Development of a novel brain protectant

• Project/Area Number: 16K15143
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Drug development chemistry
• Research Institution: Kumamoto University
• Principal Investigator: Otsuka Masami 熊本大学, 大学院生命科学研究部(薬), 教授 (40126008)
• Co-Investigator(Renkei-kenkyūsha): FUJITA Mikako 熊本大学, 薬学部, 准教授 (00322256) ; OKAMOTO Yoshinari 熊本大学, 大学院生命科学研究部, 助教 (20194409)
• Project Period (FY): 2016-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 脳保護薬 / HNE / 脳保護 / 脳神経疾患 / 薬学

Outline of Final Research Achievements

Cerebral ischemia generates oxygen free radical that induces lipid peroxidation of cerebral cell membrane to produce HNE that is toxic to cerebral nerve cells. The present research aimed at the development of a brain protecting drug that inactivates HNE.It was known that Carnosine (CAR) quenches HNE to form cyclic adduct. Histidine Hydrazide (HH) is also known to produce the similar adduct.
We now designed a compound named CNN that could form bicyclic HNE adduct that seems more stable compared with CAR or HH. CNN was found to quench HNE much more efficiently compared with CAR or HH. CNN rescued the death of PC-12 cell induced by HNE. CNN is effective by ip administration. CNN rescued the hippocampal CA1 cell death of transient cerebral ischemia model of Mongolian gerbil whereas HH did not. We developed CNN that efficiently inactivates neurotoxic HNE, the end-product of the lipid peroxidation.

Research Products

• [Journal Article] Blockade of TGF-β/Smad signaling by the small compound HPH-15 ameliorates experimental skin fibrosis (2018)
  • Author(s): Luong Vu Huy、Chino Takenao、Oyama Noritaka、Matsushita Takashi、Sasaki Yoko、Ogura Dai、Niwa Shin-ichiro、Biswas Tanima、Hamasaki Akiyuki、Fujita Mikako、Okamoto Yoshinari、Otsuka Masami、Ihn Hironobu、Hasegawa Minoru
  • Journal Title: Arthritis Research & Therapy Volume: 20 Issue: 1 Pages: 46-46
  • DOI: 10.1186/s13075-018-1534-y
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The First Pentacyclic Triterpenoid Gypsogenin Derivative Exhibiting Anti-ABL1 Kinase and Anti-chronic Myelogenous Leukemia Activities (2018)
  • Author(s): Ciftci, H.I., Ozturk, S.E., Ali, T.F.S., Radwan, M.O., Tateishi, H., Koga, R., Ocak, Z., Can, M., Otsuka, M., and Fujita, M.
  • Journal Title: Biological and Pharmaceutical Bulletin Volume: 41 Issue: 4 Pages: 570-574
  • DOI: 10.1248/bpb.b17-00902
  • NAID: 130006602535
  • ISSN: 0918-6158, 1347-5215
  • Peer Reviewed / Open Access / 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): Altintop, M.D., Ciftci, H.I., Radwan, M.O., Sever, B., Kaplancikli, Z.A., Ali, T.F.S., Koga, R., Fujita, M., Otsuka, M., and Ozdemir, A.
  • Journal Title: Molecules Volume: 23 Issue: 1 Pages: 59-59
  • DOI: 10.3390/molecules23010059
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Introduction of H2C2-type zinc-binding residues into HIV-2 Vpr increases its expression level. (2018)
  • Author(s): Koga, R., Yamamoto, M., Ciftci, H.I., Otsuka, M., and Fujita, M.
  • Journal Title: FEBS Open Bio Volume: 1 Issue: 1 Pages: 146-153
  • 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): Koga, R., Radwan, M.O., Ejima, T., Kanemaru, Y., Tateishi, H., Ali, T.F.S., Ciftci, H.I., Shibata, Y., Taguchi, Y., Inoue, J., Otsuka, M., and Fujita, M.
  • Journal Title: ChemMedChem Volume: 12 Issue: 23 Pages: 1935-1941
  • DOI: 10.1002/cmdc.201700399
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A novel inhibitor of farnesyltransferase with a zinc site recognition moiety and a farnesyl group. (2017)
  • Author(s): Tanaka, A., Radwan, M.O., Hamasaki, A., Ejima, A., Obata, E., Koga, R., Tateishi, H., Okamoto, Y., Fujita, M., Nakao, M., Umezawa, K., Tamanoi, F., and Otsuka, M.
  • Journal Title: Bioorganic & Medicinal Chemistry Letters Volume: 27 Issue: 16 Pages: 3862-3866
  • DOI: 10.1016/j.bmcl.2017.06.047
  • Peer Reviewed / Open Access / 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 Issue: 8 Pages: 248-248
  • 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 Issue: 2 Pages: 275-283
  • DOI: 10.1099/jgv.0.000701
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] A clue to unprecedented strategy to HIV eradication: “Lock-in and apoptosis”. (2017)
  • Author(s): Tateishi, H., Monde, K., Anraku, K., Koga, R., Hayashi, Y., Ciftci, H.I., DeMirci, H., Higashi, T., Motoyama, K, Arima, H., Otsuka, M., and Fujita, M.
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 8957-8957
  • DOI: 10.1038/s41598-017-09129-w
  • Peer Reviewed / Open Access / 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 Issue: 6 Pages: 647-661
  • DOI: 10.2174/157018081406170606155530
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Synthesis of the biotinylated anti-HIV compound BMMP and the target identification study. (2016)
  • Author(s): Kamo M, Tateishi H, Koga R, Okamoto Y, Otsuka M, Fujita M.
  • Journal Title: Bioorg. Med. Chem. Volume: 26 Issue: 1 Pages: 43-45
  • DOI: 10.1016/j.bmcl.2015.11.036
  • Peer Reviewed
• [Journal Article] Zinc-mediated binding of a low-molecular-weight stabilizer of the host anti-viral factor apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like 3G (2016)
  • Author(s): Radwan, Mohamed O.; Sonoda, Sachiko; Ejima, Tomohiko; Tanaka, Ayumi; Koga, Ryoko; Okamoto, Yoshinari; Fujita, Mikako; Otsuka, Masami
  • Journal Title: Bioorganic & Medicinal Chemistry Volume: 24 Issue: 18 Pages: 4398-4405
  • DOI: 10.1016/j.bmc.2016.07.030
  • Peer Reviewed
• [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
• [Presentation] 金属キレーターによるHSP70蛋白質の発現上昇 (2016)
  • Author(s): 平尚未、タハ ファロウク シェハタ アリ、古賀涼子、大塚雅巳、藤田美歌子
  • Organizer: 第33回日本薬学会九州支部大会
  • Place of Presentation: 鹿児島大学郡元キャンパス
  • Year and Date: 2016-12-03
• [Presentation] DHMEQを基盤とした新しい生物活性物質の設計と合成、および機能解析 (2016)
  • Author(s): 本邑健太、岡本良成、古賀涼子、馬塲菜々美、藤田美歌子、梅澤一夫、大塚雅巳
  • Organizer: 第33回日本薬学会九州支部大会
  • Place of Presentation: 鹿児島大学郡元キャンパス
  • Year and Date: 2016-12-03
• [Presentation] 亜鉛結合性低分子化合物によるTRAF6および下流シグナル経路に対する影響 (2016)
  • Author(s): 古賀涼子、Mohamed O. Radwan、江島智彦、金丸陽亮、柴田佑里、田口祐、井上純一郎、大 塚雅巳、藤田美歌子
  • Organizer: 第39回日本分子生物学年会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2016-11-30
• [Presentation] 抗HIV活性を持つヘテロ環化合物BMMPの作用機序解明 (2016)
  • Author(s): 加茂真宏、立石大、山本充奈美、岡本良成、森川裕子、三隅将吾、大塚雅巳、藤田美歌子
  • Organizer: 第30回日本エイズ学会学術集会
  • Place of Presentation: かごしま県民交流センター
  • Year and Date: 2016-11-24
• [Presentation] Lock-in and apoptosis strategy using a PI(4,5)P2 analog aiming at eradication of HIV (2016)
  • Author(s): Hiroshi Tateishi, Kazuaki Monde, Kensaku Anraku, Ryoko Koga, Yuya Hayashi, Keiichi Motoyama, Hidetoshi Arima, Masami Otsuka, Mikako Fujita
  • Organizer: 2 nd Kumamoto IRCMS International Symposium and 17 th Kumamoto AIDS Seminar
  • Place of Presentation: 熊本県民交流館パレア
  • Year and Date: 2016-10-31
  • Int'l Joint Research
• [Presentation] Role of zinc binding site of HIV-2 Vpx (2016)
  • Author(s): Minami Yamamoto, Ryoko Koga, Haruna Fujino, Kazunori Shimagaki, Halil Ibrahim Ciftci, Masahiro Kamo, Hiroshi Tateishi, Masami Otsuka, Mikako Fujita
  • Organizer: 2 nd Kumamoto IRCMS International Symposium and 17 th Kumamoto AIDS Seminar
  • Place of Presentation: 熊本県民交流館パレア
  • Year and Date: 2016-10-31
  • Int'l Joint Research
• [Presentation] Characters of largely overexpressed HIV accessory proteins Vpx and Vif (2016)
  • Author(s): Kazunori Shimagaki, Halil Ibrahim Ciftci, Ryoko Koga, Haruna Fujino, Minami Yamamoto, Yoshihiro Yamaguchi, Masami Otsuka, Mikako Fujita
  • Organizer: 第64回日本ウイルス学会学術集会
  • Place of Presentation: 札幌コンベンションセンター
  • Year and Date: 2016-10-23
• [Presentation] Elucidation of action mechanism of heterocyclic compound BMMP having anti-HIV activity (2016)
  • Author(s): Masahiro Kamo, Hiroshi Tateishi, Minami Yamamoto, Yoshinari Okamoto, Yuko Morikawa, Shogo Misumi, Masami Otsuka, Mikako Fujita
  • Organizer: 第64回日本ウイルス学会学術集会
  • Place of Presentation: 札幌コンベンションセンター
  • Year and Date: 2016-10-23
• [Presentation] A PI(4,5)P2 analog suppresses HIV-1 release and locked-in viralprotein. (2016)
  • Author(s): Hiroshi Tateishi, Kazuaki Monde, Ryoko Koga, Yuya Hayashi, Taishi Higashi, Keiichi Motoyama, Hidetoshi Arima, Kensaku Anraku, Masami Otsuka, Mikako Fujita
  • Organizer: Cold Spring Harbor Meeting, Retroviruses, 2016
  • Place of Presentation: Cold Spring Harbor Laboratory, NY, USA
  • Int'l Joint Research
• [Presentation] Design and synthesis of small molecule Hsp70 inducers (2016)
  • Author(s): Taha Ali, Naomi Taira, Ryoko Koga, Yoshinari Okamoto, Masami Otsuka, Mikako Fujita
  • Organizer: 252nd American Chemical Society Annual Meeting
  • Place of Presentation: Pennsylvania Convention Center, Philadelphia
  • Int'l Joint Research
• [Presentation] Zinc-mediated binding of a low-molecular-weight stabilizer of the host anti-viral factor APOBEC3G (2016)
  • Author(s): Mohamed Radwan, Sachiko Sonoda, Tomohiko Ejima, Ayumi Tanaka, Ryoko Koga, Yoshinari Okamoto, Mikako Fujita, Masami Otsuka
  • Organizer: 252nd American Chemical Society Annual Meeting
  • Place of Presentation: Pennsylvania Convention Center, Philadelphia
  • Int'l Joint Research
• [Presentation] Restructuring of the bleomycin Metal Core (2016)
  • Author(s): Taha F. S. Ali, Satomi Ida, Yosuke Kanemaru, Ryoko Koga, Ayumi Tanaka, Akiyuki Hamasaki, Tomohiko Ejima, Mohamed Osman Radwan, Halil Ibrahim Ciftci, Hiromasa Kurosaki, Yoshinari Okamoto, Mikako Fujita, Masami Otsuka
  • Organizer: Japan-Turkey International Symposium on Pharmaceutical and Biomedical Sciences
  • Place of Presentation: 熊本大学薬学部宮本記念館
  • Int'l Joint Research / Invited
• [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
• [Remarks] 生体機能分子合成学分野
  • URL: http://www.pharm.kumamoto-u.ac.jp/Labs/bunsigouseiHP/index.html