Development of amyloid beta C-terminal motifs conjugated with phenolic antioxidant

• Project/Area Number: 26460153
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Drug development chemistry
• Research Institution: Showa University
• Principal Investigator: Fukuhara Kiyoshi 昭和大学, 薬学部, 教授 (70189968)
• Co-Investigator(Renkei-kenkyūsha): OHNO Akiko 国立医薬品食品衛生研究所, 安全性予測評価部, 主任研究官 (70356236)
• Project Period (FY): 2014-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2017: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2016: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2015: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: アルツハイマー病治療薬 / アミロイドβ / 抗酸化物質 / トロロックス / カフェ酸 / アルツハイマー病 / ビタミンE / ペプチドモチーフ / 凝集阻害 / 神経細胞毒性抑制作用 / アミロイド

Outline of Final Research Achievements

The aggregation pathway of β-amyloid (Aβ) is a key target to prevent the onset of Alzheimer’s diseases (AD). The aggregation of the 42-mer peptides (Aβ42) induces the oxidative stress which is related to neurotoxicity. We synthesized Aβ42 C-terminal motifs (Aβn-42) conjugated to the antioxidant trolox (Tx) or caffeic acid (Ca). These compounds showed anti-aggregation activities toward Aβ42. The most potent inhibitory activity was found in Tx-Aβ36-42 and CA-Aβ38-42. Protective effects against Aβ42 induced neurotoxicity was also shown by TxAβ36-42 and CaAβ38-42. These compounds demonstrated potent antioxidative activities toward Aβ42-induced intracellular ROS generation. Finally, conjugating C-terminal motif to Trolox and caffeic acid is proved to be crucial for the protective effects on Aβ-induced neurotoxicity. TxAβ36-42 and CaAβ38-42 may be a starting point for the future development of drugs that prevent neurotoxicity and deposition of Aβ in the brain of AD.

Research Products

• [Journal Article] A Metabolic Study on the Biochemical Effects of Chiral Illegal Drugs in Rats Using ¹H-NMR Spectroscopy (2017)
  • Author(s): K. Fukuhara, A. Ohno, R. Kikura-Hanajiri
  • Journal Title: YAKUGAKU ZASSHI Volume: 137 Issue: 9 Pages: 1147-1154
  • DOI: 10.1248/yakushi.17-00046
  • NAID: 130006038236
  • ISSN: 0031-6903, 1347-5231
  • Year and Date: 2017-09-01
  • Peer Reviewed
• [Journal Article] Enhanced radical scavenging activity of a procyanidin B3 analogue comprised of a dimer of planar catechin (2017)
  • Author(s): M. Mizuno, I. Nakanishi, K. Matsumoto, K. Fukuahra
  • Journal Title: Bioorg Med Chem Lett Volume: 27 Issue: 22 Pages: 5010-5013
  • DOI: 10.1016/j.bmcl.2017.10.007
  • Peer Reviewed
• [Journal Article] A novel entecavir analogue constructing with a spiro[2.4]heptane core structure in the aglycon moiety: Its synthesis and evaluation for anti-hepatitis B virus activity. (2017)
  • Author(s): Hiroki Kumamoto, Misato Fukano, Shuhei Imoto, Satoru Kohgo, Yuki Odanaka, Masayuki Amano, Nobuyo Kuwata-Higashi, Hiroaki Mitsuya, Kazuhiro Haraguchi & Kiyoshi Fukuhara.
  • Journal Title: Nucleosides, nucleotides & nucleic acids Volume: 36 Issue: 7 Pages: 463-473
  • DOI: 10.1080/15257770.2017.1322209
  • Peer Reviewed
• [Journal Article] 52.Synthesis of Methylated Quercetin Analogues for Enhancement of Radical-Scavenging Activity (2017)
  • Author(s): Kohei Imai, Ikuo Nakanishi, Kei Ohkubo, Yusuke Ohba, Takuya Arai, Mirei Mizuno, Shunichi Fukuzumi, Ken-ichiro, and Matsumoto, Kiyoshi Fukuhara
  • Journal Title: RSC Adv. Volume: 7 Issue: 29 Pages: 17968-17979
  • DOI: 10.1039/c7ra02329d
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Synthesis and Antioxidant Activity of a Procyanidin B3 Analogue (2017)
  • Author(s): 水野 美麗，中西 郁夫，松林 智子，今井 耕平，荒井 卓也，松本 謙一郎，福原 潔
  • Journal Title: Bioorganic & Medicinal Chemistry Letters Volume: 27 Issue: 4 Pages: 1041-1044
  • DOI: 10.1016/j.bmcl.2016.12.067
  • Peer Reviewed
• [Journal Article] Design, synthesis, and evaluation of Trolox-conjugated amyloid-beta C-terminal peptides for therapeutic intervention in an in vitro model of Alzheimer's disease (2016)
  • Author(s): Takuya Arai, Akiko Ohno, Kazunori Mori, Taeko Kakizawa, Hiroshi Kuwata, Toshihiko Ozawa, Motoko Shibanuma, Shuntaro Hara, Seiichi Ishida, Masaaki Kurihara, Naoki Miyata, Hidehiko Nakagawa, Kiyoshi Fukuhara
  • Journal Title: Bioorg. Med. Chem. Volume: 24 Issue: 18 Pages: 4138-4143
  • DOI: 10.1016/j.bmc.2016.06.057
  • Peer Reviewed
• [Journal Article] Inhibition of amyloid fibril formation and cytotoxicity by caffeic acid-conjugated amyloid-beta C-terminal peptides (2016)
  • Author(s): Takuya Arai, Akiko Ohno, Kazunori Mori, Hiroshi Kuwata, Mirei Mizuno, Kohei Imai, Shuntaro Hara, Motoko Shibanuma, Masaaki Kurihara, Naoki Miyata, Hidehiko Nakagawa, Kiyoshi Fukuhara
  • Journal Title: Bioorg. Med. Chem. Lett. Volume: 26 Issue: 22 Pages: 5468-5471
  • DOI: 10.1016/j.bmcl.2016.10.027
  • Peer Reviewed
• [Journal Article] A double bond-conjugated dimethylnitrobenzene-type photolabile nitric oxide donor with improved two-photon cross section (2015)
  • Author(s): 1.N. Ieda, K. Hishikawa, K. Eto, K. Kitamura, M. Kawaguchi, T. Suzuki, K. Fukuhara, N. Miyata, T. Furuta, J. Nabekura, H. Nakagawa
  • Journal Title: Bioorg. Med. Chem. Lett. Volume: 25 Issue: 16 Pages: 3172-3175
  • DOI: 10.1016/j.bmcl.2015.05.095
  • Peer Reviewed / Open Access
• [Journal Article] The hydroxy group of resveratrol is functionally important for direct activation of PPARalpha (2015)
  • Author(s): Yoshie Takizawa, Rieko Nakata, Hiroyasu Inoue
  • Journal Title: PLOS ONE Volume: 印刷中 Issue: 3 Pages: 1-8
  • DOI: 10.1371/journal.pone.0120865
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Visible light-induced nitric oxide release from a novel nitrobenzene derivative cross-conjugated with a coumarin fluorophore (2014)
  • Author(s): Kai Kitamura, Hidehiko Nakagawa et al.
  • Journal Title: Bioorg. Med. Chem. Lett. Volume: 24 Issue: 24 Pages: 5660-5662
  • DOI: 10.1016/j.bmcl.2014.10.075
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] アミロイドβによる神経細胞毒性を抑制するプロアントシアニジン誘導体の開発 (2018)
  • Author(s): 水野美麗、森一憲、中西郁夫、松本謙一郎、柴沼質子、福原潔
  • Organizer: 日本農芸化学会2018年度大会
• [Presentation] カテキンのプロオキシダント効果：キノン代謝を経由する活性酸素毒性の解析 (2018)
  • Author(s): 水野美麗、阿部眞優奈、生澤瑞季、福原潔
  • Organizer: 日本農芸化学会2018年度大会
• [Presentation] アルツハイマー病治療薬を目指したアミロイドβのC末端ペプチドモチーフを有するフェノール性抗酸化剤の開発 (2017)
  • Author(s): 福原潔、荒井卓也、大野彰子、森一憲、芝沼質子、宮田直樹、中川秀彦
  • Organizer: 日本農芸化学会2017年度大会
  • Place of Presentation: 京都
  • Year and Date: 2017-03-18
• [Presentation] アミロイドβ凝集阻害作用を有するプロアントシアニジン誘導体の創製 (2017)
  • Author(s): 水野美麗、森一憲、中西郁夫、松本謙一郎、柴沼質子、福原潔
  • Organizer: 第35回メディシナルケミストリーシンポジウム
• [Presentation] カテキン類のラジカル消去反応機構の化学的解析 (2017)
  • Author(s): 江部靖弘、堀内柊吾、水野美麗、福原潔
  • Organizer: 第61回 日本薬学会 関東支部大会
• [Presentation] アミロイドβの C 末端モチーフを有する新規アルツハイマー病治療薬の開発 (2016)
  • Author(s): 荒井卓也、大野彰子、栗原正明、宮田直樹、中川秀彦、福原潔
  • Organizer: 第34回メディシナルケミストリーシンポジウム
  • Place of Presentation: つくば
  • Year and Date: 2016-11-30
• [Presentation] AβのC末端もチーフを含有したトロロックス誘導体によるAβの細胞毒性および酸化ストレスの抑制 (2016)
  • Author(s): 荒井卓也、大野彰子、森一憲、柿澤多恵子、石田誠一、桑田浩、小澤俊彦、原俊太郎、柴沼質子、栗原正明、宮田直樹、中川秀彦、福原潔
  • Organizer: 日本薬学会第136年会
  • Place of Presentation: 横浜
  • Year and Date: 2016-03-26
• [Presentation] 新規アルツハイマー病治療薬の開発を目指したAβ1-42のC末端モチーフ含有ジヒドロカフェ酸誘導体の合成 (2015)
  • Author(s): 荒井卓也、大野彰子、須賀真里奈、栗原正明、小澤俊彦、宮田直樹、中川秀彦、福原潔
  • Organizer: 日本酸化ストレス学会学術集会
  • Place of Presentation: 鹿児島
  • Year and Date: 2015-06-11
• [Presentation] Aβ1-42のC末端モチーフを有するカフェ酸およびジヒドロカフェ酸誘導体の合成とAβ凝集阻害活性の解析 (2015)
  • Author(s): 荒井卓也、大野彰子、栗原正明、宮田直樹、中川秀彦、福原潔
  • Organizer: 日本薬学会第135年会
  • Place of Presentation: 神戸
  • Year and Date: 2015-03-25 – 2015-03-28
• [Patent(Industrial Property Rights)] 新規スチルベン誘導体 (2014)
  • Inventor(s): 福原潔、熊本浩樹、樋口明弘、坪田一男
  • Industrial Property Rights Holder: 福原潔、熊本浩樹、樋口明弘、坪田一男
  • Industrial Property Rights Type: 特許
  • Filing Date: 2014-08-29