Synthesis and evaluation of antiviral activities of branched oxetanosine A.

• Project/Area Number: 24590144
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Drug development chemistry
• Research Institution: Nihon Pharmaceutical University (2013-2014); Showa University (2012)
• Principal Investigator: HARAGUCHI kazuhiro 日本薬科大学, 薬学部, 教授 (10218638)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2012: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: オキセタノシン / グリカール / オキセタン / 求電子付加 / グリコシル化 / ラジカル反応 / 抗ウイルス活性 / ヌクレオシド

Outline of Final Research Achievements

When oxetanoid glycal was reacted silylated N6-benzoyladenine in the presence of N-iodosuccinimide, the desired glycoside was obtained in 25% yield. Reaction of the glycoside with allyltributylstannanen was carried out in the presence of AIBN to furnish 3'-C-allyl derivative in 78% yield as diastereomeric mixture. The allylated nucleoside wa sublected hydride reduction of the ester moety followed by NaOMe-mediated removal of the benzoyl group of the adenine moiety provied the target 3'-C-allyl-oxetanosine A.

Research Products

• [Journal Article] Unlike Catalyzing Error-Free Bypass of 8-Oxo-dG, DNA Polymerase λ Is Responsible for a Major Part of Fapy-dG-Induced G→T Mutations in Human Cells (2015)
  • Author(s): Pande, P.; Haraguchi, K.; Greenberg, M. M.; Basu, A. Y .
  • Journal Title: Biochemistry Volume: 54 Issue: 10 Pages: 1859-1862
  • DOI: 10.1021/acs.biochem.5b00119
  • Peer Reviewed
• [Journal Article] Design, Synthesis and Evaluation of Anti-HBV Activity of Hybrid Molecules of Entecavir and Adefovir (2015)
  • Author(s): Imoto, S.; Kohgo, S.; Tokuda, R; Kumamoto, H.; Aoki, M.; Amano, M.; Kuwata-Higashi, N.; mitsuya, H.; Haraguchi, K.
  • Journal Title: Nucleosides, nucleotides & Nucleic Acids Volume: 43
  • Peer Reviewed
• [Journal Article] KAY-2-41, a novel nucleoside analogue inhibitor of orthopoxviruses in vitro and in vivo (2014)
  • Author(s): Duraffour, S.; Drillien, R.; Haraguch, K. Balzarini, J.; van den Oord, J. J.; Andrei, G.; Snoeck, R.
  • Journal Title: Antimicrob. Agents Chemother. Volume: 58 Pages: 27-37
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Unique spectrum of anti-herpesvirus activity and potent in vitroand in vivo efficacy against Epstein-Barr virus mediated by 4’-thiothymidine analogs (2014)
  • Author(s): Coen, N.; Duraffour, S; Haraguch, K.; Van den Oord, J. J.; Balzarini, J.; Snoeck, R .; Andrei, G.
  • Journal Title: Antimicrob. Agents Chemother. Volume: 58 Issue: 8 Pages: 4328-4340
  • DOI: 10.1128/aac.02825-14
  • Peer Reviewed
• [Journal Article] Synthesis of 3’,4’-difluoro-3’-deoxyribonucleosides and its evaluation of the biological activities: Discovery of a novel type of anti-HCV agent 3’,4’-difluorocordycepin (2014)
  • Author(s): Shimada, H.; Haraguchi, K.; Hotta, K.; Miyaike. T.; Kitagawa, Y.; Tanaka, H.; Kaneda, R.; Abe, H.; Shuto, S.; Mori, K.; Ueda, Y.; Kato, N.; Snoeck, R.; Andrei, G.; Balzarini, Y.
  • Journal Title: Bioorg. Med. Chem. Volume: 22 Pages: 6174-6182
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] From the chemistry of epoxy-sugar nucleosides to the discovery of anti-HIV agent Festinavir (2013)
  • Author(s): Haraguch, K; Takeda, S; Kubota, Y; Kumamoto, H; Tanaka, H; Hamasaki, T; Baba, M; Paintsil, E; Cheng, Y.-C.
  • Journal Title: Current Pharmaceutical Design Volume: 19 Pages: 1880-1897
  • Peer Reviewed
• [Journal Article] Synthesis of Novel 4’-C-Methyl-1’,3’-dioxolane pyrimidine nucleosides and evaluation of its anti-HIV-1 activity (2013)
  • Author(s): Kubota, Y.; Kaneda, Y.; Haraguch, K. Abe, H.; Shuto, S. J.; Hamasaki, T.; Baba, M.; Tanaka, H.
  • Journal Title: Tetrahedron Volume: 69 Pages: 10884-10892
  • Peer Reviewed
• [Journal Article] Tuning efficiency of the 4-exo-trig cyclization by the electronic effect : ring closure of 3, 3-difluoro-4-pentenyl carbon radicals and synthesis of a gem-difluorocyclobutane nucleoside (2012)
  • Author(s): Hiroki Kumamoto, Sachiko Kawahigashi, Hiromi Wakabayashi, Tomohiko Nakano, Tomoko Miyaike, Yasuyuki Kitagawa, Hiroshi Abe, Mika Ito. Kazuhiro Haraguchi, Jan Balzarini, Masanori Baba and Hiromichi Tanaka
  • Journal Title: Chemical Communication Volume: 48 Issue: 89 Pages: 10993-10995
  • DOI: 10.1039/c2cc35876j
  • Peer Reviewed
• [Presentation] エンテカビルとアデホビルのハイブリッド型化合物：メチレンアシクロヌクレオシド誘導体の合成と抗HBV活性 (2015)
  • Author(s): 井本修平、向後 悟、徳田 亮、熊本浩樹、青木 学、天野将之、鍬田（東）伸好、満屋裕明、原口一広
  • Organizer: 日本薬学会第１３５年会
  • Place of Presentation: 神戸
  • Year and Date: 2015-03-26 – 2015-03-28
• [Presentation] スピロ[2.4]ヘプタン骨格を有する炭素環ヌクレオシドの合成と抗ウイルス作用の評価 (2015)
  • Author(s): 熊本浩樹、深野美里、徳田 亮、天野将之、鍬田（東）伸好、原口一広、満屋裕明、福原 潔
  • Organizer: 日本薬学会第１３５年会
  • Place of Presentation: 神戸
  • Year and Date: 2015-03-26 – 2015-03-28
• [Presentation] 4’-Ethynyl-2-fluoro-2’-deoxyadenosine (EFdA) has an extremely high genetic barrier, persistently exerting highly potent activity against a variety of HIV-1 isolates including EFdA-selected HIV-1 variants (2015)
  • Author(s): Maeda, K.; Takamatsu, Y.; Kohgo, S.; Haraguchi, K.; Delino, N. S.; Chang, S. B.; Das, D.; Li, Z.; Kirby, K. A.; Sarafianos, S. G.; Mitsuya, H.
  • Organizer: Conference on Retroviruses and Opportunistic Infections
  • Place of Presentation: Seattle, Washington
  • Year and Date: 2015-02-23 – 2015-02-26
• [Presentation] 4’-MODIFIED NUCLEOSIDE ANALOGS: Potent Inhibitors Active against Entecavir-resistant Hepatitis B Virus (HBVETV-RL180M/S202G/M204V) (2014)
  • Author(s): Takamatsu, Y.; Tanaka, Y.; Kohgo, S.; Murakami, S.; Singh, K.; Das, D.; Venzon, D. J.; Amano, M.; Kuwata, N.; Aoki, M.; Delino, N. S.; Hayashi, S.; Takahashi, S.; Haraguchi, K.; Sarafianos, S. G.; Maeda, K.; Mitsuya, H.
  • Organizer: 4th International Conference on Antiviral Microbial Agents and Chemotherapy
  • Place of Presentation: Washington, DC
  • Year and Date: 2014-09-05 – 2014-09-09
• [Presentation] ビニルスルホンに対する共役付加および脱硫的スタニル化を利用する3’-置換BCAの合成研究 (2013)
  • Author(s): 熊本浩樹、川東祥子、若林宏美、中野智彦、宮池朋子、阿部 洋、原口一広、田中博道
  • Organizer: 日本薬学会１３３年会
  • Place of Presentation: 横浜
• [Presentation] gem-ジフルオロシクロブタンヌクレオシドの合成とその抗ウイルス活性 (2013)
  • Author(s): 熊本浩樹、川東祥子、若林宏美、中野智彦、宮池智子、北川康行、阿部洋、伊藤美香、原口一広、Jan Balzalini、馬場昌範、田中博道
  • Organizer: 第２３回抗ウイルス療法研究会
  • Place of Presentation: 東京
• [Presentation] ビニルスルホンに対する共役付加および脱硫的スタニル化を利用する3’-置換BCAの合成研究 (2013)
  • Author(s): 熊本浩樹、川東祥子、若林宏美、中野智彦、宮池朋子、阿部 洋、原口一広、田中博道
  • Organizer: 日本薬学会第１３３年会
  • Place of Presentation: 札幌
• [Presentation] Synthesis of 4’-ethynyl-2’-deoxy-4’-thioribonucleosides and discovery of a highly potent and less toxic NRTI (2012)
  • Author(s): K. Haraguchi, H. Shimada, G. Akutsu, K. Kimura, H. Tanaka, T. Mamasaki, M. Baba, E. A. Gullen, G. E. Dutschman, Y.-C. Cheng, J. Balzarini
  • Organizer: International Conference on Antiviral Research 2012
  • Place of Presentation: Sapporo
• [Presentation] KAY-2-41: A novel nucleoside analog as inhibitor of orthopoxviruses in vitro and in vivo (2012)
  • Author(s): S. Duraffour, K. Haraguchi, R. Drillien, K. Yamada, H. Tanaka, R. Snoeck, G Andrei
  • Organizer: XIX International Poxvirus, Asfavirus and Iridovirus Conference
  • Place of Presentation: France
• [Book] Frontiers in Clininal Drug Reseach (2015)
  • Author(s): Haraguchi, K.; Takeda, S.; Kubota, Y.; Kumamoto, H.; Tanaka, H.; Hamasaki, T.; E; Baba, M.; Paintsil, E.; Cheng, Y.-C.; Urata, Y.,
  • Total Pages: 61
  • Publisher: Bentham Science Publishing