YAKUGAKU ZASSHI
Online ISSN : 1347-5231
Print ISSN : 0031-6903
ISSN-L : 0031-6903
134 巻, 9 号
選択された号の論文の10件中1~10を表示しています
総説
  • 山岸 丈洋
    2014 年 134 巻 9 号 p. 915-924
    発行日: 2014/09/01
    公開日: 2014/09/01
    ジャーナル フリー
      Phosphinyl dipeptide isosteres (PDIs) are important compounds for the development of potent and selective inhibitors of various aspartic proteases and Zn metalloproteases. The stereochemistry of PDIs affects their biological activity. PDIs were prepared successfully using the concept of asymmetric induction from the chiral phosphorus atom of the phosphinate moiety to the neighboring carbon atom. This methodology involves diastereoselective α-alkylation and β′-alkylation of P-chiral phosphinate derivatives, prepared through lipase-catalyzed kinetic resolution, which produces Phe-Ala type and Pro-Phe type PDIs. The synthesis of Leu-Pro type PDIs in a protected form was achieved through a cross-coupling reaction of stereodefined α-amino-H-phosphinate with alkenyl triflate, followed by diastereoselective hydrogenation of the alkene moiety.
  • 川瀬 篤史
    2014 年 134 巻 9 号 p. 925-929
    発行日: 2014/09/01
    公開日: 2014/09/01
    ジャーナル フリー
      Pathophysiological changes in infection or inflammation are associated with alterations in the production of numerous absorption-, distribution-, metabolism-, and excretion-related proteins. However, little information is available on the effects of inflammation on the expression levels and activities of ATP-binding cassette (ABC) transporters. We examined the effects of acute (on day 7) and chronic (on day 21) inflammation on the expression of ABC transporters in some major tissues in rats. Adjuvant-induced arthritis (AA) in rats was used as an animal model of inflammation. The mRNA levels of mdr1a and mdr1b encoding P-glycoprotein (P-gp) decreased significantly in the liver of AA rats on day 21. Hepatic protein levels of P-gp, Mrp2, and Bcrp decreased significantly in the membrane but not in the homogenate of AA rats after 7 days and after 21 days of treatment with adjuvant. Recently, ezrin/radixin/moesin (ERM) proteins have been found to show linker activity for some transporters and F-actin. We examined the expression levels and functions of ERM proteins in AA because the membrane localization of ABC transporters was decreased without any change in total expression levels. In this review, we summarize our recent work and reports of ERM proteins relevant to ABC transporters.
  • 河野 健一
    2014 年 134 巻 9 号 p. 931-937
    発行日: 2014/09/01
    公開日: 2014/09/01
    ジャーナル フリー
      Many membrane proteins are responsible for signaling and ionic transport necessary to maintain biological functions in vivo. Recently, not only conformational changes but also oligomerization have been proposed to regulate protein activation. Thus, the study of membrane protein oligomerization is crucial for new drug development. The existing destructive methodologies such as immunoprecipitation, however, are not suitable to determine oligomeric states precisely because of the artificial aggregation of proteins after detergent solubilization. In the present study, the coiled-coil tag-probe labeling method and spectral imaging were first combined to establish a new methodology based on fluorescence resonance energy transfer (FRET) for stoichiometric analysis of the oligomeric states of membrane proteins on living cells. After validating the method for mono-, di-, and tetrameric standard membrane proteins, the oligomeric state of β2-adrenergic receptors (β2ARs) was examined to clarify its functional significance. It was found that β2ARs could transduce cyclic adenosine 5′-monophosphate (cAMP) signals and internalize them upon treatment with ligands without showing any FRET signals. Thus, β2ARs do not form constitutive homooligomers, and homooligomerization is not necessary for the receptor function of β2ARs. Finally, the oligomeric state of full-length M2 proton-selective channels of influenza A virus was investigated. Although the results of X-ray crystallography and NMR studies using fragment peptides suggested that M2 stably forms a tetrameric channel, the full-length M2 proteins formed proton-conducting dimers at neutral pH and these dimers were converted to tetramers at acidic pH, indicating that the minimal functional unit of the M2 channel is a dimer.
  • 片桐 幸輔
    2014 年 134 巻 9 号 p. 939-947
    発行日: 2014/09/01
    公開日: 2014/09/01
    ジャーナル フリー
      Aromatic sulfonamides exist in a synclinal conformation with the twisted structure arising from rotation around the S-N bond in both the solid state and in solution. Simple bidentate ligands containing the sulfonamide moiety can be extended to form elongated ligands, and optically active components can be added to form a versatile building block for the construction of coordination polymers with many structures. Mixing the simple ligands 1 and 2 and the elongated ligands 3 and 4 with different Ag(I) salts yielded the corresponding complexes [Ag(1)OTf]n (1a), [Ag(2)]n•nOTf(2a), [Ag(3)OTf]n (3a), [Ag(3)]n•nBF4 (3b), [Ag(4)CH3CN]n•nBF4•nCHCl3 (4b), and [Ag(4)]n•nSbF6•nCH4O (4c). Straight chains and racemic helical polymers were observed in the crystal structure of complexes 1a and 2a, respectively. In the crystal structures of complexes 3a and 4b, infinite 1D straight chains containing a T-shaped coordination geometry about the Ag(I) centers were formed by the reaction of ligands 3 or 4 with Ag(I) salts in CH3CN/CHCl3. A continuous 1D coordination polymer containing a racemic mixture of left- and right-handed helices formed in the crystal structure of complex 3b. Furthermore, a layered coordination polymer consisting of a racemic mixture of left- and right-handed polymers was observed from the crystal structure of complex 4c. The construction of optically pure left- or right-handed 1D helical polymers via the introduction of chiral functional groups on the nitrogen atom of the sulfonamide ligand is currently under investigation in our laboratory.
  • 渡邉 真一
    2014 年 134 巻 9 号 p. 949-955
    発行日: 2014/09/01
    公開日: 2014/09/01
    ジャーナル フリー
      Therapeutic drug monitoring (TDM) is a developing field in hospital pharmacy that contributes to good clinical response. Optimal concentrations of immunosuppressants, anti-epileptic drugs, and glycopeptide antibiotics are narrow, and these drugs are widely monitored by fluorescence polarization immunoassay (FPIA) in clinical settings. Recently, a chemiluminescence immunoassay (CLIA) has also become available. We compared these two assays in monitoring serum concentrations of cyclosporin A (CsA), carbamazepine (CBZ), phenobarbital, phenytoin, and valproic acid. FPIA estimates of CsA and CBZ concentrations were higher than CLIA estimates. We also evaluated the two methods' cross-reactions to metabolites. The FPIA, but not the CLIA, method was affected by metabolites. We conclude that CLIA has adequate precision and accuracy for use in routine therapeutic drug monitoring in clinical situations. We also report a case of meningitis caused by methicillin-resistant Staphylococcus epidermidis (MRSE) in a neonatal girl. The patient had intraventricular hemorrhage and was treated with ventricular drainage. Because MRSE was detected in her cerebrospinal fluid (CSF), vancomycin (VCM) was administered intravenously, but had no beneficial effect. Subsequent treatment with linezolid (LZD) successfully ameliorated her CSF cell count and protein levels. These results indicate that LZD may be a treatment option for neonates and infants for drain-associated meningitis caused by MRSE. In conclusion, TDM can determine drug concentration and indicate optimal pharmaceutical approach for treatment.
  • 好村 守生
    2014 年 134 巻 9 号 p. 957-964
    発行日: 2014/09/01
    公開日: 2014/09/01
    ジャーナル フリー
      Tannins and related polyphenols have been reported to produce diverse biological effects that indicate their therapeutic potential, including antioxidative, antibacterial, and antiviral activities. In an exploratory study of natural antioxidants with biological effects, we investigated the tannin constituents of myrtaceous plants reported to be rich in polyphenols. We isolated 16 new compounds from five species of the Melaleuca, Eucalyptus, Syzygium, Pimenta, and Myrtus genera. Among the new polyphenols, nine were isolated from Melaleuca squarrosa and characterized as C-glucosidic ellagitannin monomers and oligomers. The structures of the other new polyphenols from myrtaceous plants and a novel compound obtained from the berries of Pyracantha coccinea (Rosaceae) were also elucidated based on spectroscopic and chemical evidence. The antioxidative activity of isolates in the present study was estimated by measuring 1,1-diphenyl-2-picrylhydrazyl radical (DPPH)-scavenging activity and in the oxygen radical absorbance capacity (ORAC) test. We found that oenothein B, a macrocyclic ellagitannin dimer, is widely distributed in the genus Eucalyptus and produces a significant immunomodulatory effect on human dendritic cells (DCs). In a survey of natural ligands that bind to the aryl hydrocarbon receptor (AhR), nepitrin, a flavonoid glycoside, and other polyphenols were revealed to be promising therapeutic candidates.
  • 榊原 紀和
    2014 年 134 巻 9 号 p. 965-972
    発行日: 2014年
    公開日: 2014/09/01
    ジャーナル フリー
      This review describes the synthesis and evaluation of novel nucleic acid derivatives performed by our research group to date. We developed a new method for the synthesis of 2-alkoxyadenosine analogs via nonaqueous diazotization-dediazoniation reactions. By applying these reactions, we effectively synthesized four types of carbocyclic oxetanocin analogs (2-alkoxy-C.OXT-A). The angiogenic activities of these compounds were evaluated using human umbilical vein endothelial cells. This resulted in increased activities of the analogs, especially of 2-methoxy-C.OXT-A and 2-isopropoxy-C.OXT-A, at a concentration of 100 μM; they showed angiogenic potency similar to or greater than that of vascular endothelial growth factor. We also synthesized and evaluated a novel series of uracil derivatives carrying a 3,5-dimethylbenzyl group at the N3-position and acting as non-nucleoside HIV-1 reverse transcriptase inhibitors. Some of these compounds showed good-to-moderate inhibitory activity, with EC50 values in the submicromolar range. Among them, the analog 6-amino-1-(4-picolyl)-uracil showed significant HIV-1 reverse transcriptase inhibition, with an EC50 value of 0.03 μM and a high selectivity index of 2863.
  • 安楽 誠
    2014 年 134 巻 9 号 p. 973-979
    発行日: 2014/09/01
    公開日: 2014/09/01
    ジャーナル フリー
      Oxidative damage results in protein modification and is observed in numerous diseases. Human serum albumin (HSA), the most abundant protein in the plasma, exerts important antioxidant activities to prevent oxidative damage. This paper focuses on the characterization of chemical changes in HSA that are induced by oxidative damage, their relevance to human pathology, and the most recent advances in clinical applications. The antioxidant properties of HSA are largely dependent on Cys-34 and its contribution to the maintenance of intravascular homeostasis, including protecting the vascular endothelium under conditions related to oxidative stress. Recent studies have also evaluated the susceptibility of other important amino acid residues to exposure to free radicals. The findings suggest that a redox change in HSA is related to the oxidation of several amino acid residues by different oxidants. On the other hand, the ratio of the oxidized form to the normal form of albumin (HMA/HNA), which is a function of the redox states of Cys-34, could serve as a useful marker for evaluating systemic redox states, which would be useful for the evaluation of disease progression and therapeutic efficacy. This review provides new insights into our current understanding of the mechanism of HSA oxidation, based on in vitro and in vivo studies.
一般論文
  • 辻 琢己, 大坪 達弥, 梅山 貴生, 首藤 みほ, 米須 香那, 松本 美菜子, 吉田 侑矢, 坂野 理絵, 三上 正, 河野 武幸
    2014 年 134 巻 9 号 p. 981-986
    発行日: 2014/09/01
    公開日: 2014/09/01
    ジャーナル フリー
      The anticancer drug dacarbazine (DTIC) is photosensitive, and the photodegradation product 5-diazoimidazole-4-carboxamide (diazo-IC) induces adverse reactions including local venous pain during intravenous injection. In this study we evaluated the effectiveness of colored shields (orange and red) to protect against photodegradation of DTIC as determined by ascertaining the concentration of diazo-IC. Samples were prepared and stored under four conditions: (1) no shield; (2) covered with an aluminum (opaque) shield; (3) covered with an orange shield; and (4) covered with a red shield. The samples were exposed to natural light for a specified time (0, 30, 60, 120, and 180 min) prior to measuring the concentration of diazo-IC by HPLC. We found that after 180 min, the diazo-IC concentration was 5.7±0.6 (S.D.) μg/mL with no shield and 1.9±0.2 μg/mL in both colored shield conditions. This production of diazo-IC under the colored shields was suppressed to a level similar to that under the aluminum shield (1.7±0.2 μg/mL). We also evaluated the effectiveness of NSAIDs (zaltoprofen, loxoprofen sodium, and diclofenac sodium) administered to mice prior to DTIC treatment on venous pain by counting their stretching and writhing reactions. Premedication with zaltoprofen significantly decreased expression of pain behavior in the DTIC-treated mice. These results suggest that storing DTIC under the protection of an orange or red shield is clinically beneficial because the shield prevents DTIC photodegradation, and that NSAIDs such as zaltoprofen are a promising premedication candidate for pain.
  • 真坂 亙, 李 英鵬, 川飛 翔, 小出 優貴, 高見 明, 矢野 健児, 今井 涼介, 八木 信宏, 鈴木 英治, 氷川 英正, 龍野 一 ...
    2014 年 134 巻 9 号 p. 987-995
    発行日: 2014/09/01
    公開日: 2014/09/01
    ジャーナル フリー
    電子付録
      We have designed a novel lipid analog (lipopeptide) that mimics the structural features of modified phospholipids. This lipopeptide is easily synthesized using a peptide synthesizer and has been shown to be useful for the modification of liposomes, which are used as an active targeted drug delivery system (DDS). Vasoactive intestinal peptide (VIP) has high homology with pituitary adenylate cyclase activating peptide (PACAP). There are three major PACAP receptors: PAC1R, VPAC1R, and VPAC2R. PAC1R has affinity only for PACAP, whereas VPAC1R and VPAC2R have the same affinity for both VIP and PACAP. In the present study, we synthesized several lipopeptides conjugated with VIP through different linkers and found that liposomes modified with these lipopeptides (VIP-Lips) selectively recognized the PACAP/VIP receptors. The anti-cancer activity of these VIP-Lips was evaluated by encapsulation of an antitumor drug, doxorubicin (DOX), into the modified liposomes (VIP-Lips-DOX) against the human osteosarcoma cell line, Saos-2, which highly expresses the VIP receptor. cAMP production was then measured to determine how well the VIP-Lips were able to recognize VPAC2R. The results clearly indicate that the proposed lipopeptide methodology holds promise as a DDS for cancer therapy.
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