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2003 Fiscal Year Annual Research Report

生物新機能と創薬をめざす生体内分子科学

Research Project

Project/Area Number 13NP0401
Research InstitutionGifu University

Principal Investigator

鈴木 正昭  岐阜大学, 大学院・医学研究科, 教授 (90093046)

Co-Investigator(Kenkyū-buntansha) 石川 智久  東京工業大学, 大学院・生命理工学研究科, 教授 (60193281)
松田 彰  北海道大学, 大学院・薬学研究科, 教授 (90157313)
渡辺 恭良  大阪市立大学, 大学院・医学研究科, 教授 (40144399)
鈴木 和年  (独)放射線医学総合研究所, 重粒子医科学センター, 室長(研究職) (90162932)
影近 弘之  東京大学, 大学院・薬学系研究科, 助教授 (20177348)
KeywordsPET / 光親和性標識法 / 蛍光プローブ / レチノイド / 人工核酸 / キナーゼ阻害剤 / 34mCl
Research Abstract

今年度に達成された主な具体的成果を箇条書きにした。
(1)分子プローブ設計グループ
Stille型sp/sp^3カップリングによる高速メチル化反応を開発し、アルキン型化合物への^<11>C導入を可能とした。アジドの光反応性の違いとStaudinger反応とを組み合わせた非放射性光親和性標識法を案出した。選択的で自動酸化にも安定な新規活性酸素種特異的蛍光プローブを創製した。ペプチドグリカンフラグメントを合成し受容体NOD2を同定した。カルボラン型新規レチノイドおよびトロポロン型Am80類縁体Tp80を合成した。イソベンゾフラノン型PKC制御分子を合成した。キラルシクロプロパン型ヒスタミンH_3受容体アゴニストの合成に成功した。ヘテロ原子を有する新規ビタミンD_3アナログの創製に成功した。人工核酸3'-amino-3',4'-BNAおよび2',4'-BNAを開発した。EAATに高親和性でNMDAに結合しない、TFB-TBOAを創製した。NEPP11類がPC12細胞におけるMn^<2+>誘導性アポトーシスを抑制することを見いだした。
(2)分子機能解析グループ
ABCB1/P糖タンパク質の高速スクリーニング系を構築し、基質予測法を開発した。Rhoキナーゼ阻害剤H1152を活用し、MARCKSがRhoキナーゼによりリン酸化されることを見いだした。Statin系薬剤が骨格筋においてCa^<2+>放出促進作用を示すことを見いだした。染色体変異と遺伝子発現プロファイルの検出・比較を行った。
(3)生体機能評価グループ
ノシセプチンがアロディニアを誘発すること、拮抗薬JTC-801が鎮痛効果を示すことを明らかにした。TG003がClk/Sty1,Sty4を疎外し、選択的スプライスングに影響を与えることを見いだした。細胞でのG12ファミリー活性化定量法を確立した。
(4)分子イメージンググループ
中大脳動脈結紮-再潅流モデルにおいて15R-[^<11>C]TIC-Meを用いたPET解析を行った。高品位34mCl製造法を確立した。パーキンソン病モデルでのPET解析によりES細胞の移植が細胞機能を改善することを確認した。βアミロイドの沈着が神経ペプチドSPによって阻止できることをin vivoで証明した。ポジトロンオートラジオグラフィー法により、虚血下における障害の程度と作用部位の解析、薬剤による保護効果の評価を行った。

  • Research Products

    (90 results)

All Other

All Publications (90 results)

  • [Publications] T.Hosoya: "Rapid methylation of terminal acetylenes by the Stille coupling of methyl iodide with alkynyltributylstannanes : a general protocol potentially useful for the synthesis of short-lived ^<11>CH_3-labeled PET tracers with a 1-propynyl group."Org.Biomol.Chem.. 2・1. 24-27 (2004)

  • [Publications] T.Satoh: "Role of heme oxygenase-1 protein in the neuroprotective effects of cyclopentenone prostaglandin derivatives under oxidative stress."Eur.J.Neurosci.. 17・11. 2249-2255 (2003)

  • [Publications] 鈴木正昭: "PET法による脳内中枢型プロスタサイクリン受容体の分子イメージング"現代化学. 387. 46-54 (2003)

  • [Publications] Y.Kazuta: "A systematic study of the hydride reduction of cyclopropyl ketones with structurally simplified sbstrates. Highly stereoselective reductions of trans substituted cyclopropyl ketones via the bisected s-cis-conformation."J.Org.Chem.. 68・9. 3511-3521 (2003)

  • [Publications] Y.Kazuta: "Cyclopropane-based conformational restriction of histamine. (1S,2S)-2-(2-Aminoethyl)-1-(1H, imidazol-4-yl)cyclopropane, a highly selective agonist for the histamine H3 receptor, having a cis-cyclopropane strusture."J.Med.Chem.. 46・10. 1980-1988 (2003)

  • [Publications] S.Shuto: "Convergent synthesis and unexpected Ca^<2+>-mobilizing activity of 8-substituted analogues of cyclic ADP-carbocyclic-ribose, a stable mimic of the Ca^<2+>-mobilizing second messenger cyclic ADP-ribose."J.Med.Chem.. 46・22. 4741-4749 (2003)

  • [Publications] N.Minakawa: "New base pairing motifs. The synthesis and thermal stability of oligodeoxynucleotides containing imidazopyridopyrimidine nucleosides with the ability to form four hydrogen bonds."J.Am.Chem.Soc.. 125・33. 9970-9982 (2003)

  • [Publications] N.Minakawa: "A versatile modification of on-column oligodeoxynucleotides using a copper-catalyzed oxidative acetylenic coupling reaction."J.Am.Chem.Soc.. 125・38. 11545-11552 (2003)

  • [Publications] L.Gan: "The immunosuppressive agent mizoribine monophosphate forms a transition state analogue complex with inosine monophosphate dehydrogenase."Biochemistry. 42・4. 857-863 (2003)

  • [Publications] S.Tamura: "Control of α/β-stereoselectivity in Lewis acid-prmoted C-glycosidation using a controlling anomeric effect based on the conformtional restriction strategy."Angew.Chem.Int.Ed.Engl.. 42・9. 1021-1023 (2003)

  • [Publications] N.Minakawa: "An improved large scale synthesis of 1,4-anhydro-4-thio-D-ribitol."Tetrahedron. 59・10. 1699-1702 (2003)

  • [Publications] M.Sukeda: "The first radical method for the introduction of an ethynyl group using a silicon tether and its application to the synthesis of 2'-deoxy-2'-C-ethynylnucleosides."J.Org.Chem.. 68・9. 3465-3475 (2003)

  • [Publications] T.Itoh: "Synthesis, thermal stability and resistance to enzymatic hydrolysis of the oligonucleotides containing 5-(N-aminohexyl)carbamoyl-2'-O-methyluridine."Nucleic Acids Res.. 31・10. 2514-2523 (2003)

  • [Publications] N.Morisaki: "Conversion of Ca^<2+> salt of an organic compound to its Li^+ salt to simplify the fast atom bombardment mass spectrum."Chem.Pharm.Bull.. 51・11. 1341-1344 (2003)

  • [Publications] Y.Hamashima: "Immobilization and reuse of Pd complexes in ionic liquid : efficient catalytic asymmetric fluorination and Michael reactions with β-ketoesters."Org.Lett.. 5・18. 3225-3228 (2003)

  • [Publications] Y.Baba: "Structure-based design of a highly selective catalytic site-directed inhibitor of Ser/Thr protein phosphatase 2B (calcineurin)."J.Am.Chem.Soc.. 125・32. 9740-9749 (2003)

  • [Publications] T.Shoda: "Development of selective, visible light-excitable, fluorescent magnesium ion probes with a novel fluorescence switching mechanism."Analyst.. 128・6. 719-723 (2003)

  • [Publications] K.Hanaoka: "Selective Detection of Zinc Ions with Novel Luminescent Lanthanide Probes."Angew.Chem.Int.Ed.Engl.. 42・26. 2996-2999 (2003)

  • [Publications] T.Miura: "Rational design principle for modulating fluorescence properties of fluorescein-based probes by photoinduced electron transfer."J.Am.Chem.Soc.. 125・28. 8666-8671 (2003)

  • [Publications] M.Yamamoto: "Production of singlet oxygen on irradiation of a photodynamic therapy agent, zinc-coproporphyrin III, with low host toxicity."Biometals.. 16・4. 591-597 (2003)

  • [Publications] H.Takakusa: "A novel design method of ratiometric fluorescent probes based on fluorescence resonance energy transfer switching by spectral overlap integral."Chemistry-A European Journal.. 9・7. 1479-1485 (2003)

  • [Publications] K.Setsukinai: "Development of novel fluorescence probes that can reliably detect reactive oxygen species and distinguish specific species."J.Biol.Chem.. 278・5. 3170-3175 (2003)

  • [Publications] 長野哲雄: "活性酸素イメージングプローブ"実験医学. 21・15. 2144-2146 (2003)

  • [Publications] 浦野泰照: "光誘起電子移動理論に基づく蛍光プローブの精密設計"ぶんせき. 8. 426-432 (2003)

  • [Publications] N.Inohara: "Host recognition of bacterial muramyl dipeptide mediated through NOD2. Implications for Crohn's disease."J.Biol.Chem.. 278・8. 5509-5512 (2003)

  • [Publications] M.Chamaillard: "An essential role for NOD1 in host recognition of bacterial peptidoglycan containing diaminopimelic acid."Nat.Immunol.. 4・7. 702-707 (2003)

  • [Publications] S.Akashi: "Lipopolysaccharide interaction with cell surface Toll-like receptor 4-MD-2 : higher affinity than that with MD-2 or CD14."J.Exp.Med.. 198・7. 1035-1042 (2003)

  • [Publications] K.Fukase: "Synthesis and Biological Activities of Lipid A Analogs Possessing β-Glycosidic Linkage at 1-Position"Bull.Chem.Soc.Jpn.. 76・3. 485-500 (2003)

  • [Publications] T.Ogawa: "Endotoxic and immunobiological activities of a chemically synthesized lipid A of Helicobacter pylori strain 206-1."FEMS Immunol.Med.Microbiol.. 36・1-2. 1-7 (2003)

  • [Publications] R.Tami: "Cell activation by monosaccharide lipid A analogues utilizing Toll-like receptor 4."Immunology. 110・1. 66-72 (2003)

  • [Publications] R.Haase: "A dominant role of Toll-like receptor 4 in the signaling of apoptosis in bacteria-faced macrophages."J.Immunol.. 171・8. 4294-4303 (2003)

  • [Publications] H.Kakuta: "Fluorescent bioprobes for visualization of puromycin-sensitive aminopeptidase in living cells."Bioorg.Med.Chem.Lett.. 13・1. 83-86 (2003)

  • [Publications] 長澤和夫: "サリドマイドの構造展開と活性拡張"細胞工学. 22・2. 152-155 (2003)

  • [Publications] G.D.Bujacz: "Crystallization and preliminary crystallographic studies of mung bean cytokinin-specific binding protein."Acta.Cryst.. D59. 522-525 (2003)

  • [Publications] 橋本祐一: "サリドマイドの過去・現在・未来"ファルマシア. 39・4. 315-319 (2003)

  • [Publications] A.Bukowska: "Transcriptional regulation of cytosol and membrane alanyl-aminopeptidase in human T cell subsets."Biol.Chem.. 384・4. 657-665 (2003)

  • [Publications] 橋本祐一: "がんにきく?使用広がるサリドマイド"Medical Technology. 31・6. 571-572 (2003)

  • [Publications] 橋本祐一: "サリドマイドの薬理作用とその構造展開"血液フロンティア. 13・7. 883-893 (2003)

  • [Publications] 橋本祐一: "サリドマイドの新しい適応"現代医療. 35・7. 1615-1619 (2003)

  • [Publications] Y.Kato: "Novel heteroatom-containing vitamin D_3 analogs : Efficient synthesis of 1α,25-dihydroxyvitamin D_3-26,23-lactam."Molecules. 8・6. 488-499 (2003)

  • [Publications] T.Ishioka: "Androgen antagonists with full antagonistic activity toward human prostate tumor LNCaP cells with mutated androgen receptor."Bioorg.Med.Chem.Lett.. 13・16. 2655-2658 (2003)

  • [Publications] Y.Hashimoto: "Structural development of synthetic retinoids and thalidomide-related molecules."Cancer Chemother.Pharmacol.. 52・1. S16-S23 (2003)

  • [Publications] A.Georgieva: "Stereoselective synthesis of novel ptilomycalin A analogs via successive 1,3-dipolar cycloaddition reactions and their Ca^<2+>-ATPase inhibitory activity."Synthesis. 2003・9. 1427-1432 (2003)

  • [Publications] M.Suizu: "Cyclooxygenase inhibitors derived from thalidomide."Chem.Pharm.Bull.. 51・9. 1098-1102 (2003)

  • [Publications] H.Kakuta: "Specific nonpeptide inhibitors of puromycin-sensitive aminopeptidase with a 2,4(1H,3H)-quinazolinedione skeleton."Chem.Pharm.Bull.. 51・11. 1273-1282 (2003)

  • [Publications] K.Nagasawa: "Synthesis and application as chemical/biological tools of marine guanidine alkaloids."Chemical Record. (印刷中).

  • [Publications] K.Takaoka: "Synthesis and photoreactivity of caged blockers for glutamate transporters."Bioorg.Med.Chem.Lett.. 13・5. 965-970 (2003)

  • [Publications] R.Sakaki: "Isolations of N-methyl-D-aspartic acid-type glutamate receptor ligands from Micronesian sponges."J.Nat.Prod.. 66・6. 784-787 (2003)

  • [Publications] Y.Ohfune: "Stereocontrolled synthesis of a potent agonist of group II metabotropic glutamate receptors, (+)-LY354740, and its related derivatives"Tetrahedron Lett.. 44・29. 5431-5434 (2003)

  • [Publications] T.Muratani: "Functional characterization of prostaglandin F_<2α> receptor in the spinal cord for tactile pain (allodynia)."J.Neurochem.. 86・2. 374-382 (2003)

  • [Publications] Y.Shigeri: "興奮性神経伝達物質グルタミン酸トランスポーターの制御分子開発と機能解析[Excitatory amino acid transporters : development of regulatory molecules for their functional analysis]"生化学. 75・4. 288-292 (2003)

  • [Publications] Y.Shigeri: "グルタミン酸トランスポーターの薬理学[Pharmacology of excitatory amino acid transporters(EAATs and VGLUTs)]"日本薬理学雑誌. 122・3. 253-264 (2003)

  • [Publications] N.Miyagawa: "Effect of synthetic retinoid, TAC-101, on experimental autoimmune disease."Pharmacology. 67・1. 21-31 (2003)

  • [Publications] S.Ishida: "Clinically potential subclasses of retinoid synergists revealed by gene expression profiling."Mol.Cancer Ther.. 2・1. 49-58 (2003)

  • [Publications] M.Farooqui: "Effects of retinoid ligands on RIP140 : molecular interaction with retinoid receptors and biological activity."Biochemistry. 42・4. 971-979 (2003)

  • [Publications] M.Iwata: "Retinoic acids exert direct effects on T cells to suppress Th1 development and enhance Th2 development via retinoic acid receptors."Int.Immunol.. 15・8. 1017-1025 (2003)

  • [Publications] Y.Endo: "Utility of boron clusters for drug design. Relation between estrogen receptor binding affinity and hydrophobicity of phenols bearing various types of carboranyl groups."Bioorg.Med.Chem.Lett.. 13・22. 4089-4092 (2003)

  • [Publications] Y.Hari: "Selective Recognition of CG Interruption by 2',4'-BNA Having 1-Isoquinolone as a Nucleobase in a Pyrimidine Motif Triplex Formation"Tetrahedron. 59・27. 5123-5128 (2003)

  • [Publications] H.Shimizu: "Characterization of mouse Abcc12 gene and its transcript encoding an ATP-binding cassette transporter, an orthologue to human ABCC12"Gene. 310. 17-28 (2003)

  • [Publications] H.Mitomo: "A functional study on the polymorphism of ATP-binding cassette transporter ABCG2 : Critical role of Arg-482 in Methotrexate transport."Biochem.J.. 373・3. 767-774 (2003)

  • [Publications] K.Sano: "Simple non-ion-paired high performance liquid chromatograhic method for simultaneous quantification of carboxylate and lactone forms of 14 new camptothecin derivatives."J.Chromatogr.B Analyt.Technol.Biomed.Life Sci.. 795・1. 25-34 (2003)

  • [Publications] T.Ishikawa: "The Genetic Polymorphism of Drug transporters : Functional Analysis Approaches."Pharmacogenomics. 5・1. 67-99 (2003)

  • [Publications] 石川智久: "ヒトABCトランスポーター:新規遺伝子の探索とSNP機能解析"Bioベンチャー. 3・. 96-99 (2003)

  • [Publications] R.Inoue: "Ca^<2+>-releasing effect of cerivastatin on the sarcoplasmic reticulum of mouse and rat skeletal muscle fibers."J.Pharmacol.Sci.. 93・3. 279-288 (2003)

  • [Publications] Y.Ishikawa: "A role of Rnd1 GTPase in dendritic spine formation in hippocampal neurons."J.Neuroscience. 23・35. 11065-11072 (2003)

  • [Publications] H.Katoh: "RhoG activates Rac1 by direct interaction with the Dock180-binding protein Elmo."Nature. 424・6947. 461-464 (2003)

  • [Publications] I.Oinuma: "Direct interaction of Rnd1 with Plexin-B1 regulates PDZ-RhoGEF-mediated Rho activation by Plexin-B1 and induces cell contraction in COS-7 cells."J.Biol.Chem.. 278・28. 25671-25677 (2003)

  • [Publications] Y.Yamaguchi: "N-terminal short sequences of α subunits of the G12 family determine selective coupling to receptors"J.Biol.Chem.. 278・17. 14936-14939 (2003)

  • [Publications] N.Mori: "Roles of Shc signaling in oxidative stress response and aging."J.Clin.Biochem.Nutr.. (印刷中).

  • [Publications] 森 望: "長寿命遺伝子の新潮流"Medical.Practice. 20・10. 1796-1797 (2003)

  • [Publications] T.Mabuchi: "Attenuation of neuropathic pain by the nociceptin/orphanin FQ antagonist JTC-801 is mediated by inhibition of nitric oxide production."Eur.J.Neurosci.. 17・7. 1384-1392 (2003)

  • [Publications] T.Muratani: "Functional evidence for interaction between prostaglandin EP3 and kappa-opioid receptor pathways in tactile pain induced by human immunodeficiency virus type-1 (HIV-1) glycoprotein gp 120."Neuropharmacology. 45・1. 96-105 (2003)

  • [Publications] T.Kitano: "Characterization of N-methyl-D-aspartate receptor subunits involved in acute ammonia toxicity."Neurochem.Int.. 44・2. 83-90 (2004)

  • [Publications] K.Suzuki: "Production of ^<34m>Cl.A new PET Radionuclide."J.Label Compd.Radiopharm.. 46・. S287 (2003)

  • [Publications] G.Zubal: "Automated kinetic analysis of FDG uptake in living rat brain slices from dynamic positron autoradiography"Cancer Biother.Radiopharm.. 18・3. 405-411 (2003)

  • [Publications] N.Omata: "Different mechanisms of hypoxic injury on white matter and gray matter as revealed by dynamic changes in glucose metabolism in rats."Neuroscience Letter. 353・2. 148-152 (2003)

  • [Publications] M.Inoue: "Functional brain mapping of the macaque related to spatial working memory as revealed by PET"Cereb.Cortex. 14・1. 106-119 (2004)

  • [Publications] A.Noda: "Determination of kinetic rate constants for FDG and partition coefficient of water in conscious macaque and alterations in aging or anesthesia examined on parametric images with an anatomic standardization technique"J.Cereb.Blood Flow Metab.. 23・12. 1441-1447 (2003)

  • [Publications] Y.Sekine: "Association of dopamine transporter loss in the orbitofrontal and dorsolateral prefrontal cortices with methamphetamine-related psychiatric symptoms,"Am.J.Psychiatry. 160・9. 1699-1701 (2003)

  • [Publications] K.Yanamoto: "Intrastriatal microinjection of sodium nitroprusside induces cell death and reduces binding of dopaminergic receptors,"Synapse. 50・2. 137-143 (2003)

  • [Publications] A.Noda: "Effect of FK960, an anti-dementia drug with a novel mechanism of action, on regional cerebral blood flow and glucose metabolism in aged rhesus macaques studies with positron emission tomography,"J.Pharmacol.Exper.Ther.. 306・1. 213-217 (2003)

  • [Publications] K.Kawamura: "An increase in sigma 1 receptors in the aged monkey brain : a positron emission tomography study with [^<11>C]SA4503"Neurobiol.Age. 24・5. 745-752 (2003)

  • [Publications] O.Inoue: "Sensitivity of benzodiazepine receptor binding and muscarinic acetylcholine receptor binding for the detection of neural cell death caused by sodium nitroprusside microinjection in rat brain"Synapse. 49・2. 134-141 (2003)

  • [Publications] H.Engler: "Multitracer study with positron emission tomography in Creutzfeldt-Jakob disease,"Eur.J.Nucl.Med.Mol.Imaging. 30・1. 85-95 (2003)

  • [Publications] 塚田秀夫: "基底核神経伝達機能の解析:動物PET"BRAIN MEDICAL. 15・3. 42-48 (2003)

  • [Publications] 塚田秀夫: "動物PETによるサル脳神経機能のイメージング"医学のあゆみ. 204・4. 243-246 (2003)

  • [Publications] Y.Sasaki: "New aspects of neurotransmitter release and exocytosis : Rho-kinase-dependent myristoylated alanine-rich C-kinase substrate phosphorylation and regulation of neurofilament structure in neuronal cells."J.Pharmacol.Sci.. 93・1. 35-40 (2003)

  • [Publications] T.Hosoya: "Novel bifunctional probe for radioisotope-free photoaffinity labeling : compact structure comprised of photospecific ligand ligation and detectable tag anchoring units."Org.Biomol.Chem.. (印刷中). (2004)

  • [Publications] K.Furuta: "A simple acromelic acid analog potentially useful for receptor photoaffinity labeling and biochemical studies."Tetrahedron Lett.. (印刷中). (2004)

  • [Publications] 石川智久: "ゲノム創薬と未来産業"エルゼビア・ジャパン. 112 (2003)

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Published: 2005-04-18   Modified: 2016-04-21  

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