A simple procedure for determining the in vitro release profile of a cataplasm for use in a quality control procedure has been developed. Since the disk assembly in the USP for patch dosage forms was unsuited for use in a release test due to penetration of the dissolution medium into the cataplasm from the screw part of the device and the cataplasm swelled, new holders were designed. In the new holder, a cataplasm is held in position by sandwiching it between a stainless-steel O-ring and a silicon O-ring on the stainless steel board, 2 acrylic boards hold the O-rings and the stainless steal board, and the entire assembly is placed at the bottom of the dissolution vessel. The release profile was determined using the “Paddle over Disk” method in USP26. Furthermore, in order to prevent the swelling of the cataplasm, artificial sweat was used as the dissolution medium. The release profiles of the nine marketed brands of cataplasm containing indomethacin, ketoprofen, and flurbiprofen, respectively, were determined over a 12-h period. By adjusting the ion concentration and volume of the media, and the release surface-area of the cataplasm exposed to each medium, the procedure was found to be reproducible for in vitro release characterization of nine marketed brands. This shows that this technique can be used as a quality control tool for assuring product uniformity.

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The purpose of the present study was to quantify the degree of suppression of the bitterness of two amino acids (L-isoleucine (L-Ile), and L-phenylalanine (L-Phe)) which could be achieved by the addition of various test chemicals, and to examine the mechanism of this bitterness suppression. The test chemicals used were two sweeteners (sucrose, aspartame), NaCl, various acidic (L-aspartic acid, L-glutamic acid), or basic (L-histidine, L-lysine and L-arginine) amino acids, tannic acid and phosphatidic acid. The combination of L-arginine (L-Arg) and NaCl together was the most effective in reducing the bitterness of 100 mM L-Ile and L-Phe solutions in human gustatory sensation tests. Even in bitterness of 0.1 mM quinine solution, L-Arg was also successful in reducing the bitterness. This bitterness-suppression effect was specific to L-Arg and not to the other basic amino acids. No comparable taste-masking effect was observed for the acidic amino acids. The artificial taste sensor failed to predict completely the bitterness-suppressing effect of L-Arg. It seems likely that the bitterness-suppressing effect of L-Arg is mediated not only by binding at the receptor site, but also elsewhere in the process of bitterness perception, such as a direct effect on the sodium channel. It is conjectured that the guanidinium group of L-Arg may interact with sodium channels in taste bud membranes.

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In search of potential anticancer drug candidates in ruthenium complexes, a series of mononuclear ruthenium complexes of the type [Ru(phen)₂(nmit)]Cl₂ (Ru1), [Ru(bpy)₂(nmit)]Cl₂ (Ru2), [Ru(phen)₂(icpl)]Cl₂ (Ru3), Ru(bpy)₂(icpl)]Cl₂ (Ru4) (phen=1,10-phenanthroline; bpy=2,2′-bipyridine; nmit=N-methyl-isatin-3-thiosemicarbazone, icpl=isatin-3-(4-Cl-phenyl)thiosemicarbazone) and [Ru(phen)₂(aze)]Cl₂ (Ru5), [Ru(bpy)₂(aze)]Cl₂ (Ru6) (aze=acetazolamide) and [Ru(phen)₂(R-tsc)](ClO₄)₂ (R=methyl (Ru7), ethyl (Ru8), cyclohexyl (Ru9), 4-Cl-phenyl (10), 4-Br-phenyl (Ru11), and 4-EtO-phenyl (Ru12), tsc=thiosemicarbazone) were prepared and characterized by elemental analysis, FTIR, ¹H-NMR and FAB-MS. Effect of these complexes on the growth of a transplantable murine tumor cell line (Ehrlich Ascites Carcinoma) and their antibacterial activity were studied. In cancer study the effect of hematological profile of the tumor hosts have also been studied. In the cancer study, the complexes Ru1—Ru4, Ru10 and Ru11 have remarkably decreased the tumor volume and viable ascitic cell count as indicated by trypan blue dye exclusion test (p<0.05). Treatment with the ruthenium complexes prolonged the lifespan of Ehrlich Ascites Carcinoma (EAC) bearing mice. Tumor inhibition by the ruthenium chelates was followed by improvements in hemoglobin, RBC and WBC values. All the complexes showed antibacterial activity, except Ru5 and Ru6. Thus, the results suggest that these ruthenium complexes have significant antitumor property and antibacterial activity. The results also reflect that the drug does not adversely affect the hematological profiles as compared to that of cisplatin on the host.

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The pyrazoline derivative edaravone is a potent hydroxyl radical scavenger that has been approved for attenuation of brain damage caused by ischemia-reperfusion. In the present work, we first determined the rate constant, k_r, at which edaravone scavenges radicals generated by a Fenton reaction in aqueous solution in the presence of the spin trap agent, 5,5-dimethyl-1-pyrroline-N-oxide (DMPO), which competed with edaravone. We detected the edaravone radicals in the process of hydroxyl radical scavenging and found that edaravone reacts with hydroxyl radical around the diffusion limit (k_r=3.0×10¹⁰ M⁻¹ s⁻¹). The EPR (electron paramagnetic resonance) spectrum of the edaravone radical was observed by oxidation with a horseradish peroxidase–hydrogen peroxide system using the fast-flow method. This radical species is unstable and changed to another radical species with time. In addition, it was found that edaravone consumed molecular oxygen when it was oxidized by horseradish peroxidase (HRP)–H₂O₂ system, and that edaravone was capable of providing two electrons to the electrophiles. The possible mechanisms for oxidation of edaravone were investigated from these findings.

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Methyl 5-amino-1H-[1,2,4]triazole-3-carboxylate hydrochloride (1) and free ester (2) were obtained and 2 was reacted with Ac₂O to give the acetylated products 3—6. Compounds 1—6 were studied using HPLC, GC-MS, FTIR and multinuclear NMR spectroscopy, including the cross-polarisation magic angle spinning (CPMAS) technique. The results of the acetylation of 2 were compared to those of the acetylation of 5-amino-1H-[1,2,4]triazole, and for 2 a significant decrease in the susceptibility to acetylation was found. The reaction of 2 with Ac₂O at 20 °C, regardless of the amount and the concentration of the latter, including neat Ac₂O, proceeds fully regioselectively and leads to one product: methyl 1-acetyl-5-amino-1H-[1,2,4]triazole-3-carboxylate (3). In sharp contrast to 5-amino-1H-[1,2,4]triazole, neither an additional monoacetylated isomer, whether annular or exocyclic, nor any diacetylated derivative could be detected. The diacetylation of 2 requires the process to be carried out in neat boiling Ac₂O and, as in the case of 5-amino-1H-[1,2,4]triazole, gives two diacetylated isomers. These are methyl 1-acetyl-3-(acetylamino)-1H-[1,2,4]triazole-5-carboxylate (4) and 1-acetyl-5-(acetylamino)-1H-[1,2,4]triazole-3-carboxylate (5). Hypothetical pathways of their formation have been suggested. A mixture of 4 and 5 upon hydrolysis of the ring acetyl group gives the monoacetylated derivative methyl 5-(acetylamino)-1H-[1,2,4]triazole-3-carboxylate (6). The spectroscopic, structural and conformational characteristics of compounds 1—6 have been given and methods for their preparation have been provided.

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The protective effects of saccharides with various molecular weights (glucose, maltose, maltotriose, maltotetraose, maltopentaose, maltoheptaose, dextran 1060, dextran 4900, and dextran 10200) against lyophilization-induced structural perturbation of model proteins (BSA, ovalbumin) were studied. Fourier transform infrared (FT-IR) analysis of the proteins in initial solutions and freeze-dried solids indicated that maltose conferred the greatest protection against secondary structure change. The structure-stabilizing effect of maltooligosaccharides decreased in increasing the number of saccharide units. Larger molecules of dextran also showed a smaller structure-stabilizing effect. Increasing the effective saccharide molecular size by a borate–saccharide complexation reduced the protein structure-stabilizing effect of all of the saccharides except glucose. The results indicate that the larger saccharide molecules, and/or the complex formation with borate ion, reduce the free and accessible hydroxyl groups to interact with and stabilize the protein structure by a water-substitution mechanism.

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The synthesis of a series of mini double-stranded peptides containing chiral–x-Phe–y-Phe–peptide residues and the diastereomeric selective effects of these compounds on Escherichia coli NIHJ JC-2 and Staphylococcus aureus FDA 209P growth are described. In the case of bis(y-Phe–x-Phe)-N,N-ethane-1,2-diamine, bis(y-Phe–x-Phe)-N,N-buthane-1,4-diamine, bis(y-Phe–x-Phe)-N,N-hexane-1,6-diamine, and bis(y-Phe–x-Phe)-N,N-dodecane-1,12-diamine, etc., the four configurations, (L-, L-), (D-, L-), (L-, D-) and (D-, D-), where the symbols x- and y- represent optical isomers with L- and D- forms, were used to investigate the relationship between chirality and antibacterial activity. The level of activity increased in the following order: (L-, L-)<(D-, D-)<(L-, D-)<(D-, L-). The data show that (D-, L-) chilarity is more potent than (L-, L-) chilarity. Then, these results suggest that the –y-Phe–x-Phe Phe–sequence in the double-stranded peptide has anti-bacterial activity and the chirality of –y-Phe–x-Phe affects the anti-bacterial activity. Our results show that the uptake by penetration through the membrane of bis(y-Phe–x-Phe)₂-Spacers is a first step in the expression of anti-bacterial activity. This study provides new insights in the chirality-antibacterial activity relationships of a series of mini double-stranded peptides.

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The sulfoxides 7b and 7d carrying thiophene or benzothiophene as heteroaromatic nucleophiles, when treated with trifluoroacetic anhydride at room temperature (Pummerer reaction), underwent an intramolecular alkylation in an exclusive manner to yield 4,5,6,7-tetrahydro-7-methyl-4-phenylsulfanylthieno[2,3-c]pyridine-6-carbaldehyde (10) and the corresponding benzothiophene derivative (12b) in high yields, respectively. Thus, this route provides biologically interesting nitrogen heterocycles (1b) and (2b). On the other hand, the sulfoxide (7c) carrying benzofuran as a nucleophile on reaction with TFAA yielded not only the Pummerer-type cyclization product (12a), but also the diastereoisomeric tandem cyclization products (13) and (14) having a noble 11-aza-2-oxa-7-thiatricyclo[4.3.3.0^1,5]dodecane ring system (B). The formation of these products can be readily rationalized by the intervention of the oxonium ion intermediate (21).

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In gas liquid chromatography (GLC), the relative retention values log γ was mainly expressed by van der Waals energy (the sum of the dispersion E_dis and repulsive E_rep energies) to the interactions between monosubstituted benzene derivatives and the nonpolar stationary liquid as squalane. The single exception was that of anilines, and it was corrected by the electrostatic energy (E_ES) due to C–H/π hydrogen bond. When the stationary liquid changed from the nonpolar to polar, log γ was estimated by the inductive interaction energy (included in E_ES) in addition to the sum of E_dis and E_rep. In the benzene solution, the relative equilibrium values log K/K_o introduced from the interactions between phenol and substituted benzene derivatives were estimated by E_ES. The E_ES of COCH₃, CO₂C₂H₅ groups is especially originated in the excited dipole moments μ_e. The relative frequency values log ν/ν_o derived from O–H or O–D stretching vibration of phenol or methanol-D gave the correlation to E_ES as well as log K/K_o. That of anilines–methanol-D however had been out of a linear relation to E_ES. The cause is concluded that the aniline–methanol-D is making the proton transfer structure from the discussion about the proton affinity (PA) of the base.

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Capillary zone electrophoresis (CZE) mobilities of fifteen anthocyanins in bilberry extract were completely characterized. Four minor anthocyanins in bilberry extract (malvidin 3-O-α-L-arabinopyranoside (Mv 3-ara), peonidin 3-O-β-D-galactopyranoside (Pn 3-gal), peonidin 3-O-α-L-arabinopyranoside (Pn 3-ara), and petunidin 3-O-α-L-arabinopyranoside (Pt 3-ara)) that remained unidentified in our previous CZE study were isolated from the bilberry extract, and the chemical structures were assigned by NMR and MS. Their CZE mobilities were then precisely examined together with those of other major anthocyanins in the extract. When the CZE mobilities of the fifteen anthocyanins assigned here were plotted against their molecular weight/numbers of free phenolic group, it was found that separation of anthocyanins by CZE is primarily determined by the type of conjugated sugar present, and secondly by the aglycon structure.

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Five new triterpenoid monodesmosides (sinocrassulosides I—V, 1—5) and six bisdesmosides (sinocrassulosides VI—XI, 6—11), in which 2—11 possess different acyl groups in the glycosidic moieties, were isolated from the roots of Sinocrassula asclepiadea FRANCH. Sinocrassulosides VI (4) and V (5) also contained a novel A-seco aglycone in their structures. All of the structures were determined on the basis of spectroscopic and physicochemical evidence.

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Four new compounds 1—4 were obtained from an oxidative coupling reaction of (E)-isorhapontigenin using FeCl₃ as oxidant. Their structures and stereochemistry were determined on the basis of spectroscopic evidence [UV, IR, MS, ¹H-, ¹³C-NMR, NOE and 2D NMR], and their possible formation mechanisms were also discussed, respectively.

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Nilvadipine (NIL) solid dispersion using crospovidone (Cross-linked-N-vinyl-2-pyrolidone, cl-PVP) and methylcellulose (MC) as carriers was applied to tablet formulation. Several grades of cl-PVP and MC were used, and their influence on tablet properties such as hardness, disintegration, dissolution and chemical stability were investigated. The agitation granulation method was used for preparation of solid dispersion granules, and the granules were compressed using a rotary tableting machine, and finally the obtained tablets were coated with film. As the particle size of cl-PVP decreased, hardness and apparent solubility were increased, while dissolution rate was lowered. When a higher viscosity grade of MC was used, hardness and dissolution rate were increased, and apparent solubility did not change. All batches of tablets were chemically stable at 40 °C, 75% relative humidity (R.H.) for six months. Finally, tablets with enhanced dissolution properties were obtained by using Polyplasdone XL-10 and Metolose SM-25 as the grades of cl-PVP and MC, respectively. These formulation tablets showed higher solubility and dissolution rate during storage as well as initial indicating good physical stability.

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Reactions of α-tellanyl-β-ethoxyvinyl lithiums of aldehydes and ketones proceeded in good to high yields and the successive treatment with acids gave the α-tellanyl α,β-unsaturated aldehydes. α-Tellanyl α,β-unsaturated aldehydes easily transformed to more useful compounds.

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Quaternary ammonium benzocycloheptene compound 1 has previously been reported as a clinical candidate for an injectable CCR5 antagonist. In order to develop an orally active CCR5 antagonist, derivatives of tertiary amine benzocycloheptene 2, the chemical precursor to 1, were investigated. The benzocycloheptene ring was converted to benzothiepine and benzazepine rings and it was found that these changes could enhance the potency of tertiary amine derivatives. In particular, the 1-benzothiepine-1,1-dioxide 11b and the N-methyl-1-benzazepine 18 showed increased activity and good preliminary pharmacokinetic properties. The synthesis of 1-benzothiepine and 1-benzazepine derivatives and their activity are described.

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A modification of the conventional static head-space gas chromatography method (SHSGC method) to determine stability constants for 1-alkanol/α-CD inclusion complexes was investigated. The 1 : 1 stability constants determined by this modified SHSGC method are in reasonable agreement with the corresponding values reported previously. The modified SHSGC method precludes the necessity of the calibration curve by the use of Henry's law constant of guest. Consequently, the modified SHSGC method is more advantageous than the conventional SHSGC method because the experimental time required for determination of the stability constant is markedly reduced.

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New synthesis approaches that have led to a series of novel tetrahydrodibenzo[b,f]furo[2,3-d]oxepin derivatives are described. According to preliminary data these novel tetracycles can be useful intermediates for the preparation of potential new therapeutic agents.

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The catalytic activity for the decomposition of hydrogen peroxide by anion-exchangers modified with metal complexes of thiacalix[4]arenetetrasulfonate (Meⁿ⁺-TCAS[4], Meⁿ⁺=Mn³⁺, Mn²⁺, Fe³⁺, Co³⁺, Co²⁺, Cu²⁺, Zn²⁺ and Ni²⁺) was investigated. As a reference, calix[4]arenetetrasulfonate, calix[6]arenehexasulfonate and calix[8]areneoctasulfonate were also examined. Mn³⁺- and Fe³⁺-TCAS[4] on the modified anion-exchangers showed high catalytic activity in alkaline buffer solutions among metal complexes tested. Mn³⁺- and Fe³⁺-TCAS[4] on the modified anion-exchangers exhibited high and constant levels of catalytic activity even after having been used 5 times, and showed catalytic activity in the presence of an excess of H₂O₂ over Mn³⁺- and Fe³⁺-TCAS[4] on the modified anion-exchangers. Only Mn³⁺-TCAS[4] on the modified anion-exchangers exhibited high catalytic activity at around a neutral pH.

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Enzymatic glycosidation of twenty-one kinds of alcohols (n-hepanol, n-octanol, 2-phenylethanol, 3-phenylpropanol, 4-phenylbutanol, 5-phenylpentanol, 6-phenylhexanol, furfury alcohol, 2-pyridinemethanol, isobutanol, isopentanol, p-methoxycinnamylalcohol) including secondary alcohols (isopropanol, cyclohexanol, 1-phenylethanol) and 1,ω-alkanediols (1,5-pentanediol, 1,6-hexanediol, 1,7-heptanediol, 1,8-octanediol, 1,9-nonanediol), salicyl alcohol and 4-nitrophenyl β-D-glucopyranoside (5) using β-glucosidase from almonds stereoselectively gave the corresponding β-D-glucopyranosides in moderate yield.

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Eight compounds were isolated from Oxytropis myriophylla. On the basis of spectral analyses, their structures were elucidated to be (6R,9R)-roseoside (1), (6R,9S)-roseoside (2), adenosine (3), myriophylloside B (4), myriophylloside C (5), myriophylloside D (6), myriophylloside E (7), and myriophylloside F (8). Five flavonoids (4—8) were new compounds, and the three known compounds were isolated from this plant for the first time.

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The bromination/dehydrobromination reactions of ethyl 3-[1-alkoxycarbonyl-2-(methylthio)indolizin-3-yl]acrylates were reinvestigated. Reactions of the title compounds with two equivalents of bromine, followed by heating of the resulting reaction mixture and then treatment with a base gave the unexpected dialkyl 7-bromothieno[2,3-b]indolizine-2,9-dicarboxylates, while similar reactions using benzyltrimethylammonium tribromide as a brominating agent afforded only non-brominated thieno[2,3-b]indolizine derivatives, which were converted to the corresponding 7-bromo derivatives upon further treatment with bromine.

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6-Hydroxy-7-methoxyisoquinolinemethanol (15) and mimosamycin (1) were recently isolated from a marine sponge, Haliclona sp. The former was prepared in ten steps from vanillin (22) in 26% overall yield using an isopropyl for phenol protection.

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A simple method for the diastereoselective synthesis of racemic 1,2-diol mediated by low-valence niobium generated in situ is described. A 1,4-dioxane-toluene solvent system was found to be essential to achieve higher selectivities and to prevent other reactions of pinacols, such as deoxygenation and acetal formation. Aromatic aldehydes and ketones were converted to the corresponding pinacols with up to 97 and 85% de, respectively.

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A novel iridoid, (4R)-4-hydroxymethylboschnialactone (1), has been isolated from Boschniakia rossica, together with three previously known compounds, (24S)-3β-hydroxy-24-ethylcholest-5-en-7-one (2), (24R)-3β-hydroxy-24-ethylcholest-5-en-7-one (3) and methyl p-coumarate, using column chromatography. The structures of compounds were elucidated by spectroscopic methods.

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