巻号一覧
115 巻, 9 号
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加藤 隆一1995 年 115 巻 9 号 p. 661-680
発行日: 1995/09/25
公開日: 2008/05/30
ジャーナル フリーStudies on drug metabolism have opened new fields in the evaluation of drug efficacy and drug safety in experimental animals and humans, especially in the development of new drugs. The author described the history of discoveries of induction and inhibition of drug-metabolizing enzymes as a key point in the development of drug interaction studies. Studies on the sex-related differences in drug-metabolism have been important fields for understanding the sex-related toxicity and effcacy of drugs and their species differences under normal and pathological conditions. Rats are unique animals among experimental animals and humans. The activities of hepatic drug-metabolizing enzymes, especially cytochrome P450 and sulfo-transferase, are regulated through the sex-related secretion pattern of growth hormone. The drug-metabolizing enzymes convert drugs into not only inactive metabolites, but produce toxic intermediates which cause mutagenesis, carcinogenesis and drug-caused allergic reactions. The author carried out extensive studies on the metabolic activation of mutagenic-carcinogenic arylamines and demonstrated important roles of O-acetylation and O-sulfation to cause DNA damages by N-hydroxyarylamines. Pharmacogenetic studies on hamster acetyltransferase were described to understand the individual differences in polymorphic acetylation of arylamines and N-hydroxyarylamines in relation to DNA damages. Finally, the author emphasizes important roles of drug metabolism studies for the development of new drugs by showing a prototype, which has multiple metabolic pathways by multiple enzymes and this shows reduced-extents of individual differences, for increaseing efficacy and safety in a future clinical drug therapy.抄録全体を表示PDF形式でダウンロード (1676K) -
阿知波 一雄1995 年 115 巻 9 号 p. 681-699
発行日: 1995/09/25
公開日: 2008/05/30
ジャーナル フリーA new designing concept, "Respective Control Concept, "for developing highly efficient chiral bisphosphines ligands has been proposed. On the basis of our concept, new chiral bisphosphine ligands, BCPM, MCCPM, MOD-BPPM, MOD-DIOP, MOD-Degphos, MOC-BIMOP, Cy-BIMOP, etc., have been synthesized. Their rodium complexes have been formed and found to show high catalytic activity and enantioselectivity in the asymmetric hydrogenation of prochiral carbonyl and olefinic compounds leading to the practical synthesis of chiral aminoalcohols, α-amino acid derivatives and succinic acid derivatives. Furthermore, asymmetric synthesis of chiral 1, 4-dihydropyridines, barbiturates, and glycerol derivatives was realized using lipase-catalyzed reactions in organic solvents. The lipase PS mutant (FVL) was indicated to show the same hydrolytic behavior as that of lipase AH.抄録全体を表示PDF形式でダウンロード (1332K) -
川端 猛夫1995 年 115 巻 9 号 p. 700-715
発行日: 1995/09/25
公開日: 2008/05/30
ジャーナル フリーTwo topics are described concerning asymmetric synthesis utilizing enolate chemistry. The first one is stereoselective β-lactam synthesis through oxidative coupling of dienolates generated from acyclic tertiary amides. Amides 4 were converted into dienolates by treatment with two equivalents of n-butyllithium or t-butyllithium, and the dienolates were oxidized with N-iodosuccinimide (NIS) or Cu (II) acetate to form β-lactams 5 stereoselectively. The stereochemistry of β-lactam formation depends on the oxidant : NIS is cis-selective, whereas Cu (II) acetate is slightly trans-selective. By the use of optically active 1-phenylethyl-amine as a chiral auxiliary, asymmetric induction of 90% de is achieved. The product 11 was transformed to an intermediate for the synthesis of monobactam antibiotic carmonam. Chemoselective epimerization of cis-β-lactam 13 was accomplished with trifluoroacetic acid, and the resulting trans-isomer 14 was converted into an intermediate of monobactam antibiotic aztreonam. The second topic is asymmetric alkylation of enolates based on a new concept, memory of chirality. An optically active ketone 20 was treated with potassium hydride and a series of alkyl halides in the presence of 18-crown-6 to furnish optically active alkylated ketones 21 in 48-73% ee without any external chiral source. These findings contravene the accepted view that chirality at the α-carbon to carbonyl groups is lost in the corresponding enolates because the enolates themselves are achiral. To explain this phenomenon, we propose a novel concept that chirality at the α-carbon to the carbonyl group is memorized as dynamic axial chirality in the intermediate enolate, and is then regenerated as central chirality in the reaction products (memory of chirality). This mechanism was supported by trapping the enolate as methyl enol ether 27 of 65% ee. The present concept was successfully applied to the development of the asymmetric α-alkylation reactions of α-amino acid derivatives. Thus, phenylalanine derivative 33 was found to undergo asymmetric α-alkylation in up to 88% ee when treated with lithium 2, 2, 6, 6-tetramethylpiperidide followed by alkyl halides.抄録全体を表示PDF形式でダウンロード (1213K) -
出町 久美子, 前田 晴世, 藤堂 洋三, 尾島 克二, 湖景 哲雄, 今泉 弘之, 田井 賢, 中島 良文, 成田 弘和1995 年 115 巻 9 号 p. 716-731
発行日: 1995/09/25
公開日: 2008/05/30
ジャーナル フリーThe structures of light degradation products of (-)-(S)-10-(1-aminocyclopropyl)-9-fluoro-3-methyl-7-oxo-2, 3-dihydro-7H-pyrido [1, 2, 3-de] [1, 4] benzoxazine-6-carboxylic acid (T-3761) in aqueous solution and in the solid state were investigated. In aqueous solution, ten products were detected using HPLC and in the solid state, one main product was detected. All these light degradation products were isolated and their structures were elucidated. It was revealed that in almost all light degradation products only the 1-aminocyclopropyl side chain at the 10-position of T-3761 is changed to various structures by light oxidation. Surprisingly we found a unique light degradation product, in which carboxylic acid at the 6-position of T-3761 is changed to the hydroxy moiety.抄録全体を表示PDF形式でダウンロード (1429K) -
丹羽 敏幸, 竹内 洋文, 日野 知証, 川島 嘉明1995 年 115 巻 9 号 p. 732-741
発行日: 1995/09/25
公開日: 2008/05/30
ジャーナル フリーLactide/glycolide copolymer (PLGA) nanospheres with nafarelin acetate (NA) used as a model peptide-drug have been developed by the emulsion-phase separation method in an oil phase as reported previously. In the present study, the aerosolization of nanospheres in dry and wet dispersion methods was investigated in vitro to evaluate their applications to pulmonary delivery of peptidedrug. The size distribution of aerosolized nanosphere dispersions and pulmonary deposition behaviors of inhaled particles were investigated using a lazer diffraction light-scattering particle sizer and an artificial model lung (Cascade Impactor : CI), respectively. It was found that the freeze-drying of nanospheres with a hydrophilic surface active agent effectively improved the inhalation behavior. Further, the mixing of nanospheres with lactose led to the reduction of their adhesion to an inhalation device (Spinhaler). It was supposed that the mists of nanosphere-suspension generated from a jet nebulizer might be inhaled into the lower bronchus and alveolus, because their respirable fraction (RF) value, i. e., the deposition percentage on stage 2 to 6 of CI, defined as a pulmonary inhalation index, reached a maximum of over 50%.抄録全体を表示PDF形式でダウンロード (1057K) -
三上 健, 堀川 次男, 村上 知教, 佐藤 則泰, 小野 幸栄, 松本 達二, 山川 紀子, 村山 尚子, 片桐 進, 鈴木 益子1995 年 115 巻 9 号 p. 742-748
発行日: 1995/09/25
公開日: 2008/05/30
ジャーナル フリーEmetic toxin-and entero toxin-producing activities were examined for 524 strains of Bacillus cereus and 90 strains of Bacillus thuringiensis to determine the distribution and contamination in natural environment, including foods, vegetable, soil and etc. Emetic toxin was assayed by the production of acid from HEp-2 cells induced by the culture supernatants of Bacillus, which was developed as an improved method for the detection of B. cereus heat-stable emetic-toxin by us. In the 524 strains of B. cereus tested, 11 out of 60 strains obtained from bean paste and 5 out of 20 strains obtained from peach produced emetic toxin which was detected by the HEp-2 cell method. All these emetic toxin-producing isolate strains were classified into H1 serotype. The 90 strains of B. thuringiensis did not produce emetic toxin, but the 47 strains produced entero toxin.抄録全体を表示PDF形式でダウンロード (741K) -
國實 秀和, 上田 浩史, 山崎 正利1995 年 115 巻 9 号 p. 749-755
発行日: 1995/09/25
公開日: 2008/05/30
ジャーナル フリーThe tumor necrosis factor (TNF) was first discovered as a substance that induced necrosis of transplanted tumors. Recently, TNF has been recognized as an important and endogenous mediator in host defense mechanisms. To prove the fact that plant foods contain substances which activate the host defense mechanisms, we first examined if the administration of flavonoids could induce TNF production in mice. Some selected flavonoids such as naringin, apiin, poncirin and rutin were shown to amplify TNF release from murine macrophages in vivo in response to OK-432 as a second stimulus. However, their aglycone forms were not effective. The differences in the saccharide-chain of flavonoids induced the variety of TNF production.抄録全体を表示PDF形式でダウンロード (653K) -
金友 昭一, 永井 外夫, 大木 一弘, 安田 由香1995 年 115 巻 9 号 p. 756-764
発行日: 1995/09/25
公開日: 2008/05/30
ジャーナル フリーCrude surfactin was simply prepared from the culture filtrate of Bacillus natto KMD 2311 twice by acidification of the filtrate and extraction of the precipitate with ethanol. Eight surfactin analogs were isolated from the crude surfactin by RP-HPLC and gel filtration. The structure of each analog was deduced by means of amino acid composition of the acid hydrolysate and FAB-MS measurement to be a cyclic depsipeptide containing a hydroxyfatty acid. The structure of the hydroxyfatty acid moieties was elucidated as n-or iso-or anteiso-3-hydroxyfatty acid composed of carbon number 13-16 by GC analysis and EI-MS after the methanolysis of the analogs. The amino acid sequence of the peptide portion was assigned as acyl-Glu-Leu-Leu-Val-Asp-Leu-Leu by EI-MS for eight analogs. The isolated four compounds were found to be identical with the known surfactin analogs, A1, B1, B2 and C1. Although surfactin A2 and C2 had not been isolated, their structures were deduced to be a surfactin analog. Surfactin A3 and D were novel analogs. The acyl groups of surfactin A2, A3, C2 and D were anteiso-3-hydroxytridecanoic acid, n-3-hydroxytridecanoic acid, anteiso-3-hydroxypentadecanoic acid and iso-3-hydroxyhexadecanoic acid, respectively.抄録全体を表示PDF形式でダウンロード (888K) -
西岡 弘美, 林田 直美, 川邉 さおり, 原山 尚1995 年 115 巻 9 号 p. 765-772
発行日: 1995/09/25
公開日: 2008/05/30
ジャーナル フリーThe reaction of bromo-methoxysalicylaldehyde (4-6) and bromo-hydroxysalicylaldehyde (18) with carbethoxymethylenetriphenylphosphorane (2) in diethylaniline under reflux gave unexpected debromocoumarins along with an expected bromocoumarin. The oxygen function might facilitate debromination in the process of coumarin synthesis at an elevated temperature.抄録全体を表示PDF形式でダウンロード (780K)
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