A simple method for synthesis of 2-aryl-substituted 3, 3-dimethylindoline derivatives was established by the reaction of 1-acyl-2-hydroxy-3, 3-dimethylindoline with electron-rich arenes in the presence of boron trifluoride-diethly ether in dioxane. In the reaction with β-naphthol, a pair of isolable diastereomeric atropisomers was isolated. The conformations of both atropisomers were determined by single crystal X-ray analyses. The substitution reaction behavior toward various arenes was accounted for in terms of frontier molecular orbital (FMO) theory.

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Regiospecific nitration of quinoline and isoquinoline was achieved via the Reissret compounds by treatment with acetyl nitrate. Nitration of 1-benzoyl-2-cyanoquinoline (3) afforded the 3-nitro derivative, which was converted to 3-nitroquinoline by hydrolysis with concentrated HCl. Meanwhile, 2-benzoyl-1-cyano-1, 2-dihydroisoquinoline (4) was converted ultimately into 4-nitroisoquinoline-1-carboxylic acid (10) via 4-nitro-1-cyanoisoquinoline by the same procedure. A novel method for introducing a nitro group at the β-position of a heterocyclic moiety has thus been developed. Crystal structure determinations and molecular orbital calculations of the Reissert compounds, are consistent with the regiospecific nitration.

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4H-Pyrazolo[1, 5-α]indole was prepared by two pathways employing the decarbonylation of 2-formyl-4H-pyrazolo[1, 5-α]indolo and the intramolecular cyclization of 1-(2'-carboethoxyphenyl)pyrazole as key reactions. The latter of approach was found to be more practical than the former one.

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11-Amino-6, 6a, 7, 8, 9, 10, 10a, 11-octahydrodibebenzo[b, e]thiepines (6a-d) and -oxepines (7a-d) were synthesized by the Leuckart reaction of 6, 6a, 7, 8, 9, 10, 10a, 11-octahydro-11-oxodibenzo[b, e]thiepines (1a, b)and -oxepines (2a, b) followed by hydrolysis of the reaction products 4a-d and 5a-d, respectively. The four diastereomers, cis(6a-H, 10a-H)-cis(10a-H, 11-H) 6a and 7a, cis(6a-H, 10a-H)-trans(10a-H, 11-H) 6b and 7b, trans(6a-H, 10a-H)-trans(10a-H, 11a-H)6c and 7c, and trans(6a-H, 10a-H)-cis(10a-H, 11-H) 6d and 7d, were isolated and their configurations and conformations were elucidated by chemical methods together with ¹H-nuclear magnetic resonance spectroscopic and X-ray crystallographic analyses.

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Three new dammarane saponins, jujubasaponins IV-VI (1-3), in addition to zizyphus saponins I-III (4-6)and jujuboside B (7) have been isolated from the fresh leaves of Zizyphus jujuba MILL. (Rhamnaceae). Their structures were established on the basis of spectral and chemical evidence. On the bioassay of the sense of taste, all of them showed antisweet activities.

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In order to clarify the reaction mechanism of [3, 3]sigmatropic ring expansion of cyclic thionocarbonates, the 8-membered thionocarbonates (6 and 7) were synthesized by treatment of the corresponding diol monothionocarbonates (5 and 13) with lithium bis(trimethylsilyl)amide. However, reaction of 7 with meta-chloroperbenzoic acid afforded an 8-membered carbonate (14) in a quantitative yield.

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The 2-methyl-1, 2, 3-triazinium iodides 2 reacted with various nucleophiles to give the corresponding 2, 5-dihydro-adducts. When 2 was treated with potassium superoxide, it was dimerized to 5, 5'-bi(2-methyl-2, 5-dihydrotriazinyl).The 2, 5-dihydro-1, 2, 3-triazines also gave the dimers on rection with superoxide. These reactions revealed the unique dual reactivities of superoxide with triazine derivatives.

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From the fresh leaves of Hovenia dulcis THUNB., five new dammarane glycosides named hodulosides I-V (1-5)were isolated besides the khown saponins hovenoside I (6), saponins C₂, (7), E (8) and H (9) and jujuboside B (10).Their structures were determined on the basis of chemical and spectral evidence. Further nuclear magnetic resonance spectral analysis of neohesperidosyl moieties of 1 led to the conclusion that the reported shifts of C₂ and C₃ of the glucosyl part in neohesperidose should be revised. All of the compounds (1-10) showed antisweet activities.

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Anodendrosins J and K, two diesters of 4-O-glycosyl-3, 5-diprenyl-4-hydroxybenzoic acid with sucrose were obtained from the seeds of Anodendron affine, and their structures were determined by spectral and chemical means.

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Two new diprenylated flavanones, derriflavanone and epi-derriflavanone, and two new diprenylated chalcones, laxichalcone and derrichalcone, have been isolated from the roots of Derris laxiflora. Thier structures were determined on the basis of spectral and chemical evidence. The two flavanones are an epimeric mixture which can be converted to derrichalcone under basic and acidic conditions.

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Facile method applicable for large-scale preparation of sialoglycosides were developed by using Lewis acid alone or the combination of trimethylsilyl chloride and lewis acid as the activator. Glycosylation catalyzed by zinc bromide using methyl (5-acetamido-4, 7, 8, 9-tetra-O-acetyl-3, 5-dideoxy-β-D-glycero-D-glacto-2-nonulopyranosyl chlorid)onate as a glycosyl donor afforded predominantly α-sialoglycosides. In the reaction using methyl 5-acetamido-2, 4, 7, 8, 9-penta-O-acetyl-3, 5-dideoxy-β-D-glycero-D-galacto-2-nonulopyranosonate as the glycosyl donor, with tin(IV) chloride as an activator, β-sialoglycosides were obtained stereoseloctively, whereas the combination of trimethylsilyl chloride and zinc triflate as an activator afforded predominantly α-sialoglycosides.

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Five new saponins, ilexosides XX-XXIV, were isolated from the fresh bark of Ilex crenate, and their structures were elucidated on the basis of chemical and physicochemical evidence. Ilexoside XX is the 3, 28-bisdesmoside of siaresinolic acid, whereas ilexosides XXI-XXIV are those of 3β, 19α, 21α-trihydroxyurs-12-en-28-oic acid.

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Tributyltin hydride-mediated radical cyclization of the (2S)-N-(α-chloroacetyl)-2-ethenylpyrrolidines 13a, b and 15 and the bis(phenylthio)acetyl congener-14 derived from (S)-prolinol gave (1R, 7aS)-hexahyrdo1-methyl-3H-pyrrolizin-3-one (17) and its derivatives 16a, b in highly regio- and diastereo-selective manner. This radical cyclization was successfully applied to the formal total synthesis of (-)-trachelanthamidine.

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Some 2-acylmethylthio-3-cyanoindolizine derivatives having a cyano or an ethoxycarbonyl group at the 1-position were prepared and their intramolecular cyclization reactions were examined. The alkaline treatment of these polyfunctionalized indolizines in refluxing ethanol gave only 3-aminothieno[2, 3-b]indolizine derivatives in moderate to good yields regardless of the kind of 1-substituent, and the other possible alternative, a thieno[3, 2-α]indolizine derivative, could not be obtained at all. The higher reactivity of the 3-cyano group over 1-cyano and 1-ethoxycarbonyl groups coincided well with the results expected from molecular orbital calculations for the model compounds. From our present and previous results, the order (3-CN>1-CN>3-ester>1-ester) of the reactivities of electron-withdrawing groups at the 1- and 3-positions on the indolizing ring was finally estblished.

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1, 3-Dioxin-4-ones having fluorine or a trifluoromethyl group at the 5-position were used as the _π2 components in Diels-Alder reactions with 1-oxygenated dienes. Use of high-perssure conditions was the essential requisite. While the 5-flurodioxinones were photolabile, the corresponding trifluoromethyl derivatives participated as the enone components in [2+2]photocycloaddition to alkenes, Ring-opening reactions of these adducts by acetal bond cleavage gave cyclobutanes and cyclohexanes. Diels-Alder reactions of the fluorinated homochiral dioxinones having l-menthone at the acetal position with Danishefsky diene proceeded in a completely diastereoselective manner to give single adducts.

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Two new phenylpropanoids, named O-geranylsinapyl alcohol (1) and O-geranylconiferyl alcohol (2), and a new acid amide, named hazaleamide (3), were isolated from the bark of Fagara vhetza (Rutaceae), an Indonesian medicinal plant from Flores Island, Indonesia. The chemical structures of 1, 2, and 3 have been plucidated on the basis of their chemical and physicochemical properties. Among the three new compounds, hazaleamide (3) was found to show a pungent taste and to exert a moderate antimalarial activity in a in vitro test system.

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7-O-Acyl-(4a-e) and 7-O-alkylmonensins (5a-d) were prepared from monensin (1). Their lipophilicity, sodium ion permeability in human erthrocysts, antibacterial activity and effect on rat tail artery were examined. There was a correlation between lipophilicity and sodium ion permeability as well as between lipophilicity and antibacterial activity.We also found that the compound having larger sodium ion permeability, showed stronger contraction of rat tail artery. 7-O-Benzylmonensin (5c) exhibited higher lipophilicity and larger sodium ion permeability than monensin (1)among the tested monesin derivatives. In addition, antibacterial activity and contractile effect on rat tail artery of 5c were comparable to those of 1.

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An effective and short synthetyic method for 4-substituted indole derivatives was developed based on the two sequential reactions, i.e. nucleophilic addition of carbanions to common precursor molecules, 3-(1, 3-dioxolan-2-yl)-1-[1-(phenylsulfonyl)- and 1-[(4-methylphenyl)sulfonyl]-3-pyrrolyl]-1-propanones (5a, b), followed by the acid-induced cyclization reaction of the resulting adducts to form 4-substituted 1-(phenylsulfonyl)- and 1-[(4-methylphenyl)-sulfonyl]indole derivatices (4a, b). This new method makes it possible resadily to synthesize imoportant intermediates, such as methyl 1-(phenylsulfonyl)indole-4-carboxylate (15), 4-formyl-1-(phenylsulfonyl)indole (16), and methyl 1-(phenylsulfonyl)indole-4-acetate (17) for numerous indole alkaloids, as well as a potent dopamine agonist, 4-[2-(diprophlamino)ethyl]indole (21).

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A novel method for the preparation of indole derivatives that are alkoxy- and hydroxy-substituted in the benzene portion of the indole nucleus is described. The acid-induced cyclization reaction of (arylsulfonyl)pyrrole derivatives (4a, 5b, and 5a) in the presence of an appropriate alcohol gave 4-, 5-, 6-, and 7-alkoxyindole derivatives (13 and 28), respectively, where the alkoxy group was originated from the alcohol employed. As an application of the present method, a short and efficient synthesis of two dopamine agonists (34 and 44) was attained by treating appropriately functionalized pyrrole derivatives (38 and 41) with an acid in the presence of 1, 3-propanediol, followed by deprotection of alkoxy function, and subsequent reduction with lithium aluminum hydride. A reaction mechanism is also suggested for the formation of an unusual product, 4-[2-(diprophlamino)-1-hydroyethyl]-6-hydroxyindole (46) in the reduction of N, N-dipropyl-(6-hydroxy-1-phenylsulfonyl)indole-4-acetamide (40).

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A new, short-step synthesis of a β-adrenergic blocking agent, pindolol, 1-(4-indolyloxy)-3-(2-propylamino)-2-propanol, is described. The acid-catalyzed indole cyclization reaction of 4-[1-(4-methylphenyl)sulfonyl-3-phrroly]-4-oxobutanal (14) in the presence of (±)-3-chloro-1, 2-propanediol (12) and (R)-1-O-[(4-methylphenyl)sulfonyl]glycerol (24) afforded (±)-1-chloro-3-[1-(4-methylphenyl)sulfonyl-4-indolyloxy]-2-propanol (15) and (R)-(-)-3-[1-(4-methyl-phenyl)sulfonyl-4-indolyloxy]-1-[(4-methylphenyl)sulfonyloxy]-2-propanol (25). Reaction of these with isoproplamine and removal of the protecting group at the indole nitrogen gave (±)- and (S)-(-)-pindolol (3 and 4), thus constituting an efficient three-step synthesis of 3 and 4 from the readily available aldehyde (14).

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Important precursors (1 and 2) for the synthesis of 4-substituted indole derivatives were readily obtained by acid treatment of a tosylamide (13), which was prepared in a single operation by treatment of 10 with N-tosyl-N', N'-dimethylformamidine (TsN=CHNMe₂). Compound (10) was effectively synthesezed from nitromethane and acrolein by way of a nitro compound (15). A novel indole formation reaction from the tosyl-amide (13) to gain short access to 4-alkoxyindoles, such as 16, 17, 19, and 21 is presented.

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The effect of the 3-carboxylic-ester variation in 2, 2-dimethyltrimethylene 3-alkoxycarbonyl-4-aryl-1, 4-dihydro-2, 6-dimethyl-5-pyridinephosphonates (1) was investigated with relation to the calcium-antagonistic and antihypertensive activities : the analogs contaning the alkyl groups of not more than 12 carbons and an amino functionality in the carboxylic-ester moiety were synthesized to be examined for biological activities. Among them, 2-[benzyl(phenyl)amino]-ethyl 5(5, 5-dimethyl-2-oxo-1, 3, 2-dioxaphosphorinan-2-yl)-1, 4-dihydro-2, 6-dimethyl-4-(3-nitrophenyl)-3-phridine-carboxylate hydrochloride ethanol (NZ-105) showed particularly beneficial activities and was selected for further pharmacological studies and clinical development. Some aspects of the structure-activity relationships and solid-state structure of NZ-105 by X-ray crystallographic analysis were described.

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Six optical isomers of 2-(4-diphenylmethyl-1-piperaziyl)ethyl 5-(4, 6-dimethyl-2-oxo-1, 3, 2-dioxaphosphorinan-2-yl)-1, 4-dihydro-2, 6-dimethyl-4-(3-mitrophenyl)-3-pyridinecarboxylate dihydrochloride (NIP-101, 1·2HCl·2H₂O), a potent calcium antagonist, were successfully prepared by using optically active (2R, 4R)-(-)- and (2S, 4S)-(+)-2, 4-pentanediols, and cis-2, 4-pentanediol and optically active (S)-(+)-2-methoxy-2-pheylethanol. Their proton nuclear magnetic resonance investigations demonstrate that the 1, 3, 2-dioxaphosphorinane group in conformationally constrained around the C-P bond. Calcium-antagonistic and hypotensive activities of the optical isomers were examined and found to depend mainly on the absoeute configuration at a stereogenic center in the 1, 4-dihydrophridine ring rather than the configuration of the 1, 3, 2-dioxaphospyorinane moiety.

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(S)-2-[Benzyl(phenyl)amino]ethyl 5-(5, 5-dimethyl -2-oxo-1, 3, 2-dioxaphosphorinan-2-yl)-1, 4-dihydro-2, 6-dimethyl-4-(3-nitrophenyl)-3-pyridinecarboxylate ((S)-NZ-105) and R isomer were synthesized throuth the fractional crystallization of (S)-2-Methoxy-2-phenylethyl 5-(5, 5-dimethyl-2-oxo-1, 3, 2-dioxaphosphorinan-2-yl)-1, 4-dihydro-2, 6-dimethyl-4-(3-nitrophenyl)-3-pyridinecarboxylate. Calcium antagonism activity was found to reside in the S isomer from single crystal X-ray diffraction analysis

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A new series of 4-(1, 4-benzoquinon-2-yl)-4-phenylbutanamides (2) were synthesized for evaluation of their pharmacological activities. All these compounds sythesized showed singnificant antilipidperoxidation (ALP) activities with brain homogenate in rats and some of them possessed a protective effect against hypobaric hypoxia in mice.Especially, a thiomopholine derivative (21, SUN-4757) showed a wide efficacy spectrum to a variety of experimental screening assays designed for cerebral protective agents, and it had a high LD₅₀ value.

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A series of 2-(4-methylphenyl)benzothiazoles was synthesized and evaluated using an adjuvant-induced arthritic rat model. This calss of desired compounds affecting the immune response was found using hemagglutination assay.4-Acetoxy-2-(4-methylphenyl)benzothiazole (7m), KB-2683, was most potent in the adjuvant-induced arthritic rat model and selected for further evalution. In contrast to nonsteroidal antiinflammatory drugs, compound 7m showed no antiinflammatory or analgesic activities. It did, however, show an immunomodulatory activity in enhanced delayed type hypersensitivity.

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A suries of 6-alkyl- or 6-(cycloalkylalkyl)-[1, 3, 4]thiadiazolo[3, 2-α]-1, 2, 3-triazolo[4, 5-d]pyrimidin-9(3H)-ones 1b-o was synthesized from the corresponding 1, 3, 4-thiadiazol-5-animes 3b-o and the antiallergic activities of the products were evaluated. Among the compounds 6-(2-cyclohexylethyl)-[1, 3, 4]thiadiazolo[3, 2-α]-1, 2, 3-triazolo[4, 5-d]pyrimidin-9(3H)-one 1h, whose X-ray crystallographic stereostructure is shown, was found to be a promising new antiallergic agent, which has low toxicity and dual activity as a leukotriene D₄ receptor antagonist and as an orally active mast cell stabilizer.

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Various 2'-phenoxymethanesulfonanilide derivatives were synthesized and evaluated for antiinflammatory and analgesic activities. Some compounds bearing an electron-attracting substituent at the 4'-position strongly inhibited adjuvant-induced arthritis in rats and acetic acid-induced writhing syndrome in mice without causing gastro-intestinal irritation. Among them, 4'-cyano-(FK867) and 4'-acetyl-(FK3311) 2'-(2, 4-difluorophenoxy)methanesulfonanilides were selected as the candidates for further development.

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The synthesis of the 1α- and the 1β-substituted (fluoro, cyano, hydroxy and acetoxy)-methyl carbapenems having a 2(1, 3, 4-thiadiazol-2-yl)thiomethyl side chain are described, and their in vitro antibacterial activities are compared with the corresponding 1β-methyl carbapenems together with imipenem. The synthesis and antibacterial activity of the 1β-substituted (fluoro and cyano)-methyl carbapenems having 2-(1-alkyl-4-pyridinio)thiomethyl side chains are also described.

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Novel oximes were prepared from the corresponding aldehyde or ketone in the usual way, and a number of oxime esters, O-lauroyl, O-2-pyridinecarbonyl, O-nicotinoyl and O-isonicotinoyl oximes were sgnthesized by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimede (EDCI)-4-dimethylaminopyridine (DMAP) method or a mixed anhydride method, in our search for potent anti-inflammatory compounds. The anti-inflammatory activity of these compounds was assessed by the carrageenan-induced paw edema assay in rats. The oximes (4, 5, and 13), O-lauroyloxime 1L, O-nicotinoyloximes (1N, 2N, 3N, and 4N), O-isonicotinoyloxime 1I, and O-2-pyridinecarbonyloxime 7P showed higher anti-inflammatory potency than aspirin, a prostaglandin cyclooxygenase inhibitor.

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In a search for were cerebral protective agents with anti-anoxic (AA) and anti-lipid peroxidation (ALP) activities, a series of 4-arylpyrimidines, bearing an amino moiety in the C-5 position of the pyrimidine nucleus, was synthesized and tested for AA and ALP activities. Among them, 6-methyl-5-(4-methylpiperazin-1-ylcarbonyl)-4-(3-nitrophenyl)-2-phenylprimidine (41, FK360) was most effective on both assays and on arachidonate-induced cerebral edema in rats.Structure-acivity relationships in regard to AA activity of this series of compounds are also discussed.

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A series of 4-furyl-2-guanidinothiazole derivatives and related compounds were synthesized and evaluated for histamine H₂-receptor antagonist and gastric acid antisecretory activities. Among them, compounds I-17, I-48 and I-49 showed high activities in these tests. In addition, compound I-17 possessed potent inhibitory activities on each of the gastric ulcers induced by stress, ethanol and HCl-aspirin. On the other hand, compound I-48 demonstrated antimicrobial activity against Helicobacter Pylori and the potenvy was faer stronger than that of clinically used H₂-antaginists. Some structure-activity relationships are discussed.

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A series of 2, 5-disubstituted 2, 3-dihydro-1, 2, 5-benzothiadiazepin-4(5H)-one 1, 1-dioxide derivatives were prepared and evaluated for the antiarrhythmic effect on ouabain-induced arrhythmias in guinea pigs. Most of the synthesized compounds showed the antiarrhythmic activity in this primary screening system. Some of the compounds with 2-(N, N-dimethylamino)ethyl, 2-(pyrrolidin-1-yl)ethyl and 2-oxo-2-(morpholin-4-yl)ethyl moieties on the 5-position of 1, 2, 5-benzothiadiazepin-4(5H)-one 1, 1-dioxide exhibited a potent antiarrhythmic activity. THe structure-activity relationship of these compounds was discussed.

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Three new withanolides, physagulins E(1), F(2), and G(3) were isolated from the fresh berries of Physalis angulate L. (Solanaceae). Their structures were established as (20S, 22R)-15α-acetoxy-5α, 6β, 14α, 28-tetrahydroxy-1-oxowitha-2, 16, 24-trienolide-28-O-D-glucopyranoside (1), (20R, 22R)-15α-acetoxy-16β, 17β-epoxy-5α, 6β-14β-trihydroxy-1-oxo-witha-2, 24-dienolide (2) and (20R, 22R)-15α-acetoxy-16β, 17β-epoxy-5α, 6β, 14β, 28-tetrahydroxy-1-oxo-witha-2, 24-dienolide 28-O-β-D-dlucopyranoside (3) by spectroscopic means.

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he root heartwood of Dalbergia odorifera T. CHEN (Leguminosae) is a Chicese medicinal drug (Japanese name koshinko) used for a stagnant blood syndrome (stagnation of disordered blood; Japanese, oketsu). In addition to 10 known compounds, five new phenolic compounds, isomucronustyrene and hydroxyobtustyrene (cinnamylphenols), (+)-isoduartin (isoflavan), odoriflavene (isoflav-3-ene) and (-)-odoricarpan (pterocarpan) were isolated and their structures were elucidated on the basis of chemical and spectroscopic methods. Of the fifteen compounds isolated, cinnamylphenols, isoflavans, isoflavene and benzoic acid derivative significantly inhibited prostaglandin biosynthesis as well as platelet aggregation induced by arachidonic acid.

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To clarify the pharmacokinetics of absorption, distribution and excretion of ginsenoside Rb₂ (Rb₂), one of the major saponins of the root of Panax ginseng, following oral administration to rats, a tritium (³H) labeling of Rb₂ was examined. The C-12 position of Rb₂ was labeled with ³H-sodium borohydride (³H-NaBH₄) and 12-³H Rb₂ and 12-³H-epi Rb₂ was synthesized. This method of specific position labeling of Rb₂ may be applicable to other ginsenosides. In the near future, the pharmacokinetics of Rb₂ in rats may be clarified with ³H labeled Rb₂.

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4-O-(2-Hidroxy-1-hydroxymethylethyl)-dihydroconifery alcohol and its 6-p-coumaroyl-glucoside, 4-O-(1-carboxy-2-hydroxyethyl)dihydroconiferyl alcohol and rhamnosyl glucoside of 2-hydroxy safrole have been isolated from the barks of Illicium difengpi. Their structures were ditermined on the basis of the nuclear magnetic resonance spectral data and chemical evidences.

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Two new cycloartane glycosides, thalictosides A (1) and C (2), were isolated from the aerial part of Thalictrum thunbergii D.C. They were constituted of a new triterpenoidal sapogenol named thalictogenin a, that is, 3β, 22S, 26-trihydroxycycloartan-24-ene. Their structures were characterized as 3-O-β-D-quinovopyranosyl (1→6)-β-D-glucopyranosyl-(1→4)-β-D-fucopyranosyl thalictogenin a (1) and 3-O-β-D-glucopyranosyl-(1→6)-[α-L-rhamnopyranosyl-(1→2)-β-D-glucopyranosyl-(1→4)-β-D-fucopyranosyl thalictogenin a (2) on the bases of the chemical evidence and spectroscopic means.

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Fresh bulbs of Ornithogalum saundersiae were found to contain five new polyhydroxylated cholestane glycosides.Their structures were ditermined to be (22S)-cholest-5-ene-3β, 11β, 16β, 22-tetrol 16-O-α-L-rhamnopyranoside (1) and its acetyl derivatives (2 and 3), and (22S)-cholesta-5, 24-diene-3β, 11β, 16β, 22-tetrol 16-O-α-L-rhamnopyranoside (4) and its acetyl derivative (5) using spectroscopic analysis and chemical correlations. Determination of the absolute configuration at the C-22 hydroxyl position of 1 was achieved by the application of the advenced Mosher's method to the aglycon (1a) of 1, and those of 2-5 by correlating them to 1. The cholestane glycosides with an acetyl group at the C-3 hydroxyl position of the rhamnose showed potent inhibitory activity on cyclic adenosine monophosphate (AMP) phosphodiesterase.

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Gene for aminoglycoside 6'-N-acetyltransferase [AAC(6')] from Serratia sp. 45 was cloned into E. coli. The enzyme produced in E. coli carrying the recombinant plasmid was compared to the Serratia enzyme. Both enzymes acetylated the 6'-C position of amikacin, dibekacin, tobramycin, sisomicin, gentamicin C_1a and kanamycin but effected gentamicin C₁, gentamicin C₂ and micronomycin minimally. No significant difference in optimal pH, isoelectric point or molecular weight was detected. The nucleotide sequence of the gene was determined. Initiating with a GTG codon for methionine, it was composed of 552 base pair coding for 184 amino acids. The molecular weight of the enzyme was about 20418. Comparison for the amino acid sequence of this AAC(6') with the amino acid sequence of aacA4 gene from Serratia marcescens (G. Tran Van Nhieu and E. Collatz, J.Bacteriol., 169, 5708(1987)) showed 98.3% homology.

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Sphingomyelinase (SMPLC) from Bacillus cereus was modified with a polyethelene glycol (PEG) derivative, methoxypolyethylene glycol-succinimidyl succinate (ss-PEG). The molecular weight of the ss-PEG-modified SMPLC was calculated to be approx. 150 kDa by gel-filtration whreas that of the native enzyme, was 25 kDa. By this modification, the enzyme increased its thermostability and retained its hydrolytic activity toward 2-(N-hexadecanoylamino)-4-nitrophenylphosphocholine (HNP) and sphingomyelin (SM) in the mixed micelles with the surfactants such as a triton X-100 and sodium deoxycholate (SDC). However, the activity toward liposomal SM was significantly decreased, and all the enzyme activities toward bovine erythrocytes, including membraneous SM-hydrolyzing and hemolytic activities as well as the enzyme adsorption onto the erythrocyte membranes, were completely lost.

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The effect of metal ions on transcription of the ada gene of Escherichia coli which is promoted by Ada protein in the presence of methylated deoxyribonucleic acid (DNA) was examined in a reconstituted system. Their effect on the O⁶-methylguanine-DNA methyltransferase (MGTase) activity of Ada protein was also examined. Ag⁺, Cd²⁺, Cu²⁺ and Hg²⁺ severely inhibited transcription of the ada gene at a dose which inhibited neither transcription of the lacUV5 gene nor MGTase activity. Zn²⁺ inhibited both transcription and MGTase activity in the same does range. Al³⁺ and Fe³⁺ inhibited transcription of both ada and lacUV5 genes without affecting the MGTase activity of Ada protein.

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The controlled Smith degradation and limited hydrolysis of glycyrrhizan GA, a representative polysaccharide with remarkable phagocytosis-enhancing activity isolated from the stolon of Glycyrrhiza glabra L. var. glandulifera REG.et HERD. were carried out. Methylation analyses of the primary and the secondary Smith degradation products and of the limited hydrolysis product indicated that the core structural features of glycyrrhizan GA include a backbone chain composed of β-1, 3-linked D-galactose residues. Three-fifths of the galactose units in the backbone carry side chains composed of β-1, 3- and β-1, 6-linked D-galactosyl residues at position 6. Anti-complementary and alkaline phosphatase-inducing activities of the polysaccharide, periodate oxidation-reduction and the controlled Smith degradation products were investigated, and the controlled Smith degradation product showed significant activity.

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An emulsion-phase separation method was devised to prepare chitosan microcapsules containing theophylline and sodium carboxymethyl cellulose (Na CMC). The effect of acid type (acetic acid, ascorbic acid or citric acid) and Na CMC consentration on the formation, micromeritic property, release behavior and floating phenomenon of chitosan microcapsules was studied. Chitosan microcapsules prepared using an acetic acid aqueous solution as a solvent showed a more compact and less porous structure, and exhibited slow release action when compared with other chitosan microcapsules made from ascorbic acid ro citric acid. We also found that the greater the amount of Na CMC used, the slower the release and the larger the particle size of the microcapsules obtanied. The acetic acid concentration significantly influenced the formation, micromeritic property and release behavior of theophylline chitosan microcapsules containing Na CMC. When the acetic acid consentration was less than 30%, chitosan mirocapsules did not form. The particle size of the microcapsules decreased with the increase of acetic acid concentration. Moreover, the higher the acetic acid concentration used the faster was the release tate of microcapsules. The interaction between chitosan and Na CMC in microcapsules caused the formation of a water-insoluble complex, and this complex might significantly affect the formation, micromeritic property and release bahavior of chitosan mirocapsules. The acetic acid and Na CMC concentrations also played an important role in controlling the floating property of the microcapsules.

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The maximum fluxes (J_max) of β-blockers through keratinized membranes were determined in vitro and compared with their physicochemical parameters such as lipophilicity (log k'_O) and melting point (mp). Rat abdominal skin and hamster cheek pouch mucosa were used as the model membranes. Propranolol, metoprolol, timolol, pindolol, nadolol and agenolol were used as β-blockers with a variety of physicochemical characters. Linear relations of J_max with either log k'_O or mp were observed both in intact rat skin and in intact hamser cheek pouch, suggesting that the lipophilicity and thermodynamic actitvity of a drug in the crystal state primarily affect the drug's permeation through these membranes.However, the slope, dJ_max/d(log k'_O), for cheek pouch mucosa was greater than that for rat skin, corresponding to the lack of appendageal shunt pathways in cheek pouch. Penetration studies using the delipidized membranes and the isolated stratum corneum sheet of hamster cheek pouch mocosa clarified that the primary rate-limiting barrier function might exist in the lipid layer of the stratum corneum. J_max values for the tape-stripped and delipidized skins correlated with both the solubilities of drugs in the vehicle and with the mp, suggesting the polar porous characteristics of both model membranes. However, a theoretical approach confirmed that the contribution of an intracellular or aqueous pore route in the intact membrane to the permeation of drugs with lipophilic indexes is negligible.

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In the present study, a water/isopropyl alcohol system was selected as the solvent in a hydroxypropylcellulose (HPC) binder solution for the preparation of lactose granules.With a fluidized bed granulation method, the mean granule diameter increased as the adhesion tension (γcosθ) and lactose solubility increased. With an agitating granulation method, the mean granule diameter was independent of the adhesion tension and lactose solubility, but it increased as the viscosity of the binder solution increased.With both granulating methods, greanule hardness increased as the adhesion tension and lactose solubility increased, while the pore volume of the granules decreased as the adhesion tension and lactose solubility increased.The quantitative relationship between the physical properties of the granules and several properties of the solvent solution was investigated by the application of multiple regression analysis.

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The usefulness of microdialysis was examined for the chronological determination of caffeine consentration in the brain and cerebrospinal fluids (CSF) following intravenous administration of caffeine in rats. The recovery percent of caffeine by microdialysis, the concentration ratio of caffeine in the dialysate against that in the brain tissue or CSF was determined. The recovery percent was proved to be constant at 5 different steady-state plasma concentrations of caffeine (0.1-280 nmol/ml) and in different collecting periods of diaysate ranging from 30s to 10 min. The mean recovery percent in the brain and CSF were 10.9 and 13.1%, respectively. Thus, microdialysis was proved useful for determination of drug consentration in the tissue and biological fluids with time resolution of more than 30s.The microdialysis method was then applied for the chronological determination of caffeine concentration in the brain and CSF following inttavenous bolus administration. The estimated caffeine concentration in the brain and CSF was the same as those obtained by direct determination in isolated brain and CSF, respectivery. Transfer of caffeine from plasma to brain and CSF were further pharmacokinetically analyzed using a modified 2-compartment model. In this kinetic model, the transfer of caffeine between the CSF and brain was neglectid, since the mutual tranfer of caffeine was not detected in vivo experiments. Calculated curves were well fitted on observed caffeine concentrations in the plasma, brain and CSF.

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The influence of liver injury on the plasma concentrations of α₁-acid glycoprotein (AGP) and albumin was examined in several different models of chemically-induced liver injury. The plasma AGP concentration in carbon tetrachloride (CCl₄), allyl alcohol, bromobenzene, acetaminophen or N-nitrosodimethylamine-induced liver injury was increased to 2-3.5 times the normal level at 24 h after the introxication. The plasma AGP concentration was unchanged in ehtionine-induced liver injury and was markedly decreased in galactosamine-induced injury. The plasma albumin concentration was significantly decreased by the damage due to galactosamine, allyl alcohol or N-nitrosodimethylamine-induced liver injury, while no influence was observed by other hepatotoxin-induced liver injury.The plasma protein binging of propranolol was also determined in relation to the plasma concentrations of AGP and albumin in all the experimental models. Propranolol binding, expressed as bound to free ratio, showed a good correlation with the AGP concentration (r=0.940; p<0.001), but not with the albumin concentration.

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We have recently demonstrated that [³H]ohmefentanyl, a non-peptidergic opioid ligand which was suggested to cross the blood brain barrier in contrast to other peptidergic opioid ligands, bound not only to μ opioid receptor sites but also toσ sites. In order to examine whether [³H]ohmefentanyl can be used as a marker for μ sites, we investigated the effects of brain lesions on [³H]ohmefentanyl binding site densities, as compared with [³H][D-Ala², MePhe⁴, Gly-ol⁵]enkephalin ([³H]DAGO), a selecticve μ ligand. These binding site dinsities were measured by quantitative auto-rediography in the rat striatum and substantia nigra, two brian structures known to contain a high density of μ receptors, following lesions of the nigro-striatal dopaminergic pathway and striatal intrinsic neurons. Following unilateral nigral lesion with 6-hydroxydopamine, [³H]ohemfentanyl binding site densities were decreased in the patches (-35%)and matrix (-20%) of the ipsilateral striatum and in the lisioned substantia nigra pars compacta (-49%). Unilateral striatal lesion with quinolinic acid induced 72%, 61% and 50% decreases in [³H]ohmefentanyl binding in the patches and matrix of the lesined striatum and in the ipsilateral substantia nigra pars reticulate, respectively. Similar results were obtained in the binding of [³H]DAGO. Indeed, a significant linear correlation was observed between [³H]-ohmefentanyl and [³H]DAGO binding site densities. Therefore, μ opioid receptors may be mainly located on intrinsic neurons in the striatum, dopaminergic cell bodies in the substantia nigra pars compacta and nerve terminals of striatal efferents in the substantia nigra pars reticulata.The present study revealed that [³H]ohmefentanyl binding sites follow a pattern similar to that observed for μ opioid receptors in response to lesions of the nigro-striatal dopaminergic pathway and striatal intrinsic neurons. Possible binding of [³H]ohmefentanyl to σ sties may not influence changes in μ sites caused by such lesions. [³H]Ohemefentanyl may thus be a useful tool as a marker for μ opioid receptors.

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The photo-irradiation of 3, 4-bis(phenylmethyl)-2(5H)-furanone (5) in acetone or in methanol resulted in selective rearrangement of the 4-phenymethyl moiety and gave 5-phenyl-1-(phenylmethyl)-3-oxabocyclo[3.1.0]hexan-2-one (9)along with cis- and trans-3, 4-bis(phenylmethyl)dihydro-2(3H)-furanone (10a and 10b). The difference in photochemical behavior from that of β-apolignan (1) is discussed.

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