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YAKUGAKU ZASSHI, 125(6),469-489, 2005
Chugaev reaction provides access to olefins from alcohols without rearrangement through pyrolysis of O-alkyl S-alkyl dithiocarbonates (xanthates) via cis elimination. Xanthates having no β-hydrogens undergo thione-to-thiol rearrangement to give S,S-dialkyl dithiocarbonates (thiolcarbonates). Based on these backgrounds, we intended to use the dithiolcarbonates as precursors of thiols. Xanthates could be converted to the corresponding dithiolcarbonates by Lewis-acid catalysis. Pyridine N-oxides and 4-dimethylaminopyridine also catalyzed the rearrangement reaction. On the other hand, O-(2-alkenyl) S-alkyl dithiocarbonates undergo [3,3]-sigmatropic rearrangement to give the allylically rearranged S-(2-alkenyl) S-alkyl dithiocarbonates. The homoallylic xanthates gave the corresponding dithiolcarbonates on heating with phenols. Pyrolysis of allylic dithiolcarbonates caused retro-ene type reaction to give the allylic sulfides in which allylic rearrangement also occurs. Coupling of these pericyclic reactions with intramolecular Diels-Alder reaction affords a one-pot synthetic method for the construction of hydroisobenzothiophenes. The mechanisms of the cascade and related reactions are demonstrated by location of the transition states using molecular orbital calculation method at various levels of theory involving density functional theory (DFT).
Key words--allylic xanthate; [3,3]-sigmatropy; retro-ene; allylic thiol; cascade reaction; molecular orbital calculation
YAKUGAKU ZASSHI, 125(6),491-498, 2005
Protease-activated receptors (PARs), a family of G-protein-coupled seven-transmembrane-domain receptors, are activated by proteolytic unmasking of the N-terminal cryptic tethered ligand by certain serine proteases. Among four PAR family members cloned to date, PAR-1, PAR-2, and PAR-4 can also be activated through a non-enzymatic mechanism, which is achieved by direct binding of exogenously applied synthetic peptides based on the tethered ligand sequence, known as PARs-activating peptides, to the body of the receptor. Various peptide mimetics have been synthesized as agonists for PARs with improved potency, selectivity, and stability. Some peptide mimetics and/or nonpeptide compounds have also been developed as antagonists for PAR-1 and PAR-4. PARs are widely distributed in the mammalian body, especially throughout the alimentary systems, and play various roles in physiological/pathophysiological conditions, i.e., modulation of salivary, gastric, or pancreatic glandular exocrine secretion, gastrointestinal smooth muscle motility, gastric mucosal cytoprotection, suppression/facilitation of visceral pain and inflammation, etc. Thus PARs are now considered novel therapeutic targets, and development of selective agonists and/or antagonists for PARs might provide a novel strategy for the treatment of various diseases that are resistant to current therapeutics.
Key words--protease (proteinase)-activated receptor (PAR); protease; gastrointestinal tract; structure-activity relationship
YAKUGAKU ZASSHI, 125(6),499-507, 2005
Methods for the effective production of plant secondary metabolites with antitumor activity using plant cell and tissue cultures were developed. The factors in tannin productivity were investigated using culture strains producing different types of hydrolyzable tannins, i.e., gallotannins (mixture of galloylglucoses), ellagi-, and dehydroellagitannins. Production of ellagi- and dehydroellagitannins was affected by the concentrations and ratio of nitrogen sources in the medium. The formation of oligomeric ellagitannins in shoots of Oenothera tetraptera was correlated with the differentiation of tissues. Cultured cells of Eriobotrya japonica producing ursane- and oleanane-type triterpenes with antitumor activities were also established.
Key words--plant tissue culture; antitumor activity; hydrolzsable tannin; triterpene
YAKUGAKU ZASSHI, 125(6),509-515, 2005
Sambucus chinensis L. is a native perennial herb distributed throughout China. In traditional Chinese medicine (TCM), this herb is known as Lu-Ying. Ursolic acid is the major effective constituent of Lu-Ying. A rapid, sensitive, and accurate liquid chromatography-mass spectrometry (LC-MS) method for the determination of ursolic acid in rat plasma was developed and validated. Plasma samples taken from rats that had received Lu-Ying extract orally were acidified with acetic acid and then extracted with a mixture of hexane-dichloromethane-2-propanol (20:10:1, v/v/v). Separation of ursolic acid was accomplished on a C18 column interfaced with a single quadrupole mass spectrometer. The mobile phase consisting of methanol and water (95:5, v/v) was delivered at a flow rate of 1.0 ml/min. Atmospheric pressure chemical ionization was operated in negative-ion mode. Using selected ion-monitoring mode, the deprotonated molecules [M-H]− at m/z 455 and 469 were used to quantify ursolic acid and glycyrrhetic acid (internal standard), respectively. The assay was shown to be linear over the range of 10-1000 ng/ml (r≥0.9960) with a lower limit of quantification of 10 ng/ml. The method was shown to be reproducible and reliable with intraday precision below 7.8%, interday precision below 8.1%, accuracy within ±4.3%, and mean extraction recovery excess of 83.6%, which were all calculated from the blank plasma sample spiked with ursolic acid at three concentrations of 20, 200, and 800 ng/ml. The LC-MS method has been successfully applied to pharmacokinetic studies of ursolic acid after oral administration of Lu-Ying ethanolic extract (at a dose containing 80.32 mg/kg ursolic acid) to rats. The main pharmacokinetic parameters were: t1/2, 4.3 h; Ke, 0.16 1/h; tmax, 1.0 h; Cmax, 294.8 ng/ml; AUC0−t and AUC0−∞, 1007.1 ng·h/ml and 1175.3 ng·h/ml, respectively.
Key words--Lu-Ying extract; ursolic acid; pharmacokinetics; liquid chromatography-mass spectrometry
YAKUGAKU ZASSHI, 125(6),517-523, 2005
The new desiccator system with measures for the prevention of dew drops and the processing of the formaldehyde (FA) gas discharged from the final desiccator was produced, and the FA removal rate for various adsorbents was examined. For the prevention of dew drops in the desiccator, a hygroscopic bottle containing silica gel was used next to the FA gas generator, and humidity was adjusted by adjusting the interval between the FA gas outlet (a) and the desiccant (b). The removal of the harmful FA gas discharged from the final desiccator (n=5) is an important in the environmental preservation. To solve this problem, the FA gas was passed through an oxidation bottle containing KMnO4-H2SO4 solution, and it was possible to confirm the complete decomposition of the FA by increase of the CO2 and elimination of the FA. For the determination of the FA concentration in the desiccator, 100 ml air was beforehand collected using a gas collector into a 100 ml vial bottle containing 2 ml distilled water, and 50 ml of air from each desiccator was injected using a glass syringe. This was left under a slightly reduced pressure for 20 min, and the FA concentration was determined by the AHMT method. The FA removal rate after 1 h for each adsorbent (0.5 g) was 50% or more for chitin, KIMCO and silica gel. The removal efficacy for activated carbon was higher for fine particles than for coarse particles, and a dose-response relationship was established.
Key words--formaldehyde; new desiccator system; adsorbent; FA removal rate; 4-amino-3-hydrazino-5-mercapto-1,2,4-triazole (AHMT)
YAKUGAKU ZASSHI, 125(6),525-530, 2005
For the purpose of quality evaluation of magnesium oxide (MgO) tablets, we considered the dissolution test method with changes in the pH of the dissolution medium as an indicator and studied the elution behavior of MgO from commercial MgO tablets. We also studied the effects of particle size on the elution rate of MgO from MgO tablets. A dissolution test was carried out using the rotating basket method in 100 ml of the first fluid (pH 1.2). The stirring speed was set at 200 rpm. The elution behaviors of MgO from two products were markedly different. The medium pH for the sample MM (Magmit) tablet after 15 min reached 9.5 but that for ML (Maglax) tablet was 2.7 even after 60 min. The apparent solubility of MgO in 100 ml of the first fluid were, respectively, 175 mg and 100 mg when medium pH as 9.5 and 1.5. The low dissolution of ML tablets is thought to be due to the large particle size (average particle size r = 226 μm) or due to the effects of additives on elution. These results suggest that neutralizing activity after ingestion of MgO tablets and subsequent laxative effects may, when conditions after ingestion of MM tablets and after ingestion of ML tablets are compared, produce differences between them. We found that the dissolution test method with pH as an indicator is useful in assessing the dissolution behavior of MgO preparations.
Key words--quality evaluation; magnesium oxide; dissolution; disintegration; neutralization