleavage reaction of the methylenedioxy ring are discussed. Various biologically active compounds, 32a, 32d, 36b, 38b, 41b and 44-47, were prepared from the 4-hydroxybenzene derivatives and their Ca²⁺ antagonistic activities were evaluated. Among these compounds, 2-(2-bromophenylthiomethoxy)-10-(2-diethylaminoacetyl)-3-methoxyphenothiazine (46) showed the most potent Ca²⁺ antagonistic activity. Biological activity could be conveniently evaluated by measurement of the peak height of the vanadyl ion (+4 oxidation ion) signal produced by redox reaction between the phenothiazine derivatives and vanadate ion +5 oxidation ion) with ESR spectroscopy.

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To mimic the folded side chain conformation of 1233A (1), which is a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) synthase inhibitor, 1233A analogs with aromatic rings in the side chain were synthesized. The 2-oxetanone moiety was kept intact. Among 1233A and its synthetic analogs, trans-3-hydroxymethyl-4-[2-(7-methoxycarbonyl-1-naphthyl)ethyl]-2-oxetanone (23) showed the highest HMG-CoA synthase inhibitory activity in vitro. The structure-activity relationship at the side chain is discussed.

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A series of 3-benzoyl or 3-phenylsulfonyl-2-substituted thiazolidine derivatives were synthesized, and evaluated for their thromboxane A₂ (TXA₂) receptor-antagonizing effect on (15S)-15-hydroxy-11α, 9α-(epoxymethano)prosta-5(Z), 13(E)-dienoic acid (U-46619)-induced aggregation of rabbit platelet-rich plasma (PRP). A simple 2-aryl-thiazolidine derivative, 3-benzoyl-2-(4-hydroxy-3-methoxyphenyl)thiazolidine (5a), showed mild TXA₂ receptor antagonist activity. Modification of 5a led to 2-chloro-4-[3-(4-chlorophenylsulfonyl)thiazolidin-2-ylmethyl]phenoxy-acetic acid (29d), which showed 10 times more potent TXA₂ receptor antagonist activity than 5a.

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The effects of methanol extracts of 80 herbs on hair growth were investigated, using normal C₃H/He mice from which telogen hair on the back had been removed. Eighteen of the extracts apparently promoted hair regrowth on the mice. As one of active principles in Polyporus umbellatus F., 3, 4-dihydroxybenzaldehyde was isolated by column chromatography on Amberlite XAD-2, Sephadex LH-20 and silica gel.

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Systematic replacement of the P₄-P₂ subsites of substrate-based human immunodeficiency virus type 1 protease (HIV-1 PR) inhibitors containing cyclohexylalanylalanine hydroxyethylene dipeptide isostere (Cha-ψ[H.E.]-Ala) at positions corresponding to the scissile sites of substrates was carried out. The structure-activity relationship revealed that compounds with the combination of hydrophilic P₃ and β-branched hydrophobic P₂ amino acids generally showed strong inhibitory activity against HIV-1 PR. In particular, compounds 4 (Boc-Orn-Val-Cha-ψ[H.E.]-Ala-NHBuⁿ; Buⁿ=n-butyl, K_i=11 nM) and 6 (Z-Orn-Val-Cha-ψ[H.E.]-Ala-NHBuⁿ, K_i=8 nM) exhibited good enzyme selectivity, possessing no significant inhibitory activities toward closely related aspartic proteases, pepsin, cathepsin D, and renin. As a possible model system for evaluating these compounds, anti-retroviral (anti-Mo-MSV/MLV complex (Mo-MSV=Moloney murine sarcoma virus; MLV=murine leukemia virus)) activity was investigated. Both compounds were found to inhibit moderately the focus formation of Mo-MSV/MLV complex in NIH3T3 cells (compound 4, IC₅₀=1.8 μM; compound 6, IC₅₀= 1.0 μM).

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During the screening of novel platelet-activating factor (PAF) antagonists, we found that 1-(6-methoxy-3, 4-dihydro-2-naphthoyl)-4-(3, 4, 5-trimethoxybenzyl)piperazine and its 4-(3, 4, 5-trimethoxybenzoyl)piperazine derivatives (1b, 2b) exerted in vitro and in vivo PAF-antagonistic activities. Modifications of the 1-acyl group, the substituent at the 4-position and the piperazine ring of 1a and 2b were examined and from this series 1-(2, 3-dimethoxy-6, 7-dihydro-5H-benzocyclohepten-8-ylcarbonyl)-4-(3, 4, 5-trimethoxybenzoyl)piperazine (2g) was found to be one of the most potent PAF antagonists.

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2- or 3-Substituted 1-(2, 3-dimethoxy-6, 7-dihydro-5H-benzocyclohepten-8-ylcarbonyl)-4-(3, 4, 5-trimethoxybenzoyl)- and 4-(3, 4, 5-trimethoxybenzyl)piperazines (2a-s, 3a, b) were prepared and evaluated for antagonistic activities against platelet-activating factor (PAF)-induced platelet aggregation and blood pressure reduction. The 2-methoxymethyl derivative (2f) showed the most potent activities in this series. The enantiomers (R)-(+)-2f and (S)-(-)-2f were synthesized from carbobenzoxy-O-benzyl-L- and D-serine in several steps. In the binding experiment, (S)-(-)-2f showed thirty times greater affinity than the R isomer for the PAF receptor.

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A series of 5-methyl-4-(3-pyridyl)-2-(substituted benzimidazol-5-yl)imidazole derivatives was synthesized and tested for anti-platelet and vasodilatory activities. Some compounds were found to have potent activities and low acute toxicity. In particular, 5-methyl-4-(3-pyridyl)-2-(7-chloro-6-methoxy-2-methylbenzimidazol-5-yl)imidazole (26) and 5-methyl-4-(3-pyridyl)-2-(7-chloro-3-methoxy-2-methylbenzimidazol-5-yl)imidazole (33) exhibited 63% or 51% inhibition at a dose of 10 mg/kg for anti-patelet activity ex vivo in rats, respectively, while they showed no toxicity even at 180 or 100 mg/kg, respectively. Compound 33 also exhibited potent vasodilatory activity (ED₅₀=11 μg/ml). Enzyme studies on these imidazoles showed that the novel imidazoles inhibit some snzymes which are involved in the platelet aggregation cascade such as cyclooxygenase, phosphodiesterase (PDE), and thromboxane A₂ synthetase. The enzyme assay also suggested that the inhibitory activity on PDE may account for the vasodilatory activity of these imidazoles.

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The inhibitory effects of newly synthesized 4-alkoxyaryl β-D-glucopyranosides on histamine release from rat peritoneal mast cells induced by concanavalin A were examined. A plot of hydrophobicity (k') against inhibitory activity of the compounds showed a distinct maximum, and 4-decyloxy-2, 3, 6-trimethylphenyl β-D-glucopyranoside was the most potent inhibitor among the tested compounds.

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A series of hydroquinone monoalkyl ethers was synthesized and evaluated for anti lipid-peroxidation activity in rat liver microsomes. 4-Hexyloxy-2, 3, 6-trimethylphenol (9), having a low redox potential, as well as ascorbic acid exhibited the strongest anti lipid-peroxidation activity (IC₅₀=4.2×10^-7M). Structure-activity relationship studies demonstrated that the inhibitory effect of hydroquinone monoalkyl ethers on lipid peroxidation was increased by the acquisition of an optimum hydrophobicity and decreased by an insufficient or excessive hydrophobicity.

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As part of a search for potent and long-lasting angiotensin converting enzyme (ACE) inhibitors, various types of N-[(1S)-1-carboxy-5-(4-piperidyl)pentyl]-L-alanine derivatives (7a, 8-11) were prepared. The key synthetic intermediate, N-[(1S)-5-(1-benzyloxycarbonyl-4-piperidyl)-1-ethoxycarbonylpentyl]-L-alanine (17a), was synthesized by asymmetric reduction of the α-oxoester (13) with Lactobacillus paracasei subsp. paracasei followed by a substitution reaction with tert-butyl L-alaninate (15) and subsequent treatment with hydrogen chloride. Compounds 7a and 8-11 showed potent and long-lasting ACE-inhibitory activity in rats.

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Novel and potent ACAT (acyl-CoA : cholesterol O-acyltransferase) inhibitors, (R)-N-2-(1, 3-benzodioxol-4-yl)heptyl-N'-2, 6-diisopropylphenylurea (2a, EAB-309), and its enantiomer 2b (EAB-310), were prepared from 4-(1, 3-benzodioxole)carbaldehyde (7) via optically active (R or S)-2-(1, 3-benzodioxol-4-yl)heptanoic acid (12a or 12b). Compound 2a showed potent inhibitory effects on ACATs in vitro, and lowered plasma cholesterol in vivo. The IC₅₀ value for inhibition of rat hepatic microsomal ACAT was 5 nM. The ED₃₀ values of hypolipidemic activities in hamster and rat models were 0.25 and 0.75 mg/kg p.o., respectively. The results indicate that 2a has potential to be a novel hypocholesterolemic and antiatherosclerotic agent. The activities of 2a in vitro and in vivo were only several times more potent than those of the enantiomer 2b. Modeling studies suggested that the three-dimensional structures of the two enantiomers are similar to each other.

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To obtain metabolically stable peptide ligands with high affinity and selectivity for the δ-opioid receptor, the enzymatic stability of deltorphins and their analogs was examined by using a crude rat brain synaptosomal membrane fraction. It was found that deltorphin (DLT : Tyr-D-Met-Phe-His-Leu-Met-Asp-NH₂) was easily degraded, producing DLT (1-4) and DLT (1-5) as the major degradation products, whereas [D-Ala²]deltorphin II (DL-II : Tyr-D-Ala-Phe-Glu-Val-Val-Gly-NH₂) was very stable. Experiments with some enzyme inhibitors strongly suggested that the degradation of DLT was initiated by cleavage of the Leu⁵-Met⁶ bond by a metalloendopeptidase. On the other hand, stability experiments on DL-II analogs demonstrated that the presence of amino acids branched at the β-carbon atom or with a bulky side chain as residue 5 is of importance for the enzymatic stability. Based on these lines of evidence, some enzyme-resistant DLT analogs were synthesized.

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Reaction of 9-[3, 5-di-O-(tetrahydropyran-2-yl)-β-D-arabinofuranosyl]uracil (2) with diethylaminosulfur trifluoride in the presence of pyridine afforded 2'-deoxy-2'-fluororiboside 3a, from which 2'-deoxy-2'-fluorocytidine (4b) has been synthesized in good yield. Compound 3a was deprotected and subsequently treated with various benzyl halides or 2-chloro-4-fluoroacetophenone to give corresponding N³-substituted 2'-deoxy-2'-fluorouridines 5a-c and 6. Compounds 5a-c, as well as 6, showed weak hypnotic activity in mice. Compound 4b showed moderate antiviral activity against human immunodeficiency virus-1 but 3b, 5a-c, and 6 were virtually inactive.

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A method was developed for specific estimation of the content of a non-enzymatic protein, karasurin A, in fractions taken during the extraction and purification processes from a natural source. Anti-karokon serum was elicited in rabbits immunized with fragments of karokon, a dried root tuber of Trichosanthes kirilowii MAX. var. japonicum KITAM. Rabbit antibody specific for karasurin A was identified in anti-karokon serum by the Western blotting method. After separation by SDS-PAGE, protein bands of purified karasurin A and extracted proteins from a medicinal herb which is a karasurin A source were reacted with anti-karokon serum followed by treatment with horseradish peroxidase (HRP)-labeled Fab' of goat anti-rabbit IgG, and then bound HRP-labeled second antibody on protein bands was developed to brown by reaction with a substrate solution of the used enzyme. A novel selected antibody enzyme immunoassay (SAEIA) for karasurin A was developed using selective binding of anti-karasurin A antibody in anti-karokon serum to solid phase karasurin A and HRP-labeled Fab' of the second antibody as the tracer. Specific estimation of the content of karasurin A in several fractions taken during the isolation and purification processes of the protein were possible using the SAEIA method.

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A novel [Ile⁷]surfactin (1), which showed anti-human immunodeficiency virus activity, has been isolated from Bacillus subtilis natto. Structural and conformational analysis of the peptide backbone of [Ile⁷]surfactin was conducted by a combination of various two-dimensional (2D) nuclear magnetic resonance (NMR), circular dichroism (CD) spectroscopy and simulated annealing calculations, compared with a known [Leu⁷]surfactin (2). Both surfactins were shown to exist in different conformational states in both polar and apolar solvents.

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Two new triterpenoids, rhoiptelenol and 3α-hydroxy-isohop-22(29)-en-24-oic acid, were isolated from the fresh leaves and stems of Ficus thunbergii MAX. (Moraceae), and their structrues were determined by spectral and chemical methods. Along with these new compounds, known triterpenoids lupenyl acetate, β-amyrin acetate, α-amyrin acetate, lupeol, β-amyrin, α-amyrin, taraxerol, glutinol, ursolic acid and betulinic acid were obtained from the leaves and stems.

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In connection with the study of differentiation inducers from plants, the methanol extract of Condurango Cortex (bark of Marsdenia condurango REICH, Asclepiadaceae) was investigated to examine its differentiation-inducing activity towards mouse myeloid leukemia (M1) cell line. Six pregnane glycosides, including three new compounds, were isolated as differentiation inducers. Each of the six active glycosides has three or four deoxylated sugars which are well-known to occur in Asclepiadaceae plants. M1 cells were differentiated into phagocytic cells by these glycosides, and they were found to be more effective than their aglycones. Condurangoglycosides A (7) and C (8), having a cinnamoyl group in their aglycones, were the most potent differentiation inducers and M1 cells became phagocytic cells after 24 h treatment with these compounds.

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From the most polar fractions of Solidago virga-aurea L. (Compositae), 9 oleanane-type triterpene saponins named solidagosaponins XXI-XXIX (1-9) were isolated, together with a known saponin, virgaureasaponin 2 (10). These saponins are bisdesmosidic glycosides having two monosaccharides at C-3 and four or five monosaccharides at C-28. Their structures were established on the basis of spectroscopic and chemical evidence.

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Two acidic polysaccharides, called rehmannan SA and rehmannan SB, were isolated from the dried root of Rehmannia glutinosa LIBOSCHITZ. They were homogeneous on electrophoresis and gel chromatography, and their molecular masses were estimated to be 6.4×10⁴ and 7.9×10⁴, respectively. They were commonly composed of L-arabinose : D-galactose : L-rhamnose : D-galacturonic acid in the molar ratios of 10 : 10 : 1 : 1 (rehmannan SA) and 14 : 7 : 3 : 8 (rehmannan SB), in addition to small amounts of peptide moieties. About eighty percent (rehmannan SA) and about thirty percent (rehmannan SB) of the hexuronic acid residues exist as methyl esters. Reduction of carboxyl groups, methylation analysis, nuclear magnetic resonance and the controlled Smith degradation studies indicated the structural features of rehmannan SB, the major one in terms of the yield. It has a core structural unit of a characteristic rhamnose-rich arabino-3, 6-galactan type. Both polysaccharides showed remarkable reticuloendothelial system-potentiating activity in a carbon clearance test.

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A novel glucan, called cnidirhan SI, was isolated from the rhizome of Cnidium officinale MAKINO. It was homogeneous on electrophoresis and gel chromatography, and its molecular mass was estimated to be 1.3×10⁴. It is composed of D-glucose alone, in addition to small numbers of O-acetyl groups. Methylation analysis, nuclear magnetic resonance and enzymic degradation studies indicated it has a high-branched glucan type structure composed of α-1, 4-linked D-glucopyranose residues with both 3, 4- and 4, 6-branching points. The glucan showed significant reticuloendothelial system-potentiating activity in a carbon clearance test, as well as pronounced anti-complementary activity. This substance is the first example of a branched α-glucan with phagocytosis-stimulating and anti-complementary activities.

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Five new dammarane saponins derived from four new aglycones were isolated from the rhizomes and roots of Panax vietnamensis HA et GRUSHV. On the basis of physicochemical and spectral evidence, the structures of these compounds were established as 6-O-β-D-glucopyranosyl 20(S), 25-epoxydammarane-3β, 6α, 12β, 24α-tetrol (1), 6-O-β-D-xylopyranosyl-(1→2)-β-D-glucopyranosyl 20(S), 25-epoxydammarane- 3β, 6α, 12β, 24α-tetrol (2), 6-O-β-D-glucopyranosyl dammarane-3β, 6α, 12β, 20(S), 24ξ, 25-hexol (5), 3-O-[β-D-glucopyranosyl-(1→2)-β-D-glucopyranosyl]-20-O-β-D-glucopyranosyl dammarane-3β, 12β, 20(S), 24ξ, 25-pentol (8) and 6-O-β-D-xylopyranosyl-(1→2)-β-D-glucopyranosyl 20(S), 24(S)-epoxydammarane-3β, 6α, 12β, 25ξ, 26-pentol (10). The trivial names, vina-ginsenoside-R10, -R11, -R12, -R13 and -R14, respectively, were assigned to the new saponins.

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From the roots of Polygala senega L. six new oligosaccharides, called senegoses J-O, were isolated and their structures were elucidated by spectroscopic and chemical means. These oligosaccharides were esterified with acetic, benzoic, p-coumaric and ferulic acids.

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The distribution style of prostaglandin E₁ (PGE₁) in injectable lipid emulsion (Lipo-PGE₁) was analyzed using a three-phase model : an aqueous phase, an oil phase and an oil/water interface. A combination of the oil phase and the oil/water interface was obtained as the particle phase. Initial diffusion rates of PGE₁ from lipid particls to the aqueous phase were determined by the dialysis method, and equilibrium concentrations were calculated by the diffusion rates using an equation derived from Fick's theory. Lipo-PGE₁ enclosed in cellulose tubing was immersed in buffer solutions (pH 5.5, 7.4), then incubated at various constant temperatures. Each concentration of PGE₁ in the aqueous phase was measured at appropriate intervals. By using these values, partition coefficients between the particle phase and the aqueous phase were calculated. It was found that a larger portion of PGE₁ was distributed in the particle phase compared with the aqueous phase in Lipo-PGE₁ at each temperature. Furthermore, actural partition coefficients between oil and aqueous phases were measured. From the results of two partition coefficients, the distribution ratio of PGE₁ in Lipo-PGE₁ was determined as : oil : oil/water interface : water=0.2 : 93.1 : 6.7, that is, 93% PGE₁ was found to be distributed in lipid particles. On the other hand, by diluting PGE₁ one hundred times with transfusion, the distribution ratio of PGE₁ in lipid particles decreased as the pH of the transfusion increased. The ratios after 2 h were 74% and 47% for pH 5.5 and 7.4, respectively.In conclusion, a large portion of PGE₁ was found to be distributed in the particle phase when Lipo-PGE₁ was diluted with transfusion. Since most PGE₁ exists in an oil/water interface, it is considered that it has a strong affinity for phospholipids. Thus, this affinity may contribute to the remarkable increase in activity in clinical treatment.

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We investigated the possibility of developing an oily gel formed by hydrogenated soybean phospholipids (HSL) as a percutaneous absorption-type ointment base. Liquid paraffin (LP) was used as the oil, and indomethacin (IM), ketoprofen (KP), flurbiprofen (FP) and ibuprofen (IP) were used as model drugs. IM did not dissolve in LP, but solubilized when heated with HSL at a concentration of about 1% with 15% HSL at 95°C. IM gel was thus prepared as follows : IM and HSL were mixed, added into LP, capped tightly, heated in a water bath and cooled. The consistency of the gel increased with increasing IM concentration, indicating some kind of interaction between IM and HSL. The release of IM from the IM gel was faster than that from a preparation in which IM was mixed in gel at room temperature (Gel+IM). The release rate of IM from IM gel was proportional to IM concentrations up to 1%, but became constant above that. Permeation of IM through hairless rat abdominal skin from IM gel was higher than that from the Gel+IM. The permeation rate was proportional to IM concentrations in the range of 0.1 to 0.5% in 15% HSL gel. KP and FP also solubilized in gel when subjected to the same procedure as IM, and their release and permeation increasd when they were formulated as gels. However, no evident improvement of permeation was observed in the case of IP, which had high LP solubility. It was suggested that HSL showed no enhancing effect, but solubilized IM, KP or FP, leading to high permeation from the gel. After 3 months' storage, the permeation rate did not change for 0.5% IM in 15% HSL gel, but decreased for 1% IM in 15% HSL gel. This indicates that in the case of 1% IM in 15% HSL gel, IM is in a supersaturated state immediately after preparation and then recrystallizes with time.

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We examined the film formation of an aqueous suspension system using micronized ethylcellulose (EC) in comparison with an EC latex system. The minimum film-forming temperatures (MFT) of the two systems and the glass transition temperature (T_g) of EC were measured with a micro melting point apparatus and a differential scanning calorimeter, respectively. Replicas of the free films prepared from the two systems were examined under a transmission electron microscope. The release of theophylline from granules coated with the two systems was compared to investigate the effect of curing, in which the coated granules were heated for an hour at 80°C. MFT and T_g decreased as the amount of triethyl citrate used as a plasticizer increased in both systems. MFT of the suspension system was higher than T_g, while that of the latex system was lower than T_g. A replica of the free film from the suspension system showed no shapes of the EC particles used; in contrast, that from the latex system showed the shape of individual latex spheres in coalescence. Curing had no effect on the release behavior of the suspension-coated granules, whereas it remarkably delayed release from the latex-coated granules. The replica method revealed that the coalescence of latex particles was more complete after curing than before. These results demonstrate that the mechanisms of film formation of these two systems are different, and that this difference results in different properties of films prepared by the two systems.

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Based on the moisture control system developed previously, we have already reported that the operational moisture content during aqueous polymeric coating by a type of fluidized bed should be controlled for a better coating efficiency.In this paper, effects of operational moisture content and agitator rotational speed on the properties of granules prepared by the aqueous polymeric coating were investigated experimentally, and optimization of this process was conducted. Core granules (mean diameter 600 μM) containing a model drug, pigment Blue No. 1, were coated with the aqueous dispersion of enteric polymer (Eudragit L30D) by the tumbling fluidized bed with controlling the operational moisture content. The coated granules were evaluated by dissolution tests in JP 1st (pH 1.2) and 2nd fluid (pH 6.8) and by agglomeration tendency. Film thickness and specific surface area of the granules were examined to discuss the film forming process. Based on the evaluation, effects of the operational variables on the drug release rate and agglomeration tendency were investigated. It was found that the drug release rate was suppressed with increase in moisture content at any rotational speed in the JP 1st and 2nd fluid, and the agglomeration tendency was prevented with increase in moisture content and agitator rotational speed. It was concluded from the results that the aqueous coating with the enteric polymer by the tumbling fluidized bed process should be carried out under a condition of moisture content between 12 and 14% with agitation below 5 rps.

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During the course of studies on the blue pigment formation by the reaction of genipin with methylamine, nine red to brownish-red intermediary pigments were obtained under conditions excluding oxygen. They were identified as monomer, dimer, trimer and tetramer of 2-methyl-4-carbomethoxy-2-pyrindine derivatives on the basis of spectroscopic evidence.

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As a part of a study to elucidate the functional difference between Glu and Gln side-chains in terms of the recognition of guanine base by tryptophan-containing peptides via cooperative stacking and hydrogen-bond pairing interactions, the binding of 7-methylguanine to Trp-Gly-Gly-Glu and Trp-Gly-Gly-Gln was examined by fluorescence and ¹H-NMR methods. Comparison of fluorescence experiments showed a binding preference for Trp-Gly-Gly-Glu over Trp-Gly-Gly-Gln. The analyses of the downfield and upfield shifts of the C2 amino and N7 methyl protons of 7-methylguanine base showed there was hydrogen-bond pairing of Glu and Gln side chains with the base and a stacking interaction of the Trp residue with the base, respectively. However the hydrogen-bond pairing was more effective in the case of the Glu residue than the Gln residue, indicating the preference of the carboxyl group over the carbamoyl group to form hydrogen-bond pairing with the guanine base.

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(±)-Normethylgomisin A (3) was synthesized by the samarium-Barbier reaction of the phenylpropene 4 and the phenylacetone 5 to give the butanol 6, followed by oxidative aryl-aryl coupling reaction of the butanol.

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Chemically synthesized (26)- and (27)-methyl-¹³C-labeled desmosterol (3, 5) were separately incubated with rat liver homogenate. ¹³C-NMR analysis of the incubation products indicated that the C-25 hydrogen of cholesterol was introduced from the si-face of 3 and the re-face of 5.

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(2S, 3S)-2-(4-Methoxybenzyloxy)-3, 4-O-(3-pentylidene)-1, 3, 4-butanetriol (3), a versatile chiral building block for an essential structural unit of complex natural products, was synthesized starting from dimethyl L-(+)-tartrate (5) on both a small scale and a large scale in good yield.

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2-Aminooxyethyliminodiacetic acid, designed as a possible bifunctional chelating agent with a hydroxylamino group that can bind a carbonyl group of biomolecules, was synthesized by three different methods. Its oxime derivatives with some carbonyl compounds were readily prepared.

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Chiral chelated lithium amides ((R))-1a-g) were designed and synthesized in optically pure forms starting from (R)-phenylglycine.

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Two components having an immunosuppressive activity were isolated together with non-active pisolactone from Pisolithus tinctorius, and they were deduced to be 24-methyllanosta-8, 24(28)-diene-3β, 22ξ-diol and a mixture of two new compounds, (22S, 24R)-24-methyllanosta-8-en-22, 28-epoxy-3β, 28α-diol and (22S, 24S)-24-methyllanosta-8-en-22, 28-epoxy-3β, 28β-diol, respectively. Among them, pisolactone and 24-methyllanosta-8, 24(28)-diene-3β, 22ξ-diol have previously been isolated from the same mushroom. Ergosterol peroxide and 9(11)-dehydroergosterol peroxide were also isolated as active components from this mushroom in small amounts, and from Microporus flabelliformis and Lenzites betulina. The IC₅₀ values of these components were evaluated against proliferation of mouse spleen lymphocytes stimulated with concanavalin A and lipopolysaccharide.

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In an investigation of the anti-inflammatory properties of five-membered ring nitrogen-containing heterocyclic compounds, two series of derivatives of imidazole were prepared by altering the sites of substitution and by joining aliphatic chains to the nitrogen atom in the 1 position of the imidazole ring. Some of them were more potent inhibitors of carragenan-induced edema than indomethacin. An electron spin resonance study indicated that these compounds possess anti-radical activity.

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We prepared new antitumor active platinum complexes containign N, N'-bis(2-chloroethyl)ethylenediamine (ClEn) as an alkylating carrier ligand in order to obtain increased antitumor effects. Some of the platinum complexes synthesized showed enhanced antitumor activity. However, palladium(II) complexes containing ClEn were inactive against L1210 and P388.

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In order to analyze the separation processes taking place in liquid chromatography, a video image analyzing system was developed. A video camera, video tape recorder and an image processor were linked to a microcomputer. The distribution of fluorescent solutes in a glass column was measured as a densitogram which was regarded as a chromatogram inside the column. The apparent migration rate, which was the migration distance for a unit migration volume, was determined by this method and was found to have a good linear relationship with the capacity factor k'. Band broadening during separation was also estimated at various flow rates. It was concluded that the band broadening was mainly due to multiple-path diffusion.

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