YAKUGAKU ZASSHI
Online ISSN : 1347-5231
Print ISSN : 0031-6903
ISSN-L : 0031-6903
126 巻, 8 号
選択された号の論文の13件中1~13を表示しています
総説
  • 鮫島 啓二郎
    2006 年 126 巻 8 号 p. 529-542
    発行日: 2006/08/01
    公開日: 2006/08/01
    ジャーナル フリー
      This review describes my work in the field of polyamine research for the last 35 years. My research started with developing the improved synthesis of decarboxylated S-adenosylmethionine and then moved to the purification of spermidine synthase from rat prostate. I also took considerable efforts to find the synthetic procedure for various polyamines with high yield in order to prepare 15N-labeled polyamines. On the basis of these methodological work, I searched for the inhibitor of spermidine synthase and found trans-4-methylcyclohexylamine (MCHA), the most effective one at the present time. I also developed a new analytical method for polyamines using stable isotope and ionspray ionization mass spectrometry (IS-MS). Based on these studies I examined the role of polyamines in liver regeneration and found that oral administration of MCHA effectively changed the concentration of polyamines and inhibited the hepatic growth. I also found the close relationship between the concentration ratio of spermidine to spermine and the extent of liver regeneration. These results may shed new light on the control of cell growth by polyamine in vivo.
  • 原山 尚
    2006 年 126 巻 8 号 p. 543-564
    発行日: 2006/08/01
    公開日: 2006/08/01
    ジャーナル フリー
      This review covers the concise synthesis of simple coumarin with salicyl aldehydes and Wittig reagent, and a convenient synthesis of polycyclic aromatic heterocyclic compounds using the aryl-aryl coupling reaction of aryl benzamides and aryl benzoates with a Pd reagent is presented. In the first section, the reactions of salicyl aldehydes with OMe, OH, Br, CO2Me, and NO2 groups with carbethoxymethylenetriphenylphophorane are described. Specifically, the reaction of 3-nitrosalicylaldehyde with amines gave benzoxazoles in moderate yield. In the second section, the syntheses of benzo[c]phenanthridine alkaloids, quinazoline alkaloids, and graphislactones in the Pd-mediated biaryl coupling reaction are described. Moreover, the synthesis of benzonaphthazepine and pyrrolophenanthridine alkaloids utilizing regioselective C-H activation with intramolecular coordination of a benzylamine to Pd is described, and the effects of oxygen substituents in the benzoyl part of benzanilides on the coupling position in its biaryl coupling reaction are presented. An effective Pd reagent for the coupling reaction of aryl tolyflate and arene was developed.
  • 中山 貢一
    2006 年 126 巻 8 号 p. 565-577
    発行日: 2006/08/01
    公開日: 2006/08/01
    ジャーナル フリー
      Mechanoreception and subsequent cellular/molecular mechanisms of signal transduction pathways in response to mechanical stresses, including hemodynamic factors, passive stretching, and exercise, are ubiquitous in living organisms. Of these, the cardiovascular system involving the heart and blood vessels is known to be particularly sensitive to mechanical stimuli, for example, stretching and intraluminal pressurization, which might mimic an acute and/or chronic change in blood pressure and flow, induce a variety of responses including contraction, activation of various kinases and ionic channels, production of vasoactive substances, gene expression, and phenotype changes. We have started to clarify the mechanisms underlying this basic principle in the cardiovascular system as it is now generally considered that obesity and a lack of exercise are serious risk factors for cardiovascular diseases such as hypertension, atherosclerosis, and type 2 diabetes. We further extended our research field of mechanotransduction into adipocytes, skeletal muscle cells, and pancreatic beta cells, all of which are related to the core concerns in cardiovascular disease, including the so-called metabolic syndrome. In the present article, we discuss briefly the prologue to our study of mechanotransduction and several topics in the recent progress in this interesting area. We also emphasize that it is important to recognize biomechanical factors and control them not only for improvement in our knowledge of health and disease but also for the development of new drugs.
  • 市川 聡
    2006 年 126 巻 8 号 p. 579-595
    発行日: 2006/08/01
    公開日: 2006/08/01
    ジャーナル フリー
      Some of nucleoside antibiotics include complex structures as well as sensitive functionality, which are challenging targets for organic chemists. Among complex nucleoside antibiotics, there are also good drug candidates because they possess a variety of interesting biological properties. Herbicidin B and fully protected tunicaminyluracil, which were undecose nucleoside antibiotics, were synthesized using a samarium diiodide (SmI2) mediated aldol reaction with the use of α-phenylthioketones as enolate sources. The characteristics of the SmI2-mediated aldol reaction are that the enolate can be regioselectively generated and the aldol reaction proceeds under near neutral condition. This reaction is proved to be a powerful reaction for the synthesis of complex nucleoside antibiotics. The synthesis of caprazol, the core structure of caprazamycins, was conducted by the strategy including β-selective ribosylation without using a neighboring group participation and the construction of a diazepanone by a modified reductive amination. Our synthetic route would provide a range of key analogues with partial structures to define the pharmacophore, which can be a lead for the development of more effective anti-bacterial agents.
  • 佐藤 和之
    2006 年 126 巻 8 号 p. 597-605
    発行日: 2006/08/01
    公開日: 2006/08/01
    ジャーナル フリー
      Novel fluoroalkylated products where a CF2COOEt group was introduced at the α-position of α,β-unsaturated ketones or the Reformatsky-type products have been obtained selectively by the reaction of BrCF2COOEt and α,β-unsaturated ketones with Et2Zn in the presence of RhCl(PPh3)3 depending on the solvents. Furthermore, the novel α-fluoroalkylated products could synthesize by using various halofluoroalkyl compounds (Rf-X) instead of BrCF2COOEt. On the other hand, this Reformatsky-type reaction by imines gave difluoro-β-lactams or 3-amino-2,2-difluorocalboxylic esters without or with MgSO4•7H2O, selectively.
  • 高鳥 悠記
    2006 年 126 巻 8 号 p. 607-616
    発行日: 2006年
    公開日: 2006/08/01
    ジャーナル フリー
      Donepezil, galanthamine, and tacrine are therapeutic acetylcholinesterase (AChE) inhibitors used for the treatment of Alzheimer's disease. The aim of this paper is to review recent findings on their neuroprotective properties and the mechanisms of neuroprotection against glutamate neurotoxicity in rat cortical neurons. First, the hallmark of neurotoxicity induced by two different glutamate treatment conditions was examined, revealing that acute glutamate treatment (1 mM, 10 min) induces necrotic neuronal death and that moderate glutamate treatment (100 μM, 24 hr) induces apoptotic neuronal death. Next, we showed that therapeutic AChE inhibitors protect cortical neurons from glutamate neurotoxicity in a time- and concentration-dependent manner. We examined the mechanism of this neuroprotective effect and found that the neuroprotective effects against both acute and moderate glutamate treatments are mediated through nicotinic acetylcholine receptors (nAChRs), or more specifically, the effects of donepezil and galanthamine are mediated through α4- and α7-nAChR. We also showed that donepezil and galanthamine protect cortical neurons against acute glutamate treatment-induced neurotoxicity at steps before, and that tacrine protects at steps after, nitric oxide radical formation. On the other hand, the neuroprotective effects of donepezil and galanthamine, but not of tacrine, against neurotoxicity induced by moderate glutamate treatment were mediated through the phosphatidylinositol 3-kinase-Akt pathway. These findings unveiled the hitherto unknown neuroprotective effects of therapeutic AChE inhibitors and provided valuable insights into its neuroprotective mechanisms. They may very likely form the basis for a novel treatment strategy against Alzheimer's disease.
  • 門口 大輝
    2006 年 126 巻 8 号 p. 617-627
    発行日: 2006/08/01
    公開日: 2006/08/01
    ジャーナル フリー
      Optically active α,α-disubstituted α-amino acids belong to an important class of unnatural amino acids. Since the synthesis of such amino acids involves the creation of a quaternary stereocenter, methods for their synthesis have been extensively studied. We have reported that N-t-butoxycarbonyl(Boc)-N-methoxymethyl(MOM)-amino acid derivatives undergo asymmetric α-alkylation in up to 93% ee. Original chiral information on an amino acid is preserved in axially chiral enolate intermediates, and thus asymmetric induction is achieved without the aid of external chiral sources (i.e., memory of chirality). Recently, we have reported a new protocol for the asymmetric cyclization of amino acid derivatives, which enables straightforward synthesis of cyclic amino acids with a tetrasubstituted carbon center from the usual α-amino acids in up to 98% ee. Here we report the asymmetric construction of highly substituted chiral nitrogen heterocycles via intramolecular conjugate addition of chiral enolates generated from N-Boc-N-alkylylamino acid derivatives. This method is applicable to the asymmetric construction of pyrrolidine, piperidine, tetrahydroisoquinoline, and indoline derivatives with contiguous quaternary and tertiary stereocenters.
一般論文
  • 河添 仁, 久保 智美, 飯原 なおみ, 土居 智明, 奥條 真紀子, 福岡 憲泰, 藤本 さとし, 金地 伸拓, 坂東 修二, 石田 俊彦 ...
    2006 年 126 巻 8 号 p. 629-642
    発行日: 2006年
    公開日: 2006/08/01
    ジャーナル フリー
      The purpose of this study was to assess patient participation in cancer therapy and the sharing of patient information among the medical care team (physicians, nurses, pharmacists, and especially patients). We monitored the side effects of cancer chemotherapy with patients, and developed two support tools: One scored the points of subjective symptoms (fatigue, anorexia, nausea, etc) by patients, and the other recorded objective symptoms (clinical examination data) by pharmacists. It is most important that they attend each patient at their bedside. At this time, the trial was evaluated by questionnaire survey by inpatients receiving cancer chemotherapy (n=15). As a result, all patients (15/15) responded that this trial was necessary. This trial addressed the following: 1) increased communication between patients and medical staff concerning side effects (14/15), 2) increased interest in side effects (10/15), 3) when a patient tells medical staff about side effects, they act on it (10/15). None of the patients felt inconvenienced by scoring every day (0/15), or anxiety about side effects (0/15). Furthermore, all patients (15/15) responded that “participation of pharmacists in cancer chemotherapy” was necessary. This trial revealed no problems and suggested that patients related to the center of medical care. We should be careful in interpreting results of this small sized trial; however, the following conclusions should be reached: 1) introduction of monitoring side effects of cancer chemotherapy with patients, 2) develop communication among the medical care team.
  • 平田 尚人, 石橋 健一, 太田 伸, 羽田 悟, 篠原 弘靖, 喜多村 美緒, 三浦 典子, 大野 尚仁
    2006 年 126 巻 8 号 p. 643-650
    発行日: 2006/08/01
    公開日: 2006/08/01
    ジャーナル フリー
      CAWS, a water-soluble extracellular polysaccharide fraction obtained from the culture supernatant of Candida albicans, is one of the fungal pathogen-associated molecular patterns (PAMPs). It has been reported to show potent activity inducing arteritis and coronaritis in mice. Especially, CAWS-induced arteritis has a 100% incidence and severe mortality in the DBA/2 mouse strain. This artificial vasculitis was reported to provide a good murine model of Kawasaki disease and other inflammatory vascular disease. However, severe mortality was observed only in DBA/2 mice, which is a CAWS-sensitive strain. In this study, to clarify the mechanisms of CAWS-induced arteritis and mortality, we investigated microscopic histopathological changes in cardiovascular tissues in DBA/2 mice. Severe inflammatory infiltration was observed from the external elastic lamina in the aorta and proximal coronary arteries within 1 week after CAWS administration. Severe stenosis of the aorta and coronary arteries was observed more than 3 weeks after CAWS administration. Fibrinoid necrosis was observed in these vessel walls. All CAWS-treated mice died between the fifth and twelfth week after administration. Severe inflammatory change with aortic valve transformation suggested that CAWS-treated mice died of valvular endocarditis or cardiac dysfunction. Based on the simple induction method and complete incidence, these data suggest that CAWS-induced arteritis is a good model of not only Kawasaki disease but also other cardiovascular diseases such as valvular endocarditis.
  • Yuebin GE, Dawei CHEN, Liping XIE, Rongqing ZHANG
    2006 年 126 巻 8 号 p. 651-656
    発行日: 2006年
    公開日: 2006/08/01
    ジャーナル フリー
      The effect of daidzein, an important isoflavone, on the differentiation and mineralization in MC3T3-E1 cells, a mouse calvaria osteoblast-like cell line, was investigated. The MTT assay, the alizarin red S and von Kossa staining, the measurement of calcium (Ca) and phosphorus (P) concentrations by inductively coupled plasma-atomic emission spectrometry and the nitrophenol liberation method were used to determine the cell proliferation, mineralization and intracellular alkaline phosphatase (ALP) activity, respectively. Daidzein enhanced the cell proliferation after the culture for 2 days and the effect reached maximum on day 6. ALP activity and cellular Ca and P contents were increased time- and dose-dependently when the cells were treated with daidzein in the presence of disodium β-glycerophosphate and L-ascorbic acid. Differentiation of the cells to the mature osteoblasts was prompted under incubation in the presence of daidzein for 21 days, by the time the mineralized nodules formed. The calcium depositions of the cells by alizarin red S staining were increased significantly after the culture with daidzein as long as 28 days. It has been demonstrated that daidzein may be able to enhance the bone differentiation and mineralization and prompt the bone formation in the early growing stage and the late growing stage of osteoblasts.
ノート
  • Sengodan Gurusamy VIJAYA KUMAR, Dina Nath MISHRA
    原稿種別: Note
    2006 年 126 巻 8 号 p. 657-664
    発行日: 2006/08/01
    公開日: 2006/08/01
    ジャーナル フリー
      The poor solubility and wettability of meloxicam leads to poor dissolution and hence showing variations in bioavailability. The present study is aimed to increase solubility and dissolution of the drug using solid dispersion techniques. The solid binary systems were prepared at various drug concentrations (5—40%) with polyethylene glycol 6000 by different techniques (physical mixing, solvent evaporation). The formulations were characterized by solubility studies, differential scanning calorimetry, fourier transform infrared spectroscopy and in vitro dissolution rate studies. The solubility of drug increased linearly with increase in polymer concentration showing AL type solubility diagrams. Infrared spectroscopy studies indicated the possibility of hydrogen bonding with polymer. The differential scanning calorimetry and powder X ray diffraction demonstrated the presence of polymer as eutectica or monotectica in solid dispersion along with the physical characteristics of the drug (crystalline, amorphous or a mixture of both). The solid dispersions of the drug demonstrated higher drug dissolution rates than physical mixtures and pure meloxicam, as a result of increased wettability and dispersibility of drug in a solid dispersion system.
  • 寺田 澄男, 伊藤 紀久夫, 吉村 朗, 野口 直人, 石田 崇
    2006 年 126 巻 8 号 p. 665-669
    発行日: 2006/08/01
    公開日: 2006/08/01
    ジャーナル フリー
      Hot water extract of the aerial part of Yacon (Smallanthus sonchifolia, Compositae) showed potent free radical-scavenging activity and inhibitory effects on lipid peroxidation in rat brain homogenate. The most potent antioxidative activity focused on the 50% MeOH-eluted fraction on DIAION HP-20 column chromatography. The structure of the major component in the fraction was identified as 2,3,5-tricaffeoylaltraric acid (TCAA) based on spectroscopic evidence. The antioxidative activity of TCAA is superior to that of natural antioxidants such as (±)-catechin, α-tocopherol, and ellagic acid, and TCAA also showed selective maltase-inhibitory activity (IC50 49 μg/ml). As the hypoglycemic activity of Yacon extract was described in a previous report, the present results showing that the aerial part of Yacon has strong antioxidative activity may encourage its potential use as a food supplement to prevent type II diabetes.
  • Yue HOU, Chunfu WU, Jingyu YANG, Xiang HE, Tao GUO
    原稿種別: Note
    2006 年 126 巻 8 号 p. 671-675
    発行日: 2006/08/01
    公開日: 2006/08/01
    ジャーナル フリー
      Previous studies have shown that acute systemic administration of ethanol induced striatal ascorbic acid (AA) release in mice and rats. Undercutting the prefrontal cortex completely eliminated ethanol-induced AA release in rat striatum. In the present study, in vivo brain dialysis coupled with high performance liquid chromatography (HPLC)-electrochemical detection was used to evaluate the effect of ethanol on the release of AA in the prefrontal cortex, compared to that in the striatum of freely moving mice. The results showed that ethanol (4.0 g/kg i.p.) similarly induced AA release in the prefrontal cortex and striatum of freely moving mice.
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