One new apocarotenoid, ficusone (1), and two novel γ-lactone derivatives, ficuspirolide (2) and ficusolide (3) as well as 4, 5-dihydrolblumenol (4), were isolated from the heartwood of Ficus microcarpa L.f. Their structures were principally determined by spectral evidence.

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Polymorphic behaviours of paracetamol and propyphenazone and interaction between these two compounds were investigated using differential scanning calorimetry (DSC), X-ray powder diffraction and Fourier transform-infrared (FT-IR)-spectroscopy. Binary mixtures containing various ratios of the compounds were prepared as physical and fused mixtures and analysed by DSC to study their thermal behaviours. Phase diagrams obtained from the melting endotherms of the binary mixtures demonstrated formation of an eutectic mixture at a paracetamol-propyphenazone combination of about 35 : 65 (w/w) with an eutectic temperature of 56°C. The FT-IR spectroscopy revealed no chemical interaction due to eutectic formation, and a lower degree of crystallinity of the eutectic mixture than individual substances was observed by X-ray powder diffraction analysis. The DSC and X-ray powder diffraction data demonstrated a polymorphic change in propyphenazone as a result of melting of the compound. Tablets, containing both paracetamol and propyphenazone in a combination formulation and prepared using standard wet granulation technology, were found to have physical instability when packed in either polyvinylchloride//aluminium or polyvinylchloride/polyvinyldienechloride//aluminium blisters and stored for one month at 40°C with either 75% relative humidity or without any humidity control. The instability of the tablets was more apparent under the high humidity condition.

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The C1-C12 part (4) of tedanolide (1) was synthesized starting from methyl (R)-3-hydroxy-2-methylpropionate (11a) via a coupling between the C1-C7 aldehyde (6) and the C8-C11 iodoalkene (7a). For a synthesis of 6, a mismatched but highly efficient Sharpless dihydroxylation of the α, β-unsaturated ester (15) with AD-mix-α was successfully applied. Compound 7a was synthesized using hydrozirconation to the alkyne (32).

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Catalytic activity of human plasmin is inhibited by bovine basic pancreatic trypsin inhibitor (BPTI, also known as aprotinin). In spite of increased interest in the function of BPTI as an inhibitor of plasmin, the 3-D structure of the plasmin-BPTI complex has not yet been determined. Therefore, in the present paper, the structure of the plasmin-BPTI complex was constructed by the homology modeling method, which provided information about the high affinity of plasmin for BPTI. Moreover, normal mode analyses of free plasmin, free BPTI and the plasmin-BPTI complex were carried out to investigate the changes in dynamics following complex formation.After study of the plasmin-BPTI interaction, we also investigated the binding of BPTI with abnormal plasmin, theoretically and experimentally. The result showing that BPTI binds to abnormal plasmin in the same way as it does to normal plasmin supports the previous finding that the difference between normal and abnormal plasmins is very small and that the abnormality is localized to the catalytic site.

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Arginine vasopressin (AVP) has a dual action, i.e. vasoconstriction and water reabsorption via V_1A and V₂ receptors, and may play a role in a number of diseases, including congestive heart failure (CHF), hypertension, renal disease, edema, and hyponatremia. We have attempted to develop a new series of AVP antagonists for both V_1A and V₂ receptors based on the hypothesis that the blockade of both V_1A and V₂ receptors might be beneficial to CHF patients. In this report, a series of compounds structurally related to 4'-[5-(substituted methylidene)-2, 3, 4, 5-tetrahydro-1H-1-benzoazepine-1-carbonyl]benzanilide (exo-olefin isomer) and 4'-[5-(substituted methyl)-2, 3-dihydro-1H-1-benzoazepine-1-carbonyl]benzanilide (endo-olefin isomer) were synthesized and examined to have AVP antagonist activity for both V_1A and V₂ receptors. As a result, it was found that the (E)-exo-olefin isomers showed more potent binding affinitiy compared with endo-olefin isomers. Among these (E)-exo-olefin isomers, (E)-N-methyl-{1-[4-(2-methylbenzoylamino)benzoyl]-2, 3, 4, 5-tetrahydro-1H-1-benzoazepin-5-ylidene}acetamide (14) exhibited the most potent binding affinitiy and (E)-N-methyl-(1-{4-[2-(4-methylphenyl)benzoylamino]benzoyl}-2, 3, 4, 5-tetrahydro-1H-1-benzoazepin-5-ylidene)acetamide (20) exhibited a high AVP antagonist activity for both V_1A and V₂ receptors after intravenous administration. Details of the synthesis and pharmacological properties of this series are presented.

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The methanolic extract from the flowers of Chrysanthemum indicum L., Chrysanthemi Indici Flos, was found to show inhibitory activity against rat lens aldose reductase. By bioassay-guided separation, the active components, such as flavone and flavone glycosides, were isolated from the extract together with three new eudesmane-type sesquiterpenes, kikkanols A, B, and C. The structures of kikkanols A, B, and C were elucidated on the basis of chemical and physicochemical evidence, which included application of the modified Mosher's method.

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Aminopropyl-silica gels modified with a nickel(II)-phthalocyanine derivative (Ni-PCS_D) were evaluated as HPLC-stationary phases for the separation of π-electron rich compounds such as polyaromatic hydrocarbons (PAHs) and mutagens. A column packed with Ni-PCS_D retains some π-electron rich compounds longer than a column packed with copper(II)-phthalocyanine derivatives (Cu-PCS_D), suggesting that a π-π electron interaction and an additional interaction between Ni-PCS and the compound. On the basis of the retention data of fourring PAHs, anthracene derivatives and heterocyclic aromatic hydrocarbons, we propose that the additional interaction would be due to an interference of the π- or n-electrons would interact and with the d-orbital of the Ni atom in Ni-PCS. Further, the Ni-PCS_D column is expected to be superior to the Cu-PCS_D column for the separations of drugs, mutagens and pollutants which have both π-electrons and ligand atom(s).

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New optically active antifungal azoles, 1-[(1R, 2R)-2-(2, 4-difluoro- and 2-fluorophenyl)-2-hydroxy-1-methyl-3-(1H-1, 2, 4-triazol-1-yl)propyl]-3-(4-substituted phenyl)-2(1H, 3H)-imidazolones (1, 2) and 2-imidazolidinones (3, 4), were prepared in a stereocontrolled manner from (1S)-1-[(2R)-2-(2, 4-difluoro- and 2-fluorophenyl)-2-oxi-ranyl]ethanols (15, 16). Compounds 1-4 showed potent antifungal activity against Candida albicans in vitro and in vivo, as well as a broad antifungal spectrum for various fungi in vitro. Furthermore, the imidazolidinones, 3b-e and 4d, e, were found to exert extremely strong growth-inhibitory activity against Aspergillus fumigatus.

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A new route for the synthesis of the optically active antifungal azole TAK-187, 2-[(1R, 2R)-2-(2, 4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1, 2, 4-triazol-1-yl)propyl]-4-[4-(2, 2, 3, 3-tetrafluoropropoxy)phenyl]-3(2H, 4H)-1, 2, 4-triazolone, was established. The key synthetic intermediate, 2-[(1R)-2-(2, 4-difluorophenyl)-2-oxo-1-methylethyl]-4-[4-(2, 2, 3, 3-tetrafluoropropoxy)phenyl]-3(2H, 4H)-1, 2, 4-triazolone (8), was prepared starting from the esters (11a, b) of (S)-lactic acid in a stereocontrolled manner. This optically active propiophenone derivative 8 was converted to the one carbon-elongated (1R, 2S)-diol 7, which was then reacted with 1H-1, 2, 4-triazole to yield TAK-187. This newly developed route was applied to the synthesis of the analogs (25a, b-28a, b)containing an imidazolone or imidazolidinone nucleus.

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In the course of our studies aimed at obtaining new drugs for treatment of bone and joint diseases, chemical modification of the potent bone resorption inhibitors justicidins, was performed and various naphthalene lactones, quinoline lactones and quinoline derivatives bearing an azole moiety at the side chain were prepared. Their inhibitory effects on bone resorption were evaluated by Raisz's method, and several compounds, including ethyl 4-(3, 4-dimethoxyphenyl)-6, 7-dimethoxy-2-(1, 2, 4-triazol-1-ylmethyl)quinoline-3-carboxylate (6c, TAK-603), were found to have activities comparable with or superior to the justicidins. The 4-(3-isopropoxy-4-methoxy)-phenyl derivative (6d), in particular, displayed a marked increase in potency. TAK-603 and compound 6d were very effective in preventing osteoclast formation and bone resorption by mature osteoclasts. Further, TAK-603 was shown to be effective in preventing bone loss in ovariectomized mice.

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Thirty-two new bakkenolides, bakkenolides-Db (1)--Dh (7), -Fa (8), -Fb (9), -I (10)--M (14), -Na (15), -Nb (16), -O (17)--T (22), -Ua (23), -Ub (24), -V (25)--X (27), -Ya (28), -Yb (29), -Za (30), -Zb (31) and -III (32), from the roots of Petasites formosanus together with thirty known compounds were isolated. The structures were characterized by spectral analysis. The locations, C-1 and/or C-9 bakkenolide skeleton, of the substituents, such as acetoxy, isobutyroyloxy and isovaleroyloxy groups, can be determined by the chemical shifts of their signals and the H-1 and/H-9 in the ¹H-NMR spectra. The cytotoxicity was also discussed.

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Following the characterization of 3S-phyllodulcin, 3R- and 3S-phyllodulcin 3'-O-glucosides, and 3R- and 3S- thunberginol H 8-O-glucosides, six new dihydroisocoumarin glycosides, 3R- and 3S-hydrangenol 4'-O-apiosylglucosides, 3R- and 3S-thunberginol I 4'-O-glucosides, thunberginol I 8-O-glucoside, and 3S-phyllodulcin 8-O-glucoside, were isolated from the dried leaves of Hydrangea macrophylla var. thunbergii and their structures were determined on the basis of chemical and physicochemical evidence. In addition, isomerization reaction at the 3- positions of phyllodulcin and its glycosides was examined.

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The isolation and characterization of three new oleanane-type triterpenoidal saponins, called gleditsiosides E-G, along with two known ones, from the anomalous fruits of Gleditsia sinensis LAM. are described. Their structural details were unambiguously determined by using a combination of modern NMR techniques, including distortionless enhancement by polarization transfer (DEPT), double-quantum filtered ¹H-¹H correlated spectroscopy (DQF-COSY), homonuclear hartmann-hahn (HOHAHA), ¹H-¹³C heteronuclear correlation (HETCOR), heteronuclear multiple-bond connectivity (HMBC) and rotating-frame overhauser enhancement spectroscopy (ROESY) experiments as well as some chemical methods. The five bisdesmosidic triterpenoidal saponins consisting of the same sugar sequence were all acylated with two different or identical monoterpenic acids to the C-2 and C-3 positions of rhamnose moiety.

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Lewis acid-promoted nitroolefination of enol silyl ethers has been developed. Enol ethers 1, 4, 5, and 6 derived from lactones and lactams furnished nitroolefines 2, 7, 8, and 9, respectively in 60-99% yields by the treatment with 3 in the presence of Lewis acids. Asymmetric nitroolefination of 5a and 6a with 12 gave 8a and 9a in 75% and 73% ee, respectively.

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Synthesis and biological evaluation of the first dicarba-closo-dodecaborane (carborane) derivatives of retinoids are described. Their retinoidal activity were examined in terms of the differentiation-inducing ability toward human promyelocytic leukemia HL-60 cells. High retinoidal activity (agonist or antagonist for retinoic acid receptor (RAR)) requires a carboxylic acid moiety and an appropriate hydrophobic group located at a suitable position on the molecule. The 4-carboranyl-substituted compounds (7, 11) showed antagonistic activity but no agonistic activity even in the presence of the potent synergist HX630. On the other hand, the 3-carboranyl-substituted compounds (8, 12) showed potential agonistic activity, but no antagonistic activity. The results indicates that carboranes are applicable as the hydrophobic moiety of biologically active molecules.

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Pellets were prepared by granulation/extrusion/spheronization. Four different procedures applying different amounts of shear were used for granulation : planetary mixer, high-shear mixer and twin-screw extruder with two different screw assemblies. Extrusion was performed on a rotary ring die press. Pellet properties were rated by size, shape, release behaviour and different mechanical characteristics like crushing strength or porosity. The study revealed that different granulation methods affected pellet properties by the application of different shear forces. The application of higher shear forces during granulation resulted in a higher water content necessary for successful pelletization. This finding is in contrast to conventional granulation and was explained by the crystal-lite-gel-model. The difference in water content of the extrudate influenced the extent of shrinking during drying, which was responsible for the different mechanical characteristics of the pellets. The release rate for paracetamol was higher for pellets with lower porosity. This is explained by the presence of drug crystals on the surface of these pellets due to the higher extent of shrinking during drying.

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Conjugates of 2-aminooxyethyliminodiacetic acid with estrone, testosterone, epiandrosterone, 17-α-hydroxy-progesterone and progesterone were synthesized and their complexes with Tc-99m were successfully prepared in good yields, which indicated the agent to be promising for metal-labeling of biomolecules and related substances containing one or more carbonyl groups. The biodistribution and scintigraphic studies in mice bearing Ehrlich tumor and mammary tumor showed that the radioactivity accumulated considerably in the tumor tissues, but the tumor images were somewhat obscured.

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Solid dispersions of carbamazepine or ethenzamide were prepared by melting and rapid cooling with liquid nitrogen using lactose as a carrier. The physical characteristics of these solid dispersions were investigated by powder X-ray diffraction, differential scanning calorimetry, and dissolution rate analysis. The degree of crystallinity of the drugs in solid dispersions decreased with decreases in the molar ratio of the drugs to lactose. Fourier-transform infrared (FT-IR) analysis demonstrated the presence of intermolecular hydrogen bonds between the primary amide group of carbamazepine and lactose. Dissolution studies indicated that the dissolution rate was markedly increased in solid dispersions compared with physical mixtures and pure drugs. These results indicated that lactose is useful as a carrier for the production of solid dispersions of drugs having a primary amide group in their structures.

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Two new phenylpropanoid glycosides and three known sesquiterpene lactones were isolated from the fresh fruits of Illicium anisatum L. (Illiciaceae). Their structures were elucidated from spectroscopic and chemical data.

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Some pseudo-peptide analogs of thiol proteinase inhibitors were synthesized by a conventional solution method. Among them, Suc-Ala-Val-Val-Ala-Ψ-(CH₂-NH)-Ala-pNA (peptide 1) and Suc-Ala-Val-Val-Ψ-(CH₂-NH)-Ala-Ala-pNA (peptide 2) showed a stronger inhibitory activity compared with parent peptide such as Suc-Ala-Val-Val-Ala-Ala-pNA. In particular, peptide 2 was about 10-fold as active as the parent peptide (IC₅₀=8 μM). Inserting Ψ-(CH₂-NH) possibly makes the inhibitor less susceptible to papain and, as a result, produces more potent inhibition.

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Diversifolide [4, 15-dinor-3-hydroxy-1(5)-xanthen-12, 8-olide], a novel dinorxanthane sesquiterpene, and a new chromone, 6-acetyl-7-hydroxy-2, 3-dimethylchromone, together with four known compounds, 2-deacetyl-11β, 13-dihydroxyxanthinin, 2-acetyl-2, 2-dimethylchromene, 6-acetyl-7-hydroxy-2, 2-dimethylchromene, and 6-acetyl-7-methoxy-2, 2-dimethylchromene were isolated from the root of Tithonia diversifolia. Their structures were spectroscopically determined by 2D-NMR experiments, including heteronuclear multiple bond correlation and nuclear Overhauser enhancement spectroscopy.

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Water-soluble benzoylphenylurea derivatives were synthesized as candidate prodrugs and their antitumor activities were examined in vivo against P388 leukemia. Some of the prodrugs were highly soluble in water and showed good antitumor activities against P388 leukemia cells in mice when injected intravenously.

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Two minor triterpenoid saponins, ardisicrenoside G [3β-O-{α-L-rhamnopyranosyl-(1→2)-β-D-glucopyranosyl-(1→4)-[β-D-glucopyranosyl-(1→2)]-α-L-arabinopyranosyl}-16α, 28-dihydroxyolean-12-en-30-oic acid] and ardisicrenoside H [3β-O-{β-D-xylopyranosyl-(1→2)-β-D-glucopyranosyl-(1→4)-[β-D-glucopyranosyl-(1→2)]-α-L-arabinopyranosyl}-16α, 28-dihydroxyolean-12-en-30-oic acid] were isolated from the roots of Ardisia crenata. Structural assignments are based on NMR, MS and chemical reactions.

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Novel chiral bisphosphine ligands bearing (2S, 5S)-dimethylphospholano group on a chiral biphenyl back-bone were designed and prepared. Asymmetric hydrogenations of a ketone and an olefin with the rhodium(I) complex catalysts prepared in situ from [Rh(COD)Cl]₂ and (R)-2, 2'-bis[(2"S, 5"S)-2", 5"-dimethylphospholano]-5, 5'-dimethoxy-4, 4', 6, 6'-tetramethyl-1, 1'-biphenyl and (S)-2, 2'-bis[(2"S, 5S")-2", 5"-dimethylphospholano]-5, 5'-dimethoxy-4, 4', 6, 6'-tetramethyl-1, 1'-biphenyl gave the corresponding alcohol and alkane in high yields. The asymmetric hydrogenations with these ligands showed a different enantioselectivity.

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Beta-carboline alkaloids in crude drugs were quantified by a reversed-phase HPLC method without interference from their artifactual formation during analysis and with fluorometric detection specific to each individual analyte. 1-Methyl-β-carboline, β-carboline, 7-hydroxy-1-methyl-β-carboline, 7-methoxy-1-methyl-β-carboline, 1-methyl-1, 2, 3, 4-tetrahydro-β-carboline and 1, 2, 3, 4-tetrahydro-β-carboline showed a wide distribution in the crude drugs and the former two β-carbolines were detected in all those tested. Schisandrae Fructus, Pinelliae Tuber, Evodiae Fructus and Passiflora incarnata contained relatively large amounts of β-carbolines at ng-μg/g dry weight levels. Beta-carboline alkaloids may be responsible for the pharmacological effects of crude drugs as the potent active substances.

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Thrombin-catalyzed peptide synthesis has been studied using nine series of "inverse substrates, " i.e., p-amidinophenyl, p- and m-guanidinophenyl, p- and m-(guanidinomethyl)phenyl, and four position isomers of guanidinonaphthyl esters derived from N^α-(tert-butyloxycarbonyl)amino acid as acyl donor components. These substrates were classified into two types with respect to their response to thrombin. One group includes p-amidino- and p-guanidinophenyl esters, which undergo less enantioselective coupling reaction. Substrates classified into the other group are m-guanidinophenyl, p- and m-(guanidinomethyl)phenyl, and four position isomers of guanidinonaphthyl esters which are involved in the enantioselective coupling reaction. Thus amino acid residues of L-series (in the present case; N^α-Boc-L-Ala) are readily coupled to afford peptides by assigning them to either of the inverse substrates. The optimum condition for the coupling reaction was studied by changing organic solvent, pH, and acyl acceptor concentration. It was found that the enzymatic hydrolysis of the resulting product was negligible.

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Two new lupin alkaloids, which are the first ester derivatives of matrine-type lupin alkaloids, (-)-14β-acetoxymatrine and (+)-14α-acetoxymatrine, were isolated from the leaves of Sophora tonkinensis along with fourteen known lupin alkaloids : 17-oxo-α-isosparteine, (-)-sophocarpine, (+)-matrine, (-)-14β-hydroxymatrine, (+)-14α-hydroxymatrine, 13, 14-dehydrosophoranol (5α-hydroxysophocarpine), (+)-sophoranol, (+)-9α-hydroxymatrine, lamprolobine, (+)-5α, 9α-dihydroxymatrine, (-)-baptifoline, (+)-matrine N-oxide, (+)-sophocarpine N-oxide, and (+)-sophoranol N-oxide.

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A conjugate from the YIGSR peptide and chitosan has been prepared on the basis of a regioselective modification strategy of chitosan, and its antimetastatic activity has been assayed. Chitosan was converted to its organosoluble derivative, 6-O-trityl-chitosan, in 3 steps, and then coupled with the peptide portion containing a spacer amino acid, Ac-Tyr-Ile-Gly-Ser-Arg-βAla-OH [βAla; β-alanine]. The product was treated with CHCl₂CO₂H to afford the desired conjugate, Ac-Tyr-Ile-Gly-Ser-Arg-βAla-chitosan, which proved to inhibit the experimental lung metastasis of B16BL6 melanoma cells in mice at lower doses than the parent peptide.

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Two labdane-type diterpenes 4 and 5 isolated from the Brazilian medicinal plant Mimosa hostilis were confirmed to have absolute configurations in enantiomeric relation to each other by X-ray crystallographic analysis of p-bromophenyl carbamate derivative 5a and comparison between 4a and 5b, readily available from 5a.

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Three new labdane-type diterpenes, excoecarins F, G1, and G2, were isolated from resinous wood of Excoecaria agallocha LINN collected from Okinawa prefecture. Stereochemistries of the new diterpenes were determined on the basis of chemical and physicochemical evidence. Excoecarin F was found to posses a chloride element in its structure.

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Total synthesis of vibrioferrin (1), a siderophore, was achieved via chiral dibenzyl citrate separated by optical resolution. It was elucidated that the configuration of the citrate moiety of vibrioferrin was R.

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