The compounds, 3-amino-1, 4-dimethyl-5H-pyrido[4, 3-b]indole(Trp-P-1) and 3-amino-1-methyl-5H-pyrido[4, 3-b]indole (Trp-P-2), are major potent mutacarcinogens isolated from tryptophan pyrolysate. In order to investigate their interaction with DNA and effects on DNA conformation, studies involving circular dichroism, fluorescence and absorption spectroscopy and viscometric titration were performed. The results show that (a) Trp-P-1 and Trp-P-2 are potent intercalators of DNA with nearly the same specificity for the A-T and G-C (alternative purine-pyrimidine) base sequences, (b) the interaction of Trp-P-1 with the B-form of DNA is biphasic so that stiffening of the B-DNA conformation occurs over the range r ([Trp-P-1]/[DNA])=0-2.5, followed by transformation of B to the non-B conformation at r>2.5, (c) the transformation to the non-B structure is not observed for Trp-P-2, although stiffening of the B-DNA conformation similarly occurs, and (d) both Trp-P-1 and Trp-P-2 promote unwinding of the salt-induced Z-DNA to give the B-form. These data indicate that the noncovalent interaction of Trp-P with DNA is mainly dependent on the B-form conformation.

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Synthesis of a novel dual inhibitor of thromboxane A₂ synthetase and 5-lipoxygenase, 5, 7-dimethyl-6-hydroxy-2-methylamino-4-(3-pyridylmethyl)benzothiazole (E3040), was accomplished via a new coupling reaction, in which a key intermediate, (3, 6-dihydroxy-2, 4-dimethylphenyl)-(3-pyridyl)methanol, was easily synthesized in a high yield from 2, 6-dimethyl-1, 4-benzohydroquinone and 3-pyridinecarboxaldehyde in 6N hydrochloric acid. The regio isomers of 3-pyridinecarboxaldehyde also gave the corresponding coupling products in high yields.

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Lycoperdic acid [(2S, 5'S)-2-amino-3-(5'-carboxy-2'-oxo-5'-tetrahydrofuranyl)propanoic acid], isolated from the mushroom Lycoperdon perlatum, was synthesized from trans-4-hydroxy-L-proline by a six-step route involving samarium diiodide (SmI₂)-mediated formation of the spiro-γ-lactone and ruthenium tetroxide (RuO₄) oxidation of the L-proline ring system to the L-pyroglutamic acid moiety. Lycoperdic acid (1) was found to undergo hydrolysis of the γ-lactone ring in 1 N hydrochloric acid at 23°C, giving an equilibrated mixture of 1 and the corresponding hydroxy acid.

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Photocyclization reactions (γ=254nm) of γ-methyl δ-(4-hydroxybutyl) and δ-(-4-hydroxypentyl) α, β-unsaturated γ, δ-epoxy nitriles gave spiroketals and spirothers diastereoselectively, whereas reaction of δ-(6-hydroxyhexyl) nitrile allorded no cyclization product. In addition, photocyclization of nitrile bearing a carboxyl group in the δ-side-chain afforded spirolactone.

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Tow new tannins, camelliatannins C (1) and E (2), were isolated from the leaves of Camellia japonica L. (Theaceae). They were found to be complex tannins of a new type, lacking C-C bond between glucose C-1 and the aroyl (hyxahydroxydiphenoyl) group at glucose O-2.

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Forty-two triterpenoids including eight novel compounds, gammacer-16-en-3β-yl acetate (1), gammacer-16-en-3β-ol (2), gammacer-16-en-3α-ol (3), gammacer-16-en-3-one (4), pichierenyl acetate (5), pichierenone (6), isopichierenyl acetate (7) and isopichierenol (8), were isolated from the fresh roots of Picris hieracioides subsp. japonica, Compositae, and their structures were elucidated by means of spectroscopic analysis, and chemical correlations. Fifteen compounds were also obtained from the fresh aerial parts.

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Three new triterpenoids, olean-12-ene-2β, 3β, 22α-triol (1), urs-12-ene-2β, 3β, 22α-triol (2), urs-12-ene-2β, 3β, 28-triol (3), and a known one, olean-12-ene-2β, 3β, 28-triol (4), were isolated from the fresh roots of Picris hieracioides subsp. japonica, and their structures were elucidated on the basis of spectral data.

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Heating of 3-(2-aminophenylthio)-2-methoxycarbonyl-4-methyl-2-penten-4-olide with triethylamine hydrochloride gave 3, 3-dimethyl-1H, 3H-furo[4, 3-b][1, 5]benzothiazepin-1-one. Some chemical modifications of the product including [2+2]cycloaddition and 1, 3-dipolar cycloaddition to the imino group in the product were performed.

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Nine myriocin analogs, 2-epi-myriocin, 14-deoxomyriocin, Z-14-deoxomyriocin, and nor-deoxomyriocins, were synthesized from 2-deoxy-D-glucose via common intermediates used in previous myriocin and Z-myriocin syntheses. Immunosuppressive activites of those myriocin analogs on mouse allogeneic mixed lymphocyte reaction were examined, and Z-14-deoxomyriocin was found to show the most potent activity among them. The structure-activity relationships are discussed.

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The title compounds were synthesized from 3-deoxy-D-glycero-D-galacto-2-nonulosonic acid (5, KDN) by a new method which is similar to the Ritter reaction. The structures on these compounds were elucidated from the MS, elemental analysis, ¹H-NMR and ¹³C-NMR, data, and the stereochemistry of methyl 4-benzoylamino-5, 7, 8, 9-tetra-O-acetyl-2, 6-anhydro-2, 3-dideoxy-D-glycero-D-galacto-non-2-enonate (13) was determined by X-ray crystallographic analysis.

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An enzymatic method for preparation of the enantiomers of chiral diols 2a, b and their monoacetates 3a, b with 100% enantiomeric purity by using lipase-catalyzed esterification and/or hydrolysis was established, The (R)-enantiomers were more reactive in both acetylation of (±)-2a, b and hydrolysis of (±)-3a, b catalyzed by lipase OF-360 from Candida cylindracea.

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Three minor peptaibols, trichokonins (TKs)-Ia, Ib, and IX, were obtained from the culture broth of Trichoderma koningii OUDEMANS. Primary structures of these peptaibols were elucidated by ion-spray ionization mass spectrometry (ISI-MS) including the collision-induced dissociation (CID) technique together with two-dimensional nuclear Overhauser enhancement spectroscopy (NOESY).

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In order to develop efficient chiral derivatizing agents (CDAs) which can be obtained readily in optically active form, synthetic studies of α-cyano-α-fluorophenylacetic acid (CFPA) analogs, 3a-e and CFNA (14a), were made. Carboxylation of 6a-e obtained from 4a-e gave 3a-e in low yield. Alternatively, benzyl cyanides 5b-e were converted successfully to the esters 7b-e, 8b-e, and 9b-e, which were fluorinated with FClO₃ to produce the fluoro esters 10b-e, 11b-e, and 12b-d, in good yields. However, the attempted ester cleavage of these compounds did not give 3b-e. Carboxyl group introduction into 5e afforded 13, and fluorination with either F₂ or FClO₃ gave complex mixtures.Carboxylation of the naphthyl analog 16 obtained from 15 did not give 14a. However, fluorination of 18 derived from 17 proceeded readily to give 19, which was hydrolyzed to produce 14a. Optically active (-)-14a was obtained through enzymatic hydrolysis. The racemic acid 14a was condensed with three representative chiral nucleophiles to give 14b-d. From the ¹H- and ¹⁹F-NMR spectra of these derivatives, it was concluded that CFNA (14a) is potentially a much better CDA than the well known α-methoxy-α-(trifluoromethyl)phenylacetic acid (MTPA).

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From the stems of Myrica gale var. tomentosa (Myricaceae), two new diarylhyptanoids (3 and 4) were isolated together with myricanone, porson, gallic acid and myricetin 3-O-(6"-galloyl)-β-D-galactopyranoside. On the basis of spectroscopic and chemical evidence, the structures of 3 and 4 have been determined as 12-dehydroporson and 12-hydroxymyricanone, respectively. The structure of porson was reinvestigated, and a revised structure, 12-hydroxy-5-O-methylmyricanone, was proposed.

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A series of optically active substituted 1, 2-dihydro-6-oxo-pyrrolo[3, 2, 1-ij]quinoline-5-carboxylic acids was prepared via optically active 2-methyl-4, 5-difluoroindoline (10) and tested for antibacterial activities. Among them, (2S)-9-[(3R, 1'S)-3-(1'-amino)ethyl-1-pyrrolidinyl]-8-fluoro-1, 2-dihydro-2-methyl-6-oxo-6H-pyrrolo[3, 2, 1, -ij]-quinoline-5-carboxylic acid (19) showed potent activity against gram-positive bacteria and (2S)-8-fluoro-1, 2-dihydro-2-methyl-9-(3-methyl-1-piperazinyl)-6-oxo-6H-pyrrolo[3, 2, 1-ij]quinoline-5-carboxylic acid (16) exhibited well balanced in vitro activity, good intravenous efficacy, and high aqueous solubility.

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Three new lactam-conformationally restricted arginine derivatives, 1-butyl-3-(6, 7-dimethoxy-2-naphthylsulfonyl)-3-(3-guanidinoropyl)-substituted γ-, δ-, and ε-lactams (2-4), were synthesized on the basis of backbone modification of the lead structure, 6, 7-dimethoxy-2-naphthylsulfonylarginine n-butylmethylamide (1). We tested these compounds for inhibitory activity toward thrombin and other trypsin-like enzymes (trypsin, factor Xa, plasmin, and kallikrein). All the compounds synthesized (1-4) potently inhibited thrombin with IC₅₀ values of 0.75, 0.70, 0.92, and 3.2μM, respectively; they inhibited thrombin over 40-fold more effectively than the other enzymes tested. The γ-lactam (2) with the most profound inhibitory activity toward thrombin was a reversible inhibitor with a K_i of 0.26μM. Compound 2 also showed better thrombin selectivity than the lead compound (1). The lactam-conformational restriction of arylsulfonylarginine amides, especially γ-lactam, has thus proved to be a useful device for the improvement of antithrombotic activity.

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A novel series of N-substituted 3-(1H-imidazol-1-ylmethyl)indole carboxylic acid derivatives were prepared and evaluated for thromboxane A₂ (TXA₂) synthetase-inhibitory and histaminergic H₁-blocking activity. Among the compounds synthesized, indole-6-carboxylic acid derivatives showed higher activities than the other positioal isomers of carboxylic acid. 1-[3-(4-Benzhyrdyl-1-piperazinyl)propyl]-3-(1H-imidazol-1-ylmethyl)-1H-indole-6-carboxylic acid (12) had the strongest thromboxane synthetase inhibitory activity (IC₅₀=5×10^-8M) and H₁-blocking activity (IC₅₀=8×10^-9M).

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Novel N-(2-sulfonylamino-5-trifluoromethyl-3-pyridyl)carboxamide derivatives have been prepared and evaluated as phospholipase A₂ (PLA₂) inhibitors. Among these compounds, IS-741 (sodium salt of 1j), which showed the highest and the most stable therapeutic effect on acute hemorrhagic pancreatitis induced by the closed duodenal loop method in rats, was selected as a candidate for further development.

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A series of arylnaphthalene lignans were synthesized and tested for hypolipidemic activity. The most potent compound (4b) (TA-7552) not only reduced serum cholesterol, but also increased high-density lipoproteins cholesterol in rats. The effective dose of 4b is 100 times less than that of cholestyramine. Structure-activity relationships are discussed.

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Dolastatin 10 (1) is a potent antineoplastic pentapeptide. Novel dolastatin 10 analogs each modified at one of the constituent amino acid derivatives, were synthesized and their antitumor activity was evaluated against P388 leukemia in mice. The structural requirements for antitumor activity are discussed. Some of the analogs, 31c, 35c, 38b, and 50c showed excellent activity in vivo. Highly active 50c, which lacks the thiazole group of 1, was selected for further development as an antitumor agent.

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Optical isomers of TZC-1370 (1) were prepared from (R)- and (S)-1-(2-chlorophenoxy)-2, 3-epoxypropane. When given intravenously to anesthetized rats, the (S)-isomer was about 40 times more potent in terms of β-blocking activity than the (R)-isomer, while their hypotensive activities were equipotent with that of the racemic compound, TZC-1370.

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A search for potent inhibitors of release of 12(S)-hydroxyeicosatetraenoic acid (12-HETE), which plays an important role in the pathogenesis of various circulatory disorders and arteriosclerosis, led us to 6-[4-(1-cyclohexyl-5-tetrazolyl)butoxy]-3, 4-dihydro-2(1H)-quinolinone (cilostazol) and 2(1H)-quinoinone derivatives having an azole group in the side chain. Many 2(1H)-quinolilnone derivatives were synthesized and tested in vitro for the inhibitory activity in human platelets. 3, 4-Dihydro-6-[3-(1-o-tolylimidazol-2-yl)sulfinylpropoxy]-2(1H)-quinolinone (5k) was found to be one of the most potent inhibitors of 12-HETE release, being more potent than esculetin. In addition, the sulfoxide 5k showed in vivo inhibitory activity on platelet adhesion in rats. Since 5k is recemic, the enantiomers were prepared and their potencies were compared in vitro and in vivo. (S)-(+)-5k had the best pharmacological profile and was selected as a candidate drug for further development. The structure-activity relationships are discussed.

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The roots of Cynanchum caudatum M. (Asclepiadaceae) afforded eleven new pregnane glycosides which had cynanchogenin, caudatin, 12-O-benzoyllineolon and 12-O-benzoyldeacylmetaplexigenin as the aglycone moiety and 2, 6-dideoxy-3-O-methylhexopyranoses as component sugars. The structures of these compounds were elucidated by spectroscopic methods and from chemical evidence.

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Eight new eremophilenolides, 6β-angeloyloxy-3β, 9α-dihydroxyeremophil-7(11)-en-12, 8β-olide (1), 6β-angeloyl-oxy-3β, 9β-dihydroxyeremophil-7(11)-en-12, 8β-olide (2), 6β-angeloyloxy-3β, 8β, 9β-trihydroxyeremophil-7(11)-en-12, 8α-olide (3), 6β-(3'-chloro-2'-hydroxy-2'-methylbutyloyloxy)-3β-hydroxyeremophil-7(11)-en-12, 8β-olide (4), 6β-epoxyangeloyloxy-3β-hydroxyeremophil-7(11)-en-12, 8β-olide (5), 3β-hydroxy-6α-methoxyeremophil-7(11)-en-12, 8β-olide (6), 3β-hydroxy-6β-methoxyeremophil-7(11)-en-12, 8α-olide (7) and 8β-hydroxy-3-oxoeremophil-7(11)-en-12, 8α-olide (8) were isolated from the dried rhizomes of Petasites japonicus MAXIM. (Compositae) together with a new eremophilane-type sesquiterpenoid, 3β-hydroxy-8-oxoeremophil-6-en-12-oic acid methyl ester (9). Compound 4 is the first chlorine-containing eremophilenolide derivative isolated from natural sources. The structures of these compounds were elucidated by spectroscopy.

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Nafagrel hydrochloride exists as both a hemihydrate and monohydrate. Conversion from the hemihydrate to the monohydrate is not reversible, and both hydrates can coexist in stable equilibrium between 23% relative humidity (RH) and 64% RH. In order to clarify the dehydration behavior, the kinetics of the thermal dehydration of the hydrates was studied by means of isothermal gravimetry at atmospheric pressure with a controlled water vapor pressure. This revealed that dehydration did not depend on absolute humidity but on RH. The dehydration of the hemihydrate proceeded by two-dimensional gorwth of the nuclei, A₂, but the mechanism of monohydrate dehydration changed from A₂ to a two-dimensional phase boundary, R₂, with an increase in RH. The dehydration of the monohydrate proceeded by R₂, resulting in the production of the hemihydrate at 6.5% RH or above. These kinetic analyses showed that the monohydrate dehydrated faster than the hemihydrate.

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Because an amphiphile with a positive or negative charge, shch as dialkylphosphate or stearylamine, is often added to liposomal phosphatidylcholine (PC) dispersions to prevent aggregation of the liposomes, we investigated the long-term stability of liposomes prepared from saturated PC in the presence of various amphiphiles. On storage of these liposomes at 40°C, PC was gradually hydrolyzed by dialkylphosphate, a negatively charged lipid, while neither stearylamine, a positively charged lipid, nor a non-charged lipid hydrolyzed PC at all. This hydrolysis of PC was examined using dialkylphosphates of various alkyl chain lengths (C10, C12, C14, C16, C18 and C20) and PC with different fatty acyl chain lengths (C14, C16 and C18). The rate of hydrolysis was maximum when the alkyl chain length of dialkylphosphate was almost equal to the fatty acyl chain length of PC. That is, the hydrolysis of dimyristoyl (C14) and dipalmitoyl (C16) acyl chains of PC was accelerated most by the incorporation of dimyristylphosphate (C14) and dipalmitylphosphate (C16), respectively. Distearoyl (C18) acyl chains of PC were hydrolyzed effectively by the incorporation of distearylphosphate (C18) as well as dipalmitylphosphate (C16). The hydrolysis did not occur when methyl dipalmitylphosphate was added instead of dipalmitylphosphate, or when the liposomal structure was decomposed by adding ethanol. These results suggest that dialkylphosphate and PC are aligned head to tail in liposomes and that the phosphate functional group causes the hydrolysis of the esters of PC.The incorporation of cholesterol into PC bilayers suppressed the hydrolysis of PC above the phase transition temperature (T_c) of PC, but increased it below the T_c. The hydrolysis of PC by dialkylphosphate appears to depend on membrane fluidity and to be accelerated with increased membrane fluidity, because cholesterol reduces the fluidity of the liposomal membrane above the T_c and enhances it below the T_c.

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Liposomes were prepared from egg phosphatidylcholine (PC) for investigation of their long-term stability. When egg PC liposomes were incubated at 40°C, lowering of the pH was observed with a corresponding change in appearance. This pH lowering was suggested to be induced by peroxidation of the unsaturated fatty acyl chains in egg PC because : 1) the pH lowering was prevented by incorporation of α-tocopherol into liposomes or bubbling nitrogen into the liposomal dispersion at neutral pH; 2) the liposomes prepared from completely hydrogenated soya PC (CH-Soya PC) showed no change in pH under the same conditions. The relationship between the pH lowering and lipid peroxidation was also supported by the formation of thiobarbituric acid-reactive substances (TBA-RS) and the accumulation of carbonyl compounds in liposomes. The amount of TBA-RS reached a maximum after about 5 days' storage and then decreased gradually, while the pH lowering and production of carbonyl compounds in the liposomal dispersion continued for 20d. These results indicate that production of TBA-RS does not directly correlate with pH lowering in the liposomal dispersion; rather TBA-RS might be decomposed into secondary peroxidation products, such as carbonyl compounds, which may affect the pH of the liposomal dispersion.

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We investigated the in vitro drug release from mixed polymer films using lidocaine (LC), which is poorly water-soluble. The mixed polymer films consisted of various ratios of hydroxypropylcellulose (HPC) and hydroxypropylmethylcellulose phthalate (HPMCP).The effects of the presence glycyrrhizic acid (GL) or polyethylene glycol (PEG) in the films upon LC release were also studied. LC crystallinity decreased in the polymer film and this decrease was remarkable in the presence of GL, resulting in an amorphous state.During the initial stage, drug release was regarded as a zero-order dissolution. The apparent release rate constant, k_a, varied with the ratios of the two polymers and the amount of additives as well as with the pH of the test solution. The results indicated that GL enhanced the dissolution rate of LC from mixed polymer films, which may be due to the formation of an amorphous state. On the other hand, since PEG is a surfactant, the enhanced wettability of the polymer by the buffered solutions may have caused the increased dissolution rate.

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The kinetics of granule growth in fluidized bed granulation with moisture control was theoretically investigated. A population balance equation, in which moisture content was taken into consideration for the coalescence probability of two colliding granules, was proposed. The effects of damping speed and operation tiem on granule growth during moisture fixed command control were numerically examined. It was found that an increase in operation time resulted in an enlargement of granule diameter and a narrow size distribution during the damping process, but no significant growth was observed in the moisture fixed command control process. By contrast, a decrease in the operation time (large damping speed) caused small granule growth in the damping process, but a large growth in the moisture control process. The theory also showed good agreement with experimental granulation data for pharmaceutical powders.

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A study was made on the capping of tablets containing d-α-tocopheryl acid succinate. The study determined that capping occurs due to insufficient air escape from the granules during high-speed tablet compression. To prevent this, removal of air in the granules was necessary before tableting, and thus a degassing method by compaction was studied. In consideration of the long time required for the air to escape from the granules by compaction, a slow but continuous compacting force is thought to be more effective for degassing than an instantaneous high compression force. Consequently, a system to expel the air from the lubricated granules by compaction due to the weight of the upper punch itself was established before the pre-compression roller stage, and its effect was evaluated. This system achieved efficient degassing of the granules before tableting and completely prevented the capping of tablets containing d-α-tocopheryl acid succinate at a high concentration.

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The differences in biological activities among polychlorinated dibenzo-p-dioxins (dioxins) are strongly dependent on the substitution pattern of chlorine at various positions on the parent dibenzo-p-dioxin molecule. The absolute hardness, η, of dioxins shows a good correlation with the potency of biological activity and the chlorine substitution pattern. The result means that the soft dioxins have a small HOMO-LUMO gap, and are more toxic than the hard dioxins. Therefore, the values of absolute hardness, η, of dioxins can be used to predict their toxic potency (dioxin hardness). Moreover, we show that the absolute hardness-absolute electronegativity (η-χ) diagrams, as an activity coordinate, play an important role as a new measure in the assessment of the toxicity and potency of the biological activity of dioxins.

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The composition and stability constants of the complexes of Zn(II), Pb(II), Cd(II) and Cu(II) with hematoxylin have been studied using direct current polarography and differential pulse polarography. The results showed the formation of 1 : 2 (M : L) complexes for Zn(II) and Pb(II), and a 1 : 6 (M : L) complex for Cd(II). However, the formation of copper-hematoxylin complex is irreversible. The values of the formation constants for the above complexes at 298, 308 and 318K were calculated as well as the relevant thermodynamic parameters.

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In an attempt to improve the effectiveness and bioavailability of 6-mercaptopurine, various kinds of water-soluble analogues, such as 6-S-aminoacyloxymethyl mercaptopurine derivatives (3a-m) and 6-S, 9-disubstituted derivatives (7a, b and 9a, b), were synthesized. These compounds were evaluated for activity to augment antitumor immunity by using a double grafted tumor system. Antitumor activities against solid tumors (sarcoma 180 and colon 26) were also evaluated. Many compounds exhibited potent activities in both test systems. In particular, the aminopropionate derivative (3a) and the L-glutamate derivative (3f) showed significant enhancement of antitumor immunity together with potent antitumor activities.

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Stereochemical detection and separation of the enantiomers of DL-amino acids were performed using a high-performance liquid chromatograph (HPLC) equipped with a chiral column and a circular dichroism spectrophotometer as a detector. Various racemic amino acids were separated by the chiral column and all L-amino acids and D-amino acids were detected as positive and negative circular dichroism peaks, respectively. Mixtures of two amino acids, DL-norleucine and DL-norvaline, DL-phenylglycine and DL-dopa, and glycine and DL-leucine were also analyzed.

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Clerodane glycosides and flavonoids in Dicranopteris pedata and three varieties of D. linearis were investigated. All the ferns contained a new glycoside, (6S, 13S)-60[6-O-acetyl-β-D-glucopyranosyl-1(1→4)-α-L-rhamnopyranosyloxy]-13-[α-L-rhamnopyranosyl-(1→4)-β-D-fucopyranosyloxy]-cleroda-3, 14-diene, as a chemical marker of this group. Flavonoids were limited to flavonol 3-O-glycosides. The ferns and isolated flavonoids are as followes;D. pedata : afzelin, quercitrin. D. linearis var. brevis : afzelin, quercitrin. D. linearis var. tenuis : quercitrin, isoquercitrin. D. linearis var. sedastiana : astragarin, isoquercitrin, rutin, kaempferol 3-O-(4-O-p-coumaroyl-3-O-α-L-rhamnopyranosyl)-α-L-rhamnopyranosyl-(1→6)-β-D-glucopyranoside.

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The effects of cryoprotectants (sugars and polymers) on the eutectic crystallization of NaCl/water systems were studied by differential scanning calorimetry (DSC) and broad-line pulsed NMR. Thermal analysis of frozen NaCl solutions showed a melting peak of eutectic NaCl/water systems at around -21°C. The addition of various cryoprotectants inhibited the eutectic crystallization of the NaCl solution. The concentrations of polymers (dextran, polvinylpyrrolidone and Ficoll) required to inhibit eutectic crystallization were slightly higher than those of sugars (glucose, sucrose, trehalose and lactose). The proportions of liquid-phase protons present in frozen H₂O and D₂O sulutions, determined by broad-line pulsed NMR, showed that the addition of sugar inhibits eutectic crystallization of NaCl/water systems through the formation of an amorphous mixture containing NaCl, sugar and water between the ice crystals.

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The in vitro release characteristics of a model hydrophilic drug, clonidine hydrochloride, from pressure sensitive adhesive (PSA) matrices prepared by two coating methods, direct coating on a backing layer and transfer coating (coating on a liner layer and transfer of the resulting PSA onto a backing layer), with different drying temperatures were measured and evaluated. Hydrophilic polymer, polyethylene glycol (PEG), hydroxypropyl cellulose (HPC) or polyvinyl pyrrolidone (PVP) was added to the matrices to increase the drug release rate. A lower drying temperature showed a higher release rate. Each polymer increased the release rate compared to control (without polymer). A PSA matrix with HPC showed a low initial burst followed by a prolonged release, whereas those with PEG and PVP exhibited a high initial burst and a subsequent low release rate. The difference in the initial burst was related, to a considerable degree, to the affinity of the matrices against water. It was also related to the amount of drug on the matrix surface. The transfer coating and addition of HPV were useful in suppressing the high initial burst and in maintaining a high sustained release rate of the drug from the PSA matrices.

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When indigo carmine (B-2) was illuminated in the presence of phenylalanine in 0.1 M citrate buffer (pH 4.0), p-tyrosine, m-tyrosine and o-tyrosine were identified as hydroxylated products. However, ten other food colors did not form tyrosine isomers. The hydroxylation of B-2 was pH-dependent, and the maximum rate was found at around pH 4.0. Replacement of air with nitrogen gas completely prevented the formation of tyrosine isomers and the decomposition of B-2. In contrast, oxygen gas accelerated both the hydroxylation and the decomposition.The addition of superoxide dismutase or catalase to this system prevented hydroxylation. Chemical scavengers of the hydroxyl radical (HO·) prevented the hydroxylation. On the other hand, a singlet oxygen scavenger had no significant effect. The above results suggest that the formation of HO· may occur in the photochemical reaction system in the presence of B-2 under aerobic conditions, and that a superoxide radical and hydrogen peroxide may be involved in the HO· formation.

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Five hydroxylated sterols, stigmastane-3β, 6α-diol, poriferastane-3β, 6α-diol, stigmast-5-ene-3β, 4β-diol, poriferast-5-ene-3β, 4β-diol, and poriferasta-5, 25-diene-3β, 4β-diol, the latter four of which are new naturally occurring compounds, were isolated from the unsaponifiable lipid of the seed extract of Trichosanthes kirilowii MAXIM. The structures were determined by spectral and chemical methods.

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Asterriquinone (ARQ); 2, 5-bis[1-(1, 1-dimethyl-2-propenyl)-1H-indol-3-yl]-3, 6-dihydroxy-2, 5-cyclohexadiene-1, 4-dione and ARQ monoacetate are metabolites from mycelium of Aspergillus terreus IFO 6123. ARQ diacetate was converted into ARQ monoacetate by treatment with 5% aq. NaHCO₃ in pyridine at 80°C for 5 min, and the yield was 93.4%. Similarly, by treatment with 5% aq. NaHCO₃ in acetone at room temperature, 2, 5-diacetoxy-p-xyloquinone and 2, 5-diacetoxy-p-benzoquinone were converted into 2-acetoxy-5-hydroxy-p-xyloquinone (yield, 85.8%) and 2-acetoxy-5-hydroxy-p-benzoquinone (yield, 66.7%), respectively.

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Enantioselective and diastereoselective Darzens reaction mediated by chiral lithium amides was achieved between tert-butyl chloroacetate and aromatic aldehydes to give the corresponding trans-glycidic esters in up to 84% enantiomeric excess.

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Diels-Alder reactions of ethyl (E)-3-(1, 3-benzothiazol-2-yl)-3-cyanopropenoate (2) as a 1-aza-1, 3-butadiene are described. The diene (2), bearing electron-withdrawing ester group, reacts with electron-rich dienophiles (3a-d) under extremely mild conditions to give corresponding cycloadducts (4a-d) in high yields with high regio- and endo-selectivities. Treatment of 2 with electron-donating allyl alcohols (5a, b) causes tandem transesterification and intramolecular cycloaddition to afford cis-fused polycyclic systems (6a, b) in one step.

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4-[5H-2, 3-(2, 5-Dimethyl-2, 5-hexano)-5-methyldibenzo[b, e]diazepin-11-yl]benzoic acid (4) enhanced the differentiation-inducing activity of retinoic acid (1) and of a synthetic retinoid Am80 (2) toward human promyelocytic leukemia cells HL-60, although 4 alone did not induce differentiation. The synergistic effect of 4 on the activities of retinoids was also seen in suppression of proliferation of HL-60 cells.

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