Quantitative treatments for the equilibrium and kinetics of dimerizing, cyclodextrin (CD)-binding, and hydrolyzing systems in unbuffered and buffered solutions have been developed and applied to hydrolysis and pH data on the penicillin G (PCG)-CD system. By dimerization of PCG, the acidic hydrolysis of PCG is accelerated, whereas the basic hydrolysis is inhibited. This result is explicable in terms of electrostatic interactions of the PCG dimer with hydrogen ion and hydroxide ion, similar to the micellar effect on chemical reactions. In buffered solutions, the acidic hydrolysis of PCG is inhibited by all of α-, β, and γ-CDs. This is explained in terms of the reaction mechanism and the enolation of the secondary hydroxyl group of CD. γ-CD inhibits the acidic hydrolysis most effectively of the three CDs, since its binding constant is the greatest among them. The dimer of PCG can be incorporated into γ-CD, but not incorporated into α- and β-CDs. In a 154 mmol dm¹³ potassium chloride solution, the acidic hydrolysis of 5 mmol dm^-3 PCG is enhanced by α- and β-CDs. This striking result can be explained by the catalysis of hydrogen carbonate ion. A commercial sample of α-CD catalyzes the acidic hydrolysis of PCG linearly with the concentration of α-CD, whereas a purified sample catalyzes the same reaction, following Michaelis-Menten-like kinetics. CDs, particularly γ-CD, may be used as an additive for the stabilization of PCG.

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Irradiation of arenecarbothioamides with 2-methoxyfuran in benzene solution gave arene-fused aminobenzoates in moderate yields accompanied by small smounts of arylpyrroles or arylthiophenes. In the case of 2-trimethylsiloxyfuran, arenecarbothioamides gave arene-fused aminobenzoates in good yields as sole products. It was demonstrated that certain furan derivatives are potentially useful as building blocks in photoinduced benzannulation.

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Five new hopane derivatives, viz. 22, 28-epoxyhopane (1), 22, 28-epoxyhopan-30-ol (2), hopane-22, 30-diol (3), hop-22(29)-en-30-ol (4) and hop-22(29)-en-28-ol (5), were isolated along with other known triterpenoids from the rhizomes of Pyrrosia lingua. Their structures were elucidated by detailed two dimensional-NMR analysis.

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The NO-generating abilities of aromatic N-nitroso compounds (nitrosoureas, nitrosamides and nitrosamines), and N-acetyl-S-nitroso-DL-penicillamine at ambient temperature were compared by employing the Griess reaction. 3, 3-Dibenzyl-1-(4-tolyl)-1-nitrosourea showed the greatest NO-generating ability among the tested compounds. The NO-generating ability of the aromatic N-nitrosoureas and the N-nitrosamides was greater than that of the N-nitrosamines, presumably reflecting differences in electrostatic repulsion between the carbonyl oxygen and nitroso oxygen in these compounds. In addition, a conjugative effect between the aromatic ring carbon and neighboring nitrogen influences the NO-generating ability; the conjugative effect in the case of N-nitrosoureas and N-nitrosamides having an ortho-alkyl substituted aromatic ring, or N-nitrosamines having a bulky N-group, such as tert-butyl, is decreased by an increase in steric hindrance around the nitroso group. The N-NO bond then becomes more stable. The NO-generating ability was related to the reciprocal of the ID₅₀ value for growth inhibition of cultured L-5178 Y cells by the aromatic N-nitroso compounds. On the other hand, NO production from the aliphatic N-nitroso compounds was not observed under our conditions, and these N-nitroso compounds did not show effective cytotoxic activity.

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Nitrated gitoxins (4) and bufotoxin homologues with various lengths of alkyl chain at C-3 of the steroid nucleus (10) were prepared from gitoxin (1). The pharmacological activities of the resulting compounds (4 and 10) were evaluated by measurement of inhibitory effect on Na⁺, K⁺-adenosine triphosphatase (ATPase) prepared from dog kidney, positive inotropic effect (PIE) on isolated guinea-pig papillary muscle preparations, and the effect on smooth muscle using the mesenteric artery from spontaneously hypertensive rats. Most of the compounds showed a smaller contractile effect on the arterial muscle. Among these compounds, gitoxin 3''-nitrate (4g) exhibited the most desirable biological activities, such as PIE comparable to that of 1, 1.25 times wider concentration-dependent range than 1, and lack of contractile activity on vascular muscle.

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The photocycloaddition reaction of 5-phenylfuran-2, 3-dione (1a) to 2-trimethylsilyloxybutadiene proceeded in a [2s+2s] manner with high regio- and stereo-selectivities to give a 2-oxabicyclo[3.2.0]heptane-3, 4-dione 2 with 7-endo-OTMS-7-exo-vinyl stereochemistry. 5-Arylfuran-2, 3-diones (1a-e) on similar photocycloaddition with 1-phenyl-1-trimethylsilyloxyethylene gave the corresponding 7-aryl derivatives 3a-e with the same regio- and stereo-chemistries in good yields. This stereochemical result of O-endo selectivity is consistent with the prediction obtained from the stereo-selection rule proposed for the enone-olefin photocycloaddition reaction. The reaction provides an efficient method for the synthesis of poly-functionalized cyclobutane derivatives.

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Reactions of phenols and phenolic silyl ethers 5, 6, and 7 using Weitz' aminium salt, tris(4-bromophenyl)aminium hexachloroantimonate (BAHA), gave the corresponding quinone derivatives 8, 9, and 10, which may be useful synthons for obtaining quassinoids, the bitter principle of Simaroubaceous plants. Treatment of 10a with silica gel powder resulted in the intramolecular conjugate addition to afford the indanone 11 in good yield.

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A highly polar saponin mixture from pods of Acacia concinna (Leguminosae) was hydrolyzed with alkali to yield five new triterpenoidal prosapogenols named concinnosides A (6), B (3), C (7), D (4), and E (8), together with four known glycosides, acaciaside (2), julibroside A₁ (10), julibroside A₃ (9), albiziasaponin C (5), and their aglycone, acacic acid lactone (1). The structures of these new prosapogenols were elucidated based on spectroscopic means. A less polar saponin fraction from the pods gave spinasteryl glucoside and its dihydro derivative.

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Neohancoside C (1) is a new phenol glycoside isolated from Cynanchum hancockianum, which is a Chinese folk medicine having antitumor activity. The synthesis of 1, 2-acetylphenyl β-D-xylopyranosyl-(1→6)-β-D-glucopyranoside, was achieved by phase-transfer-catalyzed glycosidation using glycosyl bromide.

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Regioisomers of di(2-O-mesitylenesulfonyl)-β-cyclodextrin 2-4 were synthesized in 3, 4 times larger yields compared to those of the reported method using dibutyltin oxide/triethylamine/p-toluenesulfonyl chloride. Regioisomers of di-mannoepoxy-β-cyclodextrin 5-7 were prepared from 2-4 and converted to the corresponding di-altro-β-cyclodextrins (8-10) with two altrosides as macrocyclic units, respectively. Conformations of the altrose parts of di-altro-β-cyclodextrins were investigated by NMR, and the altroside was found to change its conformation depending on whether or not it is a member of the macrocyclic ring and its position in the ring.

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Sixteen triterpenoids including three new compounds, viz. glaucanol B acetate (1), 7β, 25-epoxyfern-8-ene (2), and 25-norfern-7-en-10β-yl formate (3) were isolated from the fresh leaves of Adiantum cuneatum. Their structures were elucidated on the basis of spectral data.

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Six new triterpenoids, neohop-18-en-12α-ol (1), 13-epineohop-18-en-12α-ol (2), neohop-13(18)-en-19α-ol (3), fern-7-en-25-ol (4), fern-9(11)-en-25-ol (5) and adian-5-en-25-ol (6) were isolated from the fresh leaves of Adiantum cuneatum, and their structures were elucidated by means of spectroscopic analysis.

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Two glycopeptides, supprescins A and B, that suppress the production of pisatin, a phytoalexin of pea, were synthesized. In the synthesis of supprescin A, condensation of 3, 4, 6-tri-O-acetyl-2-azido-2-deoxy-α-D-galactopyranosyl trichloroacetimidate or its glycosidic β isomer with N-(carbobenzoxy)-L-seryl-O-benzyl-L-seryl-glycine methyl ester was carried out in the presence of trimethylsilyl trifluoromethanesulfonate (TMSOTf) to give the monoglycosyl tripeptide derivatives. For the synthesis of supprescin B, glycosylation of 2, 3, 4, 6-tetra-O-acetyl-α-D-galactopyranosyl bromide and 1, 2, 3, 6-tetra-O-benzoyl-α-D-galactopyranose was promoted by silver trifluoromethanesulfonate (AgOTf) to provide a disaccharide derivative. The coupling of diglycosyl imidate, 2, 3, 4, 6-tetra-O-acetyl-β-D-galactopyranosyl-(1→4)-3, 6-di-O-benzoyl-2-azido-2-deoxy-D-galactopyranosyl trichloroacetimidate, and N-(carbobenzoxy)-L-seryl-O-benzyl-L-seryl-glycyl-4-benzyl-L-aspartyl-5-benzyl-L-glutamyl-O-benzyl-L-threonine methyl ester in the presence of TMSOTf afforded the diglycosyl hexapeptide derivatives. Reduction, followed by N-acetylation, and then removal of the remaining protecting groups afforded the desired supprescin B.

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A dirhodium(II)-catalyzed intramolecular C-H insertion reaction of 2-oxygen-substituted cyclohexyl diazoacetoacetates 1a-f was investigated. In contrast to the trans-2-methoxy- 1a and trans-2-(p-methoxybenzyloxy)-cyclohexyl derivatives 1b, which, upon treatment with 1 mol% dirhodium(II) tetraacetate in boiling benzene, gave a complex mixture, the trans-2-(tert-butyldimethylsilyoxy)cyclohexyl derivative 1c gave, in addition to the β-lactone 3c (16%), cis- and trans-fused octahydrobenzo[b]furan-2-ones 2c in 22 and 18% yields, respectively. Similar treatment of the cis-isomer 1d gave the β-lactone 3d as the major product (34%) and cis- and trans-fused γ-lactones 2d (7 and 18% yields, respectively) as minor products. The (1R^*, 2R^*, 3R^*)-3-benzyloxy-2-(tert-butyldimethylsilyloxy)cyclohexyl derivative 1e gave the γ-lactones 2e in 75% combined yield as a 5 : 2 mixture of cis- and trans-fused isomers, while the (1R^*, 2R^*, 3R^*)-isomer 1f afforded the trans-fused γ-lactone 2f in 62% yield as a single product.

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Several 5-(4-arylpiperazin-1-yl)-4-benzyl-1, 2-oxazin-6-ones have been synthesized and tested for analgesic activity in a visceral pain model (phenylbenzoquinone-induced writhing test=PBQ test). A good correlation has been found between the antinociceptive effects of drugs and both their lipophilic and steric properties. The most active derivatives 5c and 5f, with intraperitoneal ED₅₀ values of 10.5 and 10.3 mg kg^-1 respectively, were more extensively investigated by evaluating their analgesic activity in a somatosensory pain model (hot plate test), as well as their sedative properties. Furthermore, naloxone suppressed the effect of 5c and 5f in the PBQ test, though these derivatives were ineffective to potentiate morphine analgesia. Pretreatment with yohimbine did not significantly attenuate the analgesic effects of 5c and 5f. In addition, pretreatment with 5-hydroxytryptophan associated with carbidopa also failed to potentiate the antinociceptive effects of 5c and 5f. So, a part of the analgesic activity of 5c and 5f seems to be related to an opioidergic mechanism, especially at the μ receptor level. Molecular modeling studies performed on the opiate drug morphine and on the most stable conformer of 5f showed structural similarities between these two molecules.

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Two new series of 2-arylmethyl-1, 4-benzoquinones (2 and 3) were synthesized for evaluation of their pharmacological activities. These compounds showed significant inhibition of platelet aggregation and some of them possessed a protective effect against endothelial cell injury. Structure-activity relationship studies indicated that 2b, 2d and 3b are potent inhibitors of platelet aggregation induced by arachidonic acid (AA) with an IC₅₀ in the range of 1-10 μg/ml. Among them, 3b showed a significant inhibitory activity against endothelial cell injury caused by hydrogen peroxide (H₂O₂) at 1 μM.

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Short-term in vitro assays for tumor promoters and antitumor promoters (Epstein-Barr virus activation test) were carried out for semisynthetic quassinoids (3-7), which were obtained by esterification of the C-15 OH group of deacetylated isobrucein-B (2). All the ester derivatives showed higher antitumor promoting activity than that of the potent compound 2. A compound containing a fluorinated aliphatic ester showed the highest potency.

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A series of diesters of arylnaphthalene lignan and their heteroaromatic analogs were synthesized and evaluated for hypolipidemic activity. The diesters with modifications at C-3 showed excellent hypocholesterolemic and high-density lipoprotein (HDL) cholesterol-elevating activities. Structure-activity analysis indicated that the 2-pyridylmethyl ester 51 has the optimum activity.

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Seventy-nine aralkyl- and aralkenylamides related to piperamides were synthesized and their nematocidal activity against second-stage larvae of dog roundworm, Toxocara canis, was examined. The activity was greatly dependent on the alkyl chain length and the nature of the amine moiety, but was scarcely affected by the presence or absence of double bond(s) in the chain. The alkyl chain lengths which showed the strongest activity in a series of homologues were m=11 for the pyrrolidine amides and m=13 for the N-methylpiperazine amides. Although piperamides (3, 4-methylenedioxyphenyl homologues) showed the strongest activity among the homologues tested, methoxy substituent(s) on the aromatic ring did not have much effect on the activity. However, conversion of the methoxy group to a hydroxy group greatly decreased the activity and shortened the chain length giving the strongest activity. Calculated log P values of non-phenolic aryl-piperamides fell in the range from 3.5 to 4.5, whereas those of hydroxyphenyl-piperamides were smaller, suggesting that different mechanisms are involved in the nematocidal activity of phenolic and non-phenolic compounds.

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Three aromatic glycosides, lucumin, lucuminamide and lucuminic acid, were isolated from the seeds of Calocarpum sapota MERRILL (Sapotaceae). Their structures were established by spectroscopic methods, chemical evidence, and X-ray crystallography.

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Six new pyrrolidine alkaloids called broussonetine A, B, E, F, and broussonetinine A and B were isolated from the branches of Broussonetia kazinoki SIEB. (Moraceae). Broussonetine A, B, E and F were formulated as 2β-hydroxymethyl-3β-hydroxy-5α-(10-oxo-13-hydroxytridecyl)-pyrrolidine-4-O-β-D-glucopyranoside (1), 2β-hydroxymethyl-3β-hydroxy-5α-(9-oxo-13-hydroxytridecyl)-pyrrolidine-4-O-β-D-glucopyranoside (2), 2β-hydroxymethyl-3α, 4β-dihydroxy-5α-(1, 13-dihydroxy-10-oxo-tridecyl)-pyrrolidine (3), and 2β-hydroxymethyl-3α, 4β-dihydroxy-5α-(1, 13-dihydroxy-9-oxo-tridecyl)-pyrrolidine (4), respectively. Broussonetinine A and B (5 and 6) were also isolated and identified as the aglycones of 1 and 2. 3 and 4 exhibited a strong inhibition of α-glucosidase, β-glucosidase, β-galactosidase and β-mannosidase, while 5 and 6 showed a strong inhibition of β-galactosidase and α-mannosidase.

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A rotary type tablet machine (Correct 12 HUK-AW, Kikusui, Co., Ltd.) fitted with flat-faced punches 8 mm in diameter was used to measure the scraper pressure (SCR), a kind of shear stress, as a direct means of evaluating sticking. The shear stress between the tablet and lower punch surface was determined using a system of SCR detection (strain gauge type, Okada Seiko Co., Ltd.).SCR increased with increasing compression pressure for samples at all water contents teste. The SCR had a tendency to increase up to a water content of 3%, then showed a decrease at a high water content. This suggests that the adhesive force between particles increases with increasing water content, but for high water content, shear stress decreased due to the effect of water as a lubricant. It is assumed that the sticking ratio increases proportionally with water content until about 3%.Mean surface roughness (R_a) of tablets due to sticking showed the same relationship between SCR and water content. The SCR increased with an increasing value of R_a. Thus, it was suggested that the adhesive force between particles and the punch surface plays an important role in sticking.

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Characteristics of granulation scale-up with moisture variation were investigated using an agitation fluidized bed of four sizes (vessel diameter 125, 230, 500 and 750 mm). Agitation fluidized bed granulation was done under various levels of moisture content and the vessel sizes. Granule properties of mass median diameter, geometric standard deviation, apparent density, shape factor and friability were investigated to know the effect of moisture content on the scale-up characteristics. It was found that a linear relationship between granule mass median diameter and moisture content was observed regardless of the vessel size, however, the mass median diameter decreased as this size. The geometric standard deviation decreased with increase in moisture content, showing that granule size distribution was narrowed as granule growth progressed; the deviation increased, however, with increase in vessel size. The apparent density and shape factor tended to increase with moisture content and vessel size. It was concluded that these phenomena could be explained by the adhesion and separation force experienced by the granules during granulation. Also, the scale-up characteristics could be well explained by the moisture content.

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There is a continuing need for the development of new protecting groups for amines which can be cleaved under conditions that are mild and fundamentally different from what are already available. In this paper, we report our studies in using o-hydroxy-trans-cinnamic acid as a photo-sensitive protecting group for amines. The design takes advantage of the trans-cis photo-isomerization and the ensuing facile lactonization of o-hydroxy-cis-cinnamic acid and derivatives. We have found that both the protection and deprotection can be carried out in high yields for a variety of amines with different structural features. The deprotection reaction uses low intensity UV light (365 nm), which is fundamentally different from the conditions used for the deprotection of other commonly used amino-protecting groups. Therefore, the method complements other available methods in allowing for selective manipulation of different functional groups in a complex organic molecule.

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N-Aryl heterocyclic compounds were synthesized from aryl halides and heterocyclic compounds containing an -NHCO- moiety by using a catalytic amount (1-10 mol%) of a commercially available copper catalyst in satisfactory yields. This catalytic reaction was applicable to the synthesis of N-aryl-2-pyridone, -2-pyrrolidone, -1(2H)-isoquinolone, -1(2H)-phthalazinone, -4(3H)-quinazolinone and -1, 2, 3-benzotriazin-4(3H)-one derivatives.

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The reaction of 6-amino-2, 3-dimethylquinoxaline (1) with acetaldehyde in ethanol proceeded at refluxing temperature to give 10-ethoxy-2, 3, 8-trimethyl-7, 8, 9, 10-tetrahydropyrido[3, 2-f]quinoxaline (2), which was converted to 2, 3, 8-trimethylpyrido[3, 2-f]quinoxaline (4) and 2, 3, 8-trimethyl-7, 8, 9, 10-tetrahydropyrido[3, 2-f]quinoxaline (5) in an acidic medium. Crotonaldehyde also reacted smoothly at room temperature with 1 to afford several pyrido[3, 2-f]quinoxaline derivatives along with 4 and 5.

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Novel (1→3)-β-D-glucans (GPBCD, GPECD, GP6CD, and GP3CD) having reducing glucose side chains were prepared from a linear (1→3)-β-D-glucans (curdlan : CD) with halogeno glucose isopropylidene derivatives in dimethyl sulfoxide containing dimsyl sodium, followed by treatment with 40% trifluoroacetic acid to remove protecting isopropylidene groups. The side chain glucose moiety was linked directly or through a spacer at various positions except for its anomeric carbon.

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A hydroxylated metabolite (5a) of 7-hydroxy-1-[[[4-(3-methoxyphenyl)-1-piperazinyl]acetyl]amino]-2, 2, 4, 6-tetramethylindan (OPC-14117), which is a novel cerebroprotective agent with central nervous system-stimulating activity, was synthesized by use of a model cytochrome P-450 system. In order to confirm the structure of this compound it was prepared by another route. The structures of several metabolites (5a, 7 and 8) were identified by means of comparisons with the synthetic compounds.

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Eight compounds structurally related to protein kinase C inhibitor MDL 27032 and substituted with indole moieties were synthesized. Their activities towards protein kinase C (PKC) and protein kinase A (PKA) were determined. Their effect on PKC-mediated contraction of rat tracheal smooth muscle, their antiproliferative activity on two murine tumor cell lines, melanoma B16 and leukemia P388 and their antimicrobial activity on a gram-positive bacterium Bacillus cereus were also examined. The mammalian and bacterial cell antiproliferative activity, as well as vasorelaxant effect, observed for some of them could not be correlated to PKC or PKA inhibition. Only bulky bis-indolyl compounds exhibited biological activity in these experiments. Rigid indolocarbazoles had the strongest antiproliferative activity.

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We have developed a simple and rapid method for measuring 11 organophosphorus pesticides (dichlorvos, methidathion, salithion, malathion, fenitrothion, fenthion, parathion, diazinon, ethylthiometon, O-ethyl O-(4-nitrophenyl)phenylphosphonothioate (EPN) and chlorpyrifos) and one metabolite (3-methyl-4-nitrophenol) of fenitrothion in serum and urine of acute poisoning patients by HPLC with a diode-array detector. An aliquot of the biological sample after deproteinization by acetonitrile was injected into a C₁₈ column using acetonitrile-water as a mobile phase. The detection limits in serum and urine ranged from 0.05 to 6.8 μg/ml at a wavelength of 230 nm. This method was successfully applied to two actual cases of acute poisoning.

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Infection with Helicobacter pylori (H. pylori) plays an important role in the pathogenesis of gastritis, peptic ulcer and gastric cancer, and the ¹³C-urea breath test (¹³C-UBT) is a convenient and non-invasive method for the detection of H. pylori in the stomach. We have examined the sensitivity, specificity and accuracy of ¹³C-UBT.The ¹³CO₂/¹²CO₂ ratio was measured using infrared spectroscopy (IR) and gas chromatography/mass spectrometry (GC-MS).

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Two 3-oxo-28-norcycloartane-type triterpenes, 4-epicycloeucalenone and 4-epicyclomusalenone, and two known 3-oxo-29-norcycloartanes, cycloeucalenone and cyclomusalenone, were isolated from the n-hexane extract of the fruit peel of Musa sapientum L. (banana). The structures of the 28-norcycloartanes were determined by spectroscopic and chemical methods.

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A new class of 1-substituted diazen-1-ium-1, 2-diolates (nitric oxide donors previously known as NONOates) were obtained by preparing esters of the naturally occurring polyamines putreanine (1) and spermic acid (2) with either cholesterol or hexadecanol. The syntheses of the following compounds and the corresponding NONOates are reported : cholesterylputreanine (5), dicholesterylspermate (6), hexadecanylputreanine (7), and dihexadecanylspermate (8).

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Stereoselective 7α-hydroxylation reaction of Δ⁵-steroids by a Fe(PA; picolinate)₃/H₂O₂/MeCN system is presented. The 7α-hydroxylation reactions were achieved in 33-40% yields by addition of 30%-H₂O₂ to a solution of 3β-acetoxy-Δ⁵-steroids 1a-1d and a crystalline of Fe(PA)₃ in MeCN.

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Chiral lithium 2-aminoalkoxides ((1R, 2S)-4) were applied as chiral bases for the enantioselective Horner-Wadsworth-Emmons reaction between achiral phosphonates (2) and 4-tert-butylcyclohexanone (1). A chiral olefin ((R)-3b) was obtained in up to 52% enantiomeric excess (ee). It is shown that the formation of the lithium aldolate intermediate is reversible and is not responsible for the asymmetric induction.

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New bioactive seco-protostane and protostane-type triterpenes, alismalactone 23-acetate and alismaketone-A 23-acetate, were isolated from Chinese Alismatis Rhizoma originating from Fukien province, the dried rhizoma of Alisma orientale JUZEP. Absolute stereostructures of the new triterpenes were determined on the basis of chemical and physicochemical evidence, which included chemical correlations with the known triterpene alisol B monoacetate. Alismalactone 23-acetate and alismaketone-A 23 acetate were found to show inhibitory activity on the contractions induced by a high concentration of K⁺ in isolated aortic strips from rats.

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