Development of a novel brain protectant

2017 Fiscal Year Annual Research Report

• Project/Area Number: 16K15143
• Research Institution: Kumamoto University
• Principal Investigator: 大塚 雅巳 熊本大学, 大学院生命科学研究部(薬), 教授 (40126008)
• Project Period (FY): 2016-04-01 – 2018-03-31
• Keywords: 脳保護 / HNE

Outline of Annual Research Achievements

脳梗塞においては、発病直後の急性期における対応が予後を大きく左右する。脳梗塞中心部では血流が途絶え、神経細胞死が起こるが、その周囲部分（ペナンブラと呼ばれる）は血行が中程度で放置すると細胞死に至る。
脳保護薬は急性期のペナンブラを細胞死から救うもので、極めて重要である。しかし世界的にみても、脳保護薬は我が国で開発されたエダラボンのみである。脳梗塞が起こった虚血脳が再開通すると多量の酸素が流入するため、ペナンブラ部位にフリーラジカルが急増する。すると脳神経細胞の細胞膜の脂質過酸化が起こり、細胞毒性をもったアルデヒドHNEが生成して脳梗塞が増悪する。
脳保護薬エダラボンは、脳梗塞急性期に脳内に生ずるフリーラジカルを消去する脳移行性低分子化合物である。本研究は、脂質過酸化により生成する細胞毒性アルデヒドHNEを不活化するメカニズムで脳保護を行う新規化合物を創製するものである。具体的にはジペプチドであるカルノシンをリード化合物として反応性の高い誘導体の分子設計を行った。
カルノシンの構造を修飾した誘導体を各種合成し、その機能を検討した。その結果、化合物はHNEを効率的に結合消去した。また、細胞にHNEを作用させて起こる細胞死を化合物は抑制した。更に、スナネズミの脳虚血モデルを用い、化合物が海馬細胞の脱落を防ぎ、脳保護作用を持つことを確認した。
本研究はエダラボンとは作用機序を異にする新しい脳保護薬の創製につながるものである。

Research Products

• [Journal Article] Blockade of TGF-b/Smad signaling by the small compound, HPH-15, ameliorates experimental skin fibrosis (2018)
  • Author(s): Vu Huy Luong, Takenao Chino, Noritaka Oyama, Takashi Matsushita, Yoko Sasaki, Dai Ogura, Shin-ichiro Niwa, Tanima Biswas, Akiyuki Hamasaki, Mikako Fujita, Yoshinari Okamoto, Masami Otsuka, Hironobu Ihn, Minoru Hasegawa
  • Journal Title: Arthritis Research & Therapy Volume: 20 Pages: 46-46
  • DOI: https://doi.org/10.1186/s13075-018-1534-y
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] The First Pentacyclic Tripenoid Gypsogenin Derivative Having Anti-ABL1 Kinase and Anti-Chronic Myelogenous Leukemia Activities (2018)
  • Author(s): Halil Ibrahim Ciftci, Safiye Emirdag Ozturk, Taha F. S. Ali, Mohamed O. Radwan, Hiroshi Tateishi, Ryoko Koga, Mustafa Can, Masami Otsuka, Mikako Fujita
  • Journal Title: Biol. Pharm. Bull. Volume: 41 Pages: 570-574
  • DOI: https://doi.org/10.1248/bpb.b17-00902
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Design, synthesis and biological evaluation of novel 1,3,4-thiadiazole derivatives as potential antitumor agents against chronic myelogenous leukemia. Striking effect of nitrothiazole moiety (2018)
  • Author(s): Mehlika Dilek Altintop, Halil Ibrahim Ciftci, Mohamed O. Radwan, Belgin Sever, Zafer Asim Kaplancikli, Taha F.S. Ali, Ryoko Koga, Mikako Fujita, Masami Otsuka, Ahmet Ozdemir
  • Journal Title: Molecules Volume: 23 Pages: 59-59
  • DOI: 10.3390/molecules23010059
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Introduction of H2C2-type zinc-binding residues to HIV-2 Vpr increases its expression level (2018)
  • Author(s): Ryoko Koga, Minami Yamamoto, Halil Ciftci, Masami Otsuka, Mikako Fujita
  • Journal Title: FEBS OpenBio Volume: 8 Pages: 146-153
  • DOI: doi:10.1002/2211-5463.12358
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A Dithiol Compound Binds To The Zinc Finger Protein TRAF6 and Suppresses Its Ubiquitination (2017)
  • Author(s): Ryoko Koga, Mohamed O. Radwan, Tomohiko Ejima, Yosuke Kanemaru, Hiroshi Tateishi, Taha F. S. Ali, Halil Ibrahim Ciftci, Yuri Shibata, Yuu Taguchi, Jun-ichiro Inoue, Masami Otsuka, Mikako Fujita
  • Journal Title: ChemMedChem Volume: 12 Pages: 1935-1941
  • DOI: https://doi.org/10.1002/cmdc.201700399
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] A novel inhibitor of farnesyltransferase with a zinc site recognition moiety and a farnesyl group. (2017)
  • Author(s): Ayumi Tanaka, Mohamed O. Radwan, Akiyuki Hamasaki, Asumi Ejima, Emiko Obata, Ryoko Koga, Hiroshi Tateishi, Yoshinari Okamoto, Mikako Fujita, Mitsuyoshi Nakao, Kazuo Umezawa, Fuyuhiko Tamanoi, Masami Otsuka
  • Journal Title: Bioorganic & Medicinal Chemistry Letters Volume: 27 Pages: 3862-3866
  • DOI: http://dx.doi.org/10.1016/j.bmcl.2017.06.047
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Marine Inspired 2-(5-Halo-1H-indol-3-yl)-N,N-Dimethylethanamines As Modulators of Serotonin Receptors: An Example Illustrating the Power of Bromine as part of the Uniquely Marine Chemical Space (2017)
  • Author(s): Mohamed A. Ibrahim, Abir T. El-Alfy, Kelly Ezel, Mohamed O. Radwan, Abbas G. Shilabin, Anna J. Kochanowska-Karamyan, Howaida I. Abd-Alla, Masami Otsuka, Mark T. Hama
  • Journal Title: Marine Drugs Volume: 15 Pages: 248-248
  • DOI: doi:10.3390/md15080248
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Role of zinc binding site of HIV-2 Vpx prevents instability and dysfunction of the protein (2017)
  • Author(s): Minami Yamamoto, Ryoko Koga, Haruna Fujino, Kazunori Shimagaki, Halil Ibrahim Ciftci, Masahiro Kamo, Hiroshi Tateishi, Masami Otsuka, Mikako Fujita
  • Journal Title: J. General Virol. Volume: 98 Pages: 275-283
  • DOI: 10.1099/jgv.0.000701
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] A clue to non-toxic strategy to HIV eradication: “Lock-in and apoptosis” (2017)
  • Author(s): Hiroshi Tateishi, Kazuaki Monde, Kensaku Anraku, Ryoko Koga, Yuya Hayashi, Halil Ibrahim Ciftci, Hasan DeMirci, Taishi Higashi, Keiichi Motoyama, Hidetoshi Arima, Masami Otsuka, Mikako Fujita
  • Journal Title: Scientific Reports Volume: 8957 Pages: 8957
  • DOI: DOI:10.1038/s41598-017-09129-w
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Synthesis, Computational Study, and Evaluation of in vitro Antimicrobial, Antibiofilm, and Anticancer Activities of New Sulfanyl Aminonaphthoquinone Derivatives (2017)
  • Author(s): Nilufer Bayrak, Hatice Yildirim, Amac Fatih Tuyun, Emel Mataraci Kara, Berna Ozbek Celik, Girish Kumar Gupta, Halil I. Ciftci, Mikako Fujita, Masami Otsuka, Hamid R. Nasiri
  • Journal Title: Letters in Drug Design & Discovery Volume: 14 Pages: 647-661
  • DOI: https://doi.org/10.2174/157018081406170606155530
• [Presentation] HNEを標的とした新規脳保護薬 (2018)
  • Author(s): Tanima Biswas, Taha Farouk Shehata Ali, 平尚未、古賀涼子、森美晴、岡本良成、藤田美歌子、折戸公彦、野口慶、三好淳子、森岡基浩、大塚雅巳
  • Organizer: 日本薬学会第137年会
• [Presentation] Kinase Inhibitory Activity of Glycyrrhetic Acid (2018)
  • Author(s): Halil I Ciftci, Mohamed O Radwan, Masami Otsuka, Mikako Fujita
  • Organizer: The 4th International Symposium on Pharmaceutical and Biomedical Sciences
  • Invited
• [Presentation] Zinc Proteins as Drug Targets (2018)
  • Author(s): Masami Otsuka
  • Organizer: The 4th International Symposium on Pharmaceutical and Biomedical Sciences
  • Int'l Joint Research / Invited
• [Presentation] Structural basis of inositol phosphates recognition in the HIV-1 gag matrix (2017)
  • Author(s): Halilibrahim Ciftci, Hiroshi Tateishi, Kotaro Koiwai, Ryoko Koga, Masami Otsuka, Mikako Fujita, Fumiaki Yumoto, Toshiya Senda
  • Organizer: 第40回日本分子生物学会年会
• [Presentation] Structural Basis of HIV-1 Gag Matrix Targeting by IP6 Derivative (2017)
  • Author(s): Halil I. Ciftci, Hiroshi Tateishi, Kotaro Koiwai, Ryoko Koga, Masami Otsuka, Fumiaki Yumoto, Toshiya Senda
  • Organizer: 第31回日本エイズ学会学術集会
• [Presentation] HIV-2 Vpxのポリプロリンモチーフの役割 (2017)
  • Author(s): 島垣和功、古賀涼子、Halil Ibrahim Ciftci、大塚雅巳、山口佳宏、藤田美歌子
  • Organizer: 第31回日本エイズ学会学術集会
• [Presentation] TRAF6 polyubiquitination interruption by a low molecular weight zinc chelator (2017)
  • Author(s): Mohamed O. Radwan, Ryoko Koga, Tomohiko Ejima, Yosuke Kanemaru, Hiroshi Tateishi, Taha F. S. Ali, Halil Il Ciftci, Yuri Shibata, Yuu Taguchi, Jun-ichiro Inoue, Masami Otsuka, Mikako Fujita
  • Organizer: 第35回メディシナルケミストリーシンポジウム
• [Presentation] ウイルス蛋白質蓄積によりアポトーシスを誘導する新規抗HIV薬の創製 (2017)
  • Author(s): 立石大、門出和精、古賀涼子、林祐也、東大志、本山敬一、有馬英俊、安楽健作、藤田美歌子、 大塚雅巳
  • Organizer: 第35回メディシナルケミストリーシンポジウム
• [Presentation] Expression Level of HIV-2 Vpx/Vpr Proteins is Regulated by their Zinc Binding (2017)
  • Author(s): Ryoko Koga, Minami Yamamoto, Hiroshi Tateishi, Halilibrahim Ciftci, Masami Otsuka, Mikako Fujita
  • Organizer: 第65回日本ウイルス学会学術集会
• [Presentation] Structural Basis of the Interaction between HIV-1 Gag Matrix and IP6. Toward the Development of IP6 Derivative (2017)
  • Author(s): Halilibrahim Ciftci, Hiroshi Tateishi, Kotaro Koiwai, Ryoko Koga, Masami Otsuka, Mikako Fujita, Fumiaki Yumoto, Toshiya Senda
  • Organizer: 第65回日本ウイルス学会学術集会
• [Presentation] Bleomycin Revisited: Man-Made Bleomycin with New Function “Surgical Operation” of a Drug Molecule (2017)
  • Author(s): Masami Otsuka
  • Organizer: Turkish-Japanese Workshop on Bioorganic Medicinal Chemistry and Natural Products
  • Int'l Joint Research / Invited
• [Presentation] New Sirt2 Inhibitor based on S-Triryl-L-cysteins scaffold (2017)
  • Author(s): Mohamed Osman Radwan, Taha F. S. Ali, Halil Ibrahim Ciftci, Ryoko Koga, Yoshinari Okamoto, Mikako Fujita, Masami Otsuka
  • Organizer: The Second Japan-Turkey International Symposium on Pharmaceutical and Biomedical Sciences
  • Int'l Joint Research
• [Presentation] Zinc-Binding State of HIV-2 VPX/VPR Regulates (2017)
  • Author(s): Ryoko Koga, Minami Yamamoto, Haruna Fujino, Kazunori Shimagaki, Halil Ibrahim Ciftci, Masahiro Kamo, Hiroshi Tateishi, Masami Otsuka, Mikako Fujita
  • Organizer: The Second Japan-Turkey International Symposium on Pharmaceutical and Biomedical Sciences
  • Int'l Joint Research
• [Presentation] Structural Basis of Targeting HIV-Gag Matrix, Towards Finding a Cure for HIV Infection (2017)
  • Author(s): Halil Ibrahim Ciftci, Hiroshi Tateishi, Kotaro Koiwai, Ryoko Koga, Fumiaki Yumoto, Toshiya Senda, Masami Otsuka, Mikako Fujita
  • Organizer: The Second Japan-Turkey International Symposium on Pharmaceutical and Biomedical Sciences
  • Int'l Joint Research
• [Presentation] From Natural Bleomycin to Man-Made Bleomycin (2017)
  • Author(s): Masami Otsuka
  • Organizer: The Second Japan-Turkey International Symposium on Pharmaceutical and Biomedical Sciences
  • Int'l Joint Research / Invited
• [Presentation] NOVEL COMPOUND, OSSL_325096, INDUCES APOPTOSIS IN MULTIPLE MYELOMA CELLS THROUGH VCP INHIBITION (2017)
  • Author(s): Nao Nishimura, Mohamed O. Osman, Masayuki Amano, Shinya Endo, Shikiko Ueno, Nina Ueno, Hiro Tatetsu, Hitoyuki Hata, Yoshinari Okamoto, Masao Matsuoka, Masami Otsuka, Yutaka Okuno
  • Organizer: The 22nd Congress of European Hematology Association
  • Int'l Joint Research
• [Remarks] 熊本大学大学院薬学教育部 生体機能分子合成学分野
  • URL: http://www.pharm.kumamoto-u.ac.jp/Labs/bunsigouseiHP/index.html
• [Remarks] 熊本大学大学院生命科学研究部 生体機能分子合成学分野
  • URL: http://www.medphas.kumamoto-u.ac.jp/research/bunya/60.html