The mechanism of the nitrosation of sodium enolate of acetone [CH₃COCH₂]^-Na⁺ (1) with methyl nitrite CH₃ONO (2) to give 1-hydroxy-imino-2-oxo-propane CH₃COCH=NOH (3) was studied by the ab initio molecular orbital (MO) method. The complex [CH₃COCH₂NO(OCH₃)]^-Na⁺ (C-II) was first formed from the adduct (C-I) of 1 and 2 through the pericyclic transition state (TS1). Finally, Z-hydroxyimino compound (3Z) was obtained through demethoxylation of 2 moiety and abstraction of an active hydrogen atom in C-II with a base. In the final formation of 3Z, two leaving groups, the methoxy group and the active hydrogen atom in C-II, should be situated in positions with respect to each other which permit their elimination, i.e., they are antiperiplanar to one another. It has become apparent that 3Z tends to be formed predominantly when a countercation of a base coordinates to the oxygen atom of the enolate of acetone.

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The total synthesis of kealiiquinone (1), a highly substituted imidazole marine alkaloid isolated from sponge, was achieved via nine reaction steps starting from 1-methyl-1H-imidazole (5). The synthesis is based on the selective introduction of appropriate carbogenic substituents and protecting groups into the imidazole ring followed by an intramolecular cyclization of the substituents on the C4- and the C5-positions. The structure of the synthesized kealiiquinone was confirmed by X-ray crystallographic analysis.

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^6Li- and ¹⁵N-NMR spectroscopic studies on the solution structures of a chiral tridentate lithium amide have revealed that it exists as a chelated monomer in which the lithium is tri-coordinated, as a chelated dimer in which the lithium is tetra-coordinated, or as a mixture of these two species depending upon the solvent used. It is concluded that lower Lewis acidity of the tri- and tetra-coordinated lithium compared to the di-coordinated lithium makes tridentate lithium amides inferior to dibentate lithium amides as bases in enantioselective deprotonation reaction.

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Constituents of three EtOH extracts of the stem bark of Garcinia assigu LANTB., Garcinia dulcis (ROXB.) KURZ., and Garcinia latissima MIQ., belonging to the Guttiferae, collected in Central Province of Papua New Guinea, were studied. A novel depsidone named garcinisidone-A (1), six new xanthones named assiguxanthone-A (3) and -B (9) and dulxanthone-A (4), -B (6), -C (7), and -D (11), and four new pyranoxanthones named latisxanthone-A (13), -B (14), -C (15), and -D (16) were isolated, as well as some known xanthone, benzophenone, chromone, and biflavanone derivatives, and their structures were elucidated by spectroscopic methods. Among these components, garcinisidone-A (1) is the first example of a depsidone derivative having a five-carbon unit (prenyl) as a substituent to be found in nature. Latisxanthone-B (14) was found to contain a hydroperoxy moiety in the molecule. This is the second example of a xanthone hydroperoxide to be found in nature.

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2-Acyl (or sulfonyl)-c-4-bromo-r-1-cyano-t-3-methoxy-1, 2, 3, 4-tetrahydroisoquinolines treated with primary or secondary amines are stereoselectively converted into 4-amino-1, 2, 3, 4-tetrahydroisoquinoline derivatives in high yields. The 1, 4-trans and 3, 4-trans configuration of the products has been determined by X-ray crystallography. The formation of an isoquinoline o-quinone type compound 5 is suggested as an intermediate in the reaction process.

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1-Hydroxy- or 1, 8-dihydroxy-bicyclo[3.2.1]oct-3-en-2-ones were obtained from 1-methoxy- or 1-tert-butyldimethylsilyloxy-bicyclo[2.2.2]oct-5-en-2-ones via successive processes involving demethylation or desilylation and acyloin rearrangement by reaction with acids or tetra-n-butylammonium fluoride (TBAF).

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The side chain of piericidin B₁ having four (E)-olefinic linkages was prepared. The coupling reaction of the non-conjugated aldehyde (22) derived from 4, 4-dimethoxy-2-butanone and the sulfone (13) afforded a diastereomeric mixture of the hydroxy sulfone (27). Benzoylation of 27 followed by reductive olefin formation with sodium amalgam gave the desired all-trans-tetraene (29) possessing an (E)-C(5)-C(6) double bond, which was transformed to the alcohol (1) corresponding to the side chain of piericidin B₁.

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Topsentinols A-J (1-10), new 7-hydroxysterols with unusual polyalkylated side chains were obtained from the Okinawan marine sponge Topsentia sp. and their structures elucidated on the basis of spectral data. Side chains containing the 22E-24-isopropenyl-25-methyl-22-ene group (in 1, 6) and the 22Z-24-isopropyl-22-ene group (in 2, 7) are unprecedented.

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S-[2-(Dialkylaminocarbonyl)phenyl](2R)-2-[(3S, 4S)-3-[(1R)-1-(tert-butyldimethylsilyloxy)ethyl]-2-oxo-4-azetidinyl]thiopropionate (11), useful intermediates for the synthesis of 1β-methylcarbapenems including 1β-methylthienamycin, were prepared in a highly stereoselective manner by the reaction of E-1-(tert-butyldimethylsilyloxy)-1-[2-(dialkylaminocarbonyl)phenylthio]-1-propene (10) with commerically available (3S, 4R)-3-[(1R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-acetoxyazetidin-2-one (6) in the presence of zinc chloride catalyst. The diethylaminocarbonyl derivative (11b) was particularly convenient for practical production because of its highly crystalline nature.

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A series of novel ([1, 2, 4]triazolo[1, 5-b]pyridazin-6-yl)oxyalkylsulfonamides was synthesized and evaluated for the ability to inhibit platelet activating factor (PAF)-induced bronchoconstriction in guinea pigs. The compounds bearing a gem-dialkyl or a cycloalkylidene group at the 2 position of the sulfamoylpropyloxy group in the side chain and a methyl group at the 7 position were found to have potent activity. Among them, 2, 2-diethyl-3-(7-methyl[1, 2, 4]-triazolo[1, 5-b]pyridazin-6-yl)oxypropanesulfonamide (13) showed excellent anti-asthmatic activity. Compounds 13 may be of significant value in the treatment of asthma and other respiratory diseases. The structure-activity relationships in this series of compounds are discussed.

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A series of succinamide derivatives containing the 5, 11-dihydro-6H-pyrido[2, 3-b][1, 4]benzodiazepin-6-one skeleton (6a-z) was prepared and evaluated for binding affinity to muscarinic receptors in vitro and for antagonism of bradycardia and salivation in vivo in comparison with AF-DX 116 (1a). Structure-activity relationships (SAR) studies in vitro indicated that the 4-(4-alkyl-1-piperazinyl)benzylamino moiety plays a crucial role in enhancing the affinity for M₂ muscarinic receptors. Compound 6y, containing a 4-(4-isopropyl-1-piperazinyl)benzylmethylamino moiety, exhibited the highest affinity for M₂ muscarinic receptors (pK_i=9.2), being 200 times as potent as 1a, and compound 6u, containing a 4-(4-ethyl-1-piperazinyl)benzylethylamino moiety, showed the highest selectivity for M₂ over M₃ muscarinic receptors (M₃/M₂ ratio=320). Both 6y and 6u antagonized the oxotremorine-induced bradycardia in rats after intravenous or oral administration. Oral evaluation in conscious dogs showed that the efficacy for increasing the heart rate was at least 3-fold greater than that of 1a.

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Novel benzophenone derivatives were synthesized and screened for cytotoxic and antitumor activity. Friedel-Crafts condensation was employed to construct the benzophenone skeleton. Among the compounds synthesized, morpholino and thiomorpholino benzophenones 3a-d exhibited potent cytotoxic activity against P388 murine leukemia and PC-6 human lung carcinoma cells in vitro, and compounds 3a, 3c, and 3j, when administered intraperitoneally, showed significant antitumor activity against the malignant ascites caused by intraperitoneal inoculation of P388 cells in mice.

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A series of novel 1, 5-diphenylpyrazole derivatives bearing hydrophilic substituents was prepared. The anti-inflammatory and analgesic activities of these compounds were evaluated by using the adjuvant arthritis and Randall-Selitto assays in rats, and the structure-activity relationships were studied. The optimal compound was 3-(difluoromethyl)-1-(4-methoxyphenyl)-5-[4-(methylsulfinyl)phenyl]pyrazole (10) with oral ED₅₀ values of 0.31 and 2.6 mg/kg on adjuvant-induced arthritis and carrageenin-induced foot edema, respectively. Compound 10 showed analgesic activities not only toward inflamed paw but also toward normal paw (ED₃₀=0.55 and 1.8 mg/kg, respectively) in the Randall-Selitto assay, and moreover, 10 was effective in the tail-pinch assay (ED₅₀=21 mg/kg) similarly to morphine. The asymmetric synthesis and pharmacological properties of the enantiomers of 10 are also reported.

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An alternative method to an analysis of variance (ANOVA)for assessing stability variation among batches, packaging, or formulations is proposed. The new method assesses the shelf-life equivalence based on the range of the shelf-like estimate obtained for each product of a given batch, packaging, or formulation. The power of this analysis was not significantly affected by assay error, whereas that of ANOVA decreased markedly as assay error increased. Therefore, the proposed method does not exhibit a tendency to overlook stability variation from stability data of a larger assay error as does ANOVA. If the critical point is assumed to be 15% of the largest shelf-life estimate, 25% stability variation can be detected at a probability of more than 80% for degradation faster than 0.2%/month. When smaller stability variation is desired to be detected, the critical point must be smaller than 15%.

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Twenty-three phenolics including six new compounds were isolated from a commercial liquorice from North-eastern China. Structures 2-7 were assigned for the new compounds, designated as tetrahydroxy-methoxychalcone, isolicopyranocoumarin, glycyrrhiza-flavonol A, and glycyrrhiza-isoflavones A, B and C, respectively. Compound 2 showed the most potent scavenging effect on 1, 1-diphenyl-2-picrylhydrazyl radical among the tested polyphenols isolated from liquorice. Air-oxidation of 2 in alkaline dimethylsulfoxide solution gave strong ESR signals, indicating the stability of the radical species formed from 2.

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Nine new saikosaponin homologues, called clinoposaponins XII-XX, were isolated from the aerial parts of Clinopodium vulgare, C. chinense and C. chinense var. parviflorum together with nine known saikosaponin homologues. On the basis of spectral and chemical evidence, the structures of clinoposaponins XII-XX were determined to be 3-O-[β-D-glucopyranosyl-(1→2)-β-D-glucopyranosyl]saikogenin F, 3-O-β-D-fucopyranosyl-21β-hydroxysaikogenin F, 3-O-[β-D-glucopyranosyl-(1→3)-β-D-fucopyranosyl]-21β-hydroxysaikogenin F, 3-O-[β-D-glucopyranosyl-(1→2)-β-D-glucopyranosyl]saikogenin F, 3-O-{β-D-glucopyranosyl-(1→2)-[β-D-glucopyranosyl-(1→3)]-β-D-fucopyranosyl}-21β-hydroxysaikogenin F, 3-O-{β-D-glucopyranosyl-(1→2)-[β-D-glucopyranosyl-(1→3)]-β-D-fucopyranosyl}-23-oxosaikogenin E, 3-O-{β-D-glucopyranosyl-(1→2)-[β-D-glucopyranosyl-(1→3)]-β-D-fucopyranosyl}-16-ketosaikogenin F, 3-O-{β-D-glucopyranosyl-(1→2)-[β-D-glucopyranosyl-(1→3)]-β-D-fucopyranosyl}-30-hydroxysaikogenin F, 3-O-{β-D-glucopyranosyl-(1→2)-[β-D-glucopyranosyl-(1→3)]-β-D-fucopyranosyl}-30-oxo-saikogenin F, respectively. The known saponins were assigned to be clinoposaponins III, V, IX, X, XI, buddlejasaponins I, IV, 3-O-β-D-fucopyranosylsaikogenin F and saikosaponin a.

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The methanolic extract of the underground part of Rhodiola sacra (PRAIN ex HAMET) S. H. Fu was found to show inhibitory activity on the histamine release from rat peritoneal exudate cells induced by an antigen-antibody reaction. From the methanolic extract with the inhibitory activity on histamine release, a new cyanoglycoside called rhodiocyanoside D and two new monoterpene glycosides called sacranosides A and B were isolated, together with eight known compounds, rhodiocyanoside A, heterodendrin, lotaustralin, rhodioloside, 2-phenylethylα-L-arabinopyranosyl(1→6)-β-D-glucopyranoside, 2-methyl-3-buten-2-yl β-D-glucopyranoside, kenposide A, and rhodiooctanoside. The structures of new compounds were determined on the basis of chemical and physico-chemical evidence, which included the synthesis of sacranoside A from (-)-myrtenol. All major chemical constituents from R. sacra inhibited the histamine release and, among them, lotaustralin and rhodiooctanoside were found to show potent inhibitory activity.

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The necessity for antibacterial agents with greater intracellular efficacy has led to the development of endocytosable drug carriers such as liposomes. Enoxacin was selected as a model drug incorporated in various liposome formulations as a therapeutic dosage form using the ethanol injection method and freeze-drying. Liposomal behavior after preparation and stability test was characterized by determining the physicochemical properties of enoxacin encapsulation percent, vesicle size and turbidity. The non-phospholipid formulation of stratum corneum liposomes showed the highest encapsulation efficiency after preparation among nine liposomal formulations. The addition of dissacharides in liposomes also enhanced the encapsulation of enoxacin due to the protection of phospholipid bilayers during the freeze-drying process. The liposomes with negatively charged component and dissacharides showed lower enoxacin leakage after five weeks of storage at 45°C, suggesting these formulations have high stability in long-term storage. The negative liposomes showed a different behavior than others in their decrease of size and turbidity during storage, possibly due to high surface charges of the negative formulation. Cholesterol stabilized bilayers interacted with plasma and high density lipoprotein (HDL) retained enoxacin in the vesicles. Nevertheless, liposomes with cholesterol caused a hydrolysis problem after incubation with normal saline. The formulation with trehalose not only showed high stability in storage but also in plasma and HDL. This suggested trehalose was useful to incorporate with phospholipids to produce a highly encapsulated and stabilized liposomes of enoxacin. This study also demonstrated that thought is required in utilizing turbidity as a direct index of liposomal vesicle size.

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Formulation of sustained release tablets containing coated particles whose coating membrane is not damaged during compression was studied and several kinds of chitosan of different particle size were evaluated as protective agents for the membrane. Comparison was made with the dissolution rate of the coated particles. Ethylcellulolse or ethylcellulose/hydroxypropylcellulose was chosen as a coating agent. When the coated particles were compressed with the small particle size chitosan (Marine Chito), the coating membrane was not ruptured, and the protective effect was not influenced by the compression pressure. Both the Eudragit RS-coated particles and the tablets manufactured by compressing the coated particles with Marine Chito were orally administered to dogs, and the plasma theophylline levels of the two dosage forms were compared to determine the drug release characteristics in the gastrointestinal tract. It was found that the plasma concentration-time curve of the tablets coincided with that of the coated particles, and the compressed tablet would disintegrate instantly and redisperse into many particles in the body after oral administration.

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2-Bromomaleic anhydride (BrMAn) and styrene (St) were found to make a charge-transfer complex at a 1 : 1 ratio. The copolymerization followed the generalized mechanism for alternating copolymerization, and an alternating copolymer was obtained over a relatively wide feed composition range. The monomer reactivity ratios, r_BrMAn and r_St, were found to be 0 and 0.05, respectively, at 60°C. The copoly(BrMAn/St) was dehydrobrominated by heating under reduced pressure and a polymer with a structure similar to the maleic anhydride moiety in the polymer chain was obtained. The dehydrobromination was completed by heating at 190°C for 1 h.

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(+)-Monocalcium bis[(2S)-2-benzyl-3-(cis-hexahydroisoindolin-2-ylcarbonyl)propionate] dihydrate (KAD-1229, 1) is an optically active succinic acid calcium salt derivative with potent hypoglycemic effect. We investigated two optical resolution methods. 2-Benzyl-3-(cis-hexahydroisoindolin-2-ylcarbonyl)propionic acid 6 was esterified with (S)-N-benzyl mandelamide and the resulting diastereomeric esters were separated by column chromatography on silica gel to give 7 and 8 in 39.1% and 45.3% yields, respectively. The diastereomer 7 was hydrolyzed to give the optically active acid (-)-6. The absolute configuration of (-)-6 was established as S by comparison with an authentic sample. The alternative method was resolution using an optically active amine. Treatment of a solution of the racemic acid 6 with 0.65 eq of (R)-1-(1-naphthyl)ethylamine in ethanol gave the salt in 23.2% yield with an optical purity of 96.8% ee.

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Phosphatidyl-D-myo-inositol 3, 4, 5-trisphosphate, a candidate of the second messenger in cellular signal transduction, was efficiently synthesized in a homochiral form.

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A monodentate phosphine, 8-diphenylphosphino-8'-methoxy-1, 1'-binaphthyl, was shown to be active as a ligand in palladium-catalyzed reactions, including the reduction of allylic carbonates with formic acid, hydrosilylation of a terminal olefin, and hydroboration of but-1-en-3-yne, even though it has a highly hindered lone pair.

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In vitro evaluation of anti-tuberculosis activity was conducted for fifty-six quassinoids isolated in our laboratory from Simaroubaceous plants, Ailanthus altissima (=Aa, 10 compounds), Brucea antidysenterica (=Ba, 16 compounds), Picrasma ailanthoides (=Pa, 14 compounds), and Brucea javanica (=Bj, 16 compounds). Of the compounds tested, shinjulactone K (1), ailanthone (2), shinjudilactone (3), and dehydrobruceantin (4) were the most potent. Although the activities were very low (0-19%), the resulting data provided a picture of structure-activity relationships.

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The spherical copoly(2-bromomaleic anhydride/divinylbenzene) was prepared by suspension polymerization, and the spherical resin obtained (5-20 μm in diameter) was then hydrolyzed to a poly(hydroxycarboxylic acid) resin. This procedure resulted in a resin with a structure similar to the malic acid moiety in the polymer chain. We propose that it may be useful as a packing material for high-performance liquid chromatography.

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Phytochemical studies of Ilex macropoda led to the isolation of three new hemiterpene glycosides, 4-β-D-glucopyranosyloxy-5-hydroxyprenyl caffeate (aohada-glycoside A), 5-caffeoyloxy-4-β-D-glucopyranosyloxyprenyl alcohol (aohada-glycoside B), 4-(6-O-caffeoyl-β-D-glucopyranosyloxy)-5-hydroxyprenyl caffeate (aohada-glycoside C), together with betulin, acetyl ursolic acid, ilexosides XVII and XVIII, and 3, 4, 5-trimethoxyphenol β-D-5-O-caffeoyl-apiofuranosyl-(1→6)-β-D-glucopyranoside from the bark. Rotundioic acid, ursolic acid, ilexosides II and XXX, ziyu-glycoside I and rutin were also isolated from fresh leaves, and 3, 5-dicaffeoylquinic acid and 3, 4-dicaffeoylquinic acid from the wood.

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Twenty cardenolide glycosides were obtained from the leaves, wood and twigs of Thevetia ahouai (LINN.) A.DC., Apocynaceae. Among these, four compounds were determined to be new combinations of known aglycones and sugars, based on spectral and chemical evidence, and nine compounds were C-nor-D-homo cardenolide glycosides. The new compounds were thevetiogenin 3-O-β-gentiobiosyl-(1→4)-α-L-rhamnopyranoside, thevetiogenin 3-O-β-D-glucopyranosyl-(1→4)-α-L-rhamnopyranoside, digitoxigenin 3-O-β-D-glucopyranosyl-(1→4)-α-L-acofriopyranoside and digitoxigenin 3-O-β-D-glucopyranosyl-(1→4)-2'-D-acetyl-α-L-thevetopyranoside.

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The objective of this study was to produce polylactic acid (PLA) microspheres containing bovine insulin as a sparingly water soluble model drug using a water-in-oil-in-water (w/o/w) emulsion solvent evaporation method. The preparative conditions were optimized. Employment of smaller internal aqueous phase volume (50 μl or 100 μl) in the manufacturing process, resulted in the high loading efficiency (over 95% of theoretical insulin loading efficiency). The addition of 10% (w/v) NaCl to the external aqueous phase (0.5% polyvinyl alcohol solution) reduced loading efficiency compared to the case where no NaCl was added to the external phase. The mean volume diameter for prepared PLA microspheres was in the region of 15-25 μm in all cases. PLA microspheres containing 5% and 10% insulin theoretically exhibited burst release in the initial stage. After a three week dissolution test, the surface of the microspheres became more porous due to the degradable characteristics of PLA polymer itself. Nevertheless, about 80% of the insulin still remained undegraded in PLA microspherees. Finally, insulin-loaded PLA microspheres (corresponding to 4 I.U. insulin) were administered to normal rats subcutaneously, and the pharmacological effect (a decrease in serum glucose level) was demonstrated.

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Conjugates of Tn and sialyl Tn antigen with N-teradecanoyl L-seryl-β-alanine-containing D-glucosamine derivatives structurally related to lipid A as a immunoadjuvant were synthesized for the development of totally synthetic vaccines against cancers or HIV.

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2-Aminothiazoles, 2-aminobenzazoles, and 3-amino-1, 2, 4-triazines were deaminated using nitric oxide (NO) in the presence of a catalytic amount of oxygen to afford corresponding unsubstituted heterocycles in good yields.

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