細胞の増殖と死を制御する分子の創製と機能解析

• Project/Area Number: 16073203
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Science and Engineering
• Research Institution: The Institute of Physical and Chemical Research (2006-2007); Tohoku University (2004-2005)
• Principal Investigator: 袖岡 幹子 The Institute of Physical and Chemical Research, 袖岡有機合成化学研究室, 主任研究員 (60192142)
• Co-Investigator(Kenkyū-buntansha): 平井 剛 独立行政法人理化学研究所, 袖岡有機合成化学研究室, 研究員 (50359551) ; 濱島 義隆 独立行政法人理化学研究所, 袖岡有機合成化学研究室, 研究員 (40333900)
• Project Period (FY): 2004 – 2007
• Project Status: Completed (Fiscal Year 2007)
• Budget Amount: ¥31,100,000 (Direct Cost: ¥31,100,000); Fiscal Year 2007: ¥8,900,000 (Direct Cost: ¥8,900,000); Fiscal Year 2006: ¥8,900,000 (Direct Cost: ¥8,900,000); Fiscal Year 2005: ¥8,900,000 (Direct Cost: ¥8,900,000); Fiscal Year 2004: ¥4,400,000 (Direct Cost: ¥4,400,000)
• Keywords: 細胞死 / 細胞増殖 / ネクローシス / プロテインキナーゼ / プロテインホスファターゼ / フッ素 / インドリルマレイミイド / フッ素化 / バイオイソスター / 阻害剤 / フルオロホスホン酸 / RK-682

Research Abstract

本研究は、細胞の増殖や死の情報伝達にかかわるタンパク質に直接結合し、その機能を特異的に制御する低分子化合物の創製と、それを用いた情報伝達機構の解明を目的としている。
1)これまでに、天然物RK-682をもとにしたプロテインホスファターゼ阻害剤の構造展開を行い、細胞周期進行の鍵酵素であるCdc25阻害活性ならびにHL60細胞増殖抑制効果を示す化合物をみいだす事に成功している。さらに本年度は、本化合物がCdc25の活性中心と共有結合を生成することを見いだし、蛍光ラベル体を合成して細胞内局在を調べた。また本化合物を用いたプロテインホスファターゼの網羅的解析手法の開発の検討を行った。
2)これまでに我々は、酸化ストレスにより誘導されるネクローシスを選択的に抑制するインドリルマレイミド誘導体の創製に成功している。今年度は、昨年度までにアフィニティーゲルにより同定した結合タンパク質の細胞死への関与を調べるため、培養細胞を用い、RNAiによるノックダウンや過剰発現実験を行った。
3)プロテインホスファターゼ阻害剤の候補として期待されるα-フッ素化シアノホスホン酸や、医薬の骨格として重要なα-フッ素化アリール酢酸など光学活性含フッ素化合物の触媒的不斉合成法の開発に成功した。また、他にも生物活性分子合成に有用な反応の開発も行った。
4)生物活性物質合成に有用な新しいカーバメート型保護基導入試薬の開発に成功した。
5)細胞増殖の制御に重要なガングリオシドの非加水分解性アナログの合成に成功した。

Research Products

• [Journal Article] Catalytic Asymmetric Conjugate Reduction with Ethanol: A More Reactive System Pd(II)-1Pr-DUPHOS Complex with Molecular Sieves 4A (2008)
  • Author(s): Daiki Monguchi
  • Journal Title: J. Organomet. Chem. 693 Pages: 867-873
  • Peer Reviewed
• [Journal Article] Importance of interaction between C1 domain and lipids in protein kinase Cα activation: Hydrophobic side chain direction isobenzofuranone ligands controls enzyme activation level (2007)
  • Author(s): Go Hirai
  • Journal Title: ChemMedChem 2 Pages: 1006-1009
  • Peer Reviewed
• [Journal Article] Stereo-controlled and Convergent Entry to CF_2-Sialosides : Synthesis of CF_2-linked Ganglioside GM4 (2007)
  • Author(s): Go Hirai
  • Journal Title: J. Am. Chem. Soc. 129 Pages: 15420-15421
  • Peer Reviewed
• [Journal Article] A Novel Bisindolylmaleimide Derivative Enhances Functional Recovery of Heart After Long-Term Hypothermic Heart Preservation (2007)
  • Author(s): Rajesh Gopalrao Katare
  • Journal Title: Transplantation 83 Pages: 1588-1594
  • Peer Reviewed
• [Journal Article] A Novel Bisindolylmaleimide Derivative Inhibit Mitochondrial Permeability Transition Poreand Protect the Heartfrom Reperfusion Injury (2007)
  • Author(s): Rajesh Gopalrao Katare
  • Journal Title: Canad. J. Physiol. Pharmacol. 85 Pages: 979-985
  • Peer Reviewed
• [Journal Article] Pd(II)-Catalyzed Asymmetric Fluorination of α-Cyanophosphonates with the Aid of 2,6-Lutidine (2007)
  • Author(s): Ken-ichi Moriya
  • Journal Title: Synlett Pages: 1139-1142
  • Peer Reviewed
• [Journal Article] Catalytic Asymmetric Aldol Reactions of Enolizable Carbon Pronucleophiles With Formaldehyde and Ethyl Glyoxylate (2007)
  • Author(s): Isao Fukuchi
  • Journal Title: Adv. Synth. Cat. 349 Pages: 509-512
  • Peer Reviewed
• [Journal Article] Asymmetric Fluorination of α-Arylacetic Acid Derivatives Using a Novel Catalytic System Consisting of NiCl_2-BINAP/R_3SiOTf/2,6-Lutidine (2007)
  • Author(s): Toshiaki Suzuki
  • Journal Title: Angew. Chem. Int. Ed 46 Pages: 5435-5439
  • Peer Reviewed
• [Journal Article] Convenient Method for the Preparation of Carbamates, Carbonates, and Thiocarbonates. (2007)
  • Author(s): Mamoru Shimizu
  • Journal Title: Organic Letters 9 Pages: 5231-5234
  • Peer Reviewed
• [Journal Article] Enantioselective Fluorination of t-Butoxycarbonyl Lactones and Lactams Catalyzed by Chiral Pd(II)-Bisphosphine Complexes. (2007)
  • Author(s): Toshiaki Suzuki, Tomomi Goto, Yoshitaka Hamashima, Mikiko Sodeoka
  • Journal Title: J. Org. Chem. 72 Pages: 246-260
• [Journal Article] プロテインキナーゼC(PKC)の構造と活性化機構の解明を目指した新規C1ドメインリガンドの創製 (2006)
  • Author(s): 平井 剛, 清水 忠, 袖岡幹子
  • Journal Title: 有機合成化学協会誌 64 Pages: 515-527
  • NAID: 10017486844
• [Journal Article] Pd(II)-Catalyzed Asymmetric Addition Reaction of Malonates to Dihydroisoquinolines (2006)
  • Author(s): Naoki Sasamoto, Christian Dubs, Yoshitaka Hamashima, Mikiko Sodeoka
  • Journal Title: J. Am. Chem. Soc. 12 Pages: 14010-14011
• [Journal Article] A New Entry to Pd-H Chemistry : Catalytic Asymmetric Conjugate Reduction of Enones with EtOH, and a Highly Enantioselective Synthesis of Warfarin. (2006)
  • Author(s): Yasunori Tsuchiya, Yoshitaka Hamashima, Mikiko Sodeoka
  • Journal Title: Org. Lett. 8 Pages: 4851-4854
• [Journal Article] Highly enantioselective fluorination reactions of β-ketoesters and β-ketophosphonates catalyzed by chiral palladium complexes. (2006)
  • Author(s): Yoshitaka Hamashima, Toshiaki Suzuki, Hisashi Takano, Yuta Shimura, Yasunori Tsuchiya, Ken-ichi Moriya, Tomomi Goto, Mikiko Sodeoka
  • Journal Title: Tetrahedron 62 Pages: 7168-7179
• [Journal Article] Enantioselective Fluorination Reactions Catalyzed by Chiral Palladium Complexes. (2006)
  • Author(s): Yoshitaka Hamashima, Mikiko Sodeoka
  • Journal Title: Synlett Pages: 1467-1478
• [Journal Article] Structure-activity relationship of N-methyl-bisindolylmaleimide derivatives as cell death inhibitors (2005)
  • Author(s): Miho Kato
  • Journal Title: Bioorg.Med.Chem.Lett. 15 Pages: 3109-3113
• [Journal Article] Inhibition of hydrogen peroxide-induced necrotic cell death with 3-amino-2-indolylmaleimide derivatives (2005)
  • Author(s): Kosuke Dodo
  • Journal Title: Bioorg.Med.Chem.Lett. 15 Pages: 3114-3118
• [Journal Article] Optically active cantharidin analogues possessing selective inhibitory activity on Ser/Thr protein phosphatase 2B (calcineurin) : Implications for the binding mode. (2005)
  • Author(s): Yoshiyasu.Baba
  • Journal Title: Bioorg.Med.Chem. 13 Pages: 5164-5170
• [Journal Article] Development of Catalytic Asymmetric Reactions via Chiral Palladium Enolate. (2005)
  • Author(s): Mikiko Sodeoka
  • Journal Title: Bull.Chem.Soc.Jpn. 78 Pages: 941-956
• [Journal Article] An efficient catalytic enantioselective fluorination of β-ketophosphonates using chiral palladium complexes (2005)
  • Author(s): Yoshitaka Hamashima
  • Journal Title: Tetrahedron Lett. 46 Pages: 1447-1450
• [Journal Article] Catalytic Enantioselective Fluorination of Oxindoles. (2005)
  • Author(s): Yoshitaka Hamashima
  • Journal Title: J.Am.Chem.Soc. 127 Pages: 10164-10165
• [Journal Article] An Efficient Catalytic Enantioselective Fluorination of β-Keto-phosphonates Using Chiral Palladium Complexes. (2005)
  • Author(s): Yoshitaka Hamashima
  • Journal Title: Tetrahedron Lett Vol.46 Pages: 1447-1450
• [Journal Article] 低分子阻害剤によるタンパク質リン酸化の制御:構造変化と選択性 (2005)
  • Author(s): 平井 剛
  • Journal Title: 実験医学増刊 Vol.23,No.4 Pages: 199-204
• [Journal Article] Design, Synthesis, and Structure-Activity Relationship of New Isobenzofuranone Ligands of Protein Kinase C. (2004)
  • Author(s): Yoshiyasu Baba
  • Journal Title: Bioorg.Med.Chem.Lett. Vol.14 Pages: 2963-2967
• [Journal Article] Evaluation of Series of Isobenzofuranone Dimers as PKCa Ligands : Implication for the Distance between the Two Ligand Binding Sites. (2004)
  • Author(s): Yoshiyasu Baba
  • Journal Title: Bioorg.Med.Chem.Lett. Vol.14 Pages: 2969-2972
• [Journal Article] Structure-based Design of a Selective Heparanase Inhibitor as an Antimetastatic Agent. (2004)
  • Author(s): Keisuke Ishida
  • Journal Title: Mol.Cancer Therapeutics Vol.3 Pages: 1069-1077
• [Presentation] RE誘導体をプローブとしたホスファターゼ網羅的解析法の開発 (2008)
  • Author(s): 土屋綾子
  • Organizer: 日本薬学会第128年会
  • Place of Presentation: 横浜
• [Presentation] RK-682エナミド誘導体標的酵素の網羅的解析法の開発 (2008)
  • Author(s): 平井剛
  • Organizer: 日本化学会第88春季年会
  • Place of Presentation: 立教大学
• [Presentation] カルバメート型保護基を中性条件下導入可能な新規合成試薬の開発 (2008)
  • Author(s): 清水護
  • Organizer: 日本化学会第88春季年会
  • Place of Presentation: 立教大学
• [Presentation] Development of Molecular Probes for Functional Analysis of Protein Phosphatases (2007)
  • Author(s): Mikiko Sodeooka
  • Organizer: The 4th Takeda Science Foundation Symposium on PharmaSciences (Invited Lecture)
  • Place of Presentation: シェラトン都ホテル東京
  • Year and Date: 2007-12-03
• [Presentation] 有機合成化学から生命科学へのアプローチ:細胞の増殖と死を制御する化合物の開発 (2007)
  • Author(s): 袖岡 幹子
  • Organizer: 第3回未来科学講演会
  • Place of Presentation: 山口大学工学部
  • Year and Date: 2007-11-29
• [Presentation] Design and Synthesis of Protein Phosphatase Inhibitors (2007)
  • Author(s): Mikiko Sodeooka
  • Organizer: RIKEN International Symposium on Chemical Biology 2007
  • Place of Presentation: 箱根・山のホテル
  • Year and Date: 2007-11-12
• [Presentation] Synthesis of RK-682 enamide derivatives as novel dual-specificity protein phosphatase inhibitors (2007)
  • Author(s): Go Hirai
  • Organizer: RIKEN International Symposium on Chemical Biology 2007
  • Place of Presentation: 箱根・山のホテル
  • Year and Date: 2007-11-12
• [Presentation] Bioactive Molecules : Methodology, Synthesis, and Chemical Biology (2007)
  • Author(s): Mikiko Sodeooka
  • Organizer: The 13rd Nagoya Medal Seminar (Award Lecturer)
  • Place of Presentation: 名古屋国際会議場
  • Year and Date: 2007-11-09
• [Presentation] プロテインホスファターゼ阻害剤の設計と合成 (2007)
  • Author(s): 袖岡 幹子
  • Organizer: 第14回ファーマサイエンスフォーラム
  • Place of Presentation: 北海道大学薬学研究科
  • Year and Date: 2007-09-26
• [Presentation] 細胞内情報伝達を制御する分子をめざして (2007)
  • Author(s): 袖岡 幹子
  • Organizer: 平成19年度有機合成化学春季講習会
  • Place of Presentation: 駒場エミナース
  • Year and Date: 2007-06-20
• [Presentation] 細胞内情報伝達を制御する分子をめざして:プロテインホスファターゼ阻害剤の開発 (2007)
  • Author(s): 袖岡 幹子
  • Organizer: 有機合成セミナー
  • Place of Presentation: 名古屋大学工学研究科
  • Year and Date: 2007-05-24
• [Presentation] Enantioselective Catalysis Based on Palladium Enolate Chemistry (2007)
  • Author(s): Mikiko Sodeooka
  • Organizer: Forum on Asymmetric Synthesis and Technologies (FAST)2007 (Invited Lecture)
  • Place of Presentation: Cambridge, UK
• [Presentation] Enantioselective Synthesis of Heterocyclic Compounds Based on Palladium Enolate Chemistry (2007)
  • Author(s): Mikiko Sodeooka
  • Organizer: International Conference on Heterocyclic Chemistry (Plenary Lecture)
  • Place of Presentation: Sydney, Austraria
• [Presentation] Enantioselective Catalysis Based on Palladium Enolate Chemistry (2007)
  • Author(s): Mikiko Sodeooka
  • Organizer: The 7th JOM Symposium at 2007 ACS Fall National Meeting (Invited Lecture)
  • Place of Presentation: Boston, USA
• [Presentation] Enantioselective Catalysis Based on Palladium Enolate Chemistry (2007)
  • Author(s): Mikiko Sodeooka
  • Organizer: The 22nd Annual W. S. Johnson Symposium in Organic Chemistry (Invited Lecture)
  • Place of Presentation: Stanford University, USA
• [Presentation] 新規細胞死抑制剤の開発と作用機序解明研究 (2007)
  • Author(s): どど孝介
  • Organizer: 日本ケミカルバイオロジー研究会第二回年会
  • Place of Presentation: 京都大学
• [Presentation] C-グリコシド結合を有するシアリルガラクトース類の系統的合成法の開発 (2007)
  • Author(s): 渡辺亨
  • Organizer: 第91回有機合成シンポジウム
  • Place of Presentation: 東京工業大学
• [Presentation] PKCαClaドメインへ選択的に結合する蛍光標識リガンドの合成 (2007)
  • Author(s): 小山佑介
  • Organizer: 第42回天然物化学談話会
  • Place of Presentation: 仙台
• [Presentation] 新規細胞死抑制剤インドリルマレイミド誘導体の開発 (2007)
  • Author(s): 清水忠
  • Organizer: 第42回天然物化学談話会
  • Place of Presentation: 仙台
• [Presentation] Asymmetric fluorination of α-arylacetic acid derivatives using a novel catalytic system consisting of NiCl_2-BINAP/R_3SiOTf/2,6-lutidine (2007)
  • Author(s): Toshiaki Suzuki
  • Organizer: 14th IUPAC International Symposium on Organometallic Chemistry Directed Towards Organic Synthesis (OMCOS 14)
  • Place of Presentation: Nara
• [Presentation] C-結合型シアリルガラクトースを含むガングリオシドアナログの合成 (2007)
  • Author(s): 渡辺亨
  • Organizer: 第27回日本糖質学会年会
  • Place of Presentation: 九州大学
• [Presentation] Asymmetric Fluorination Reaction with the Catalytic System NiCl_2-BINAP/R_3SiOTf/2,6- Lutidine (2007)
  • Author(s): Yoshitaka Hamashima
  • Organizer: 第54回有機金属化学討論会
  • Place of Presentation: 広島大学
• [Book] 生命科学への展開(現代化学への入門15) (2006)
  • Author(s): 上村大輔, 袖岡幹子
  • Total Pages: 231
  • Publisher: 岩波書店
• [Remarks]
  • URL: http://www.riken.jp/r-world/research/lab/wako/organic/index.html
• [Patent(Industrial Property Rights)] ヘビ毒筋壊死因子阻害剤 (2008)
  • Inventor(s): 袖岡幹子
  • Industrial Property Rights Holder: 理化学研究所
  • Industrial Property Number: 2008-000629
  • Filing Date: 2008-01-07
• [Patent(Industrial Property Rights)] 3-ニトロ-1, 2, 4-トリアゾール-1H-カルボン酸エステル類の合成法、及びこれを用いた反応 (2007)
  • Inventor(s): 袖岡幹子
  • Industrial Property Rights Holder: 理化学研究所
  • Industrial Property Number: 2007-260255
  • Filing Date: 2007-10-03
• [Patent(Industrial Property Rights)] 3-ニトロ-1, 2, 4-トリアゾール-1H-カルボン酸エステル類の合成法、及びこれを用いた反応 (2007)
  • Inventor(s): 袖岡幹子
  • Industrial Property Rights Holder: 理化学研究所
  • Industrial Property Number: 2007-338931
  • Filing Date: 2007-12-28