Synthesis of 4'-substtituted 4'-thionucleosides and evaluation of its biological activity

• Project/Area Number: 21590123
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Drug development chemistry
• Research Institution: Showa University
• Principal Investigator: HARAGUCHI Kazuhiro 昭和大学, 薬学部, 准教授 (10218638)
• Project Period (FY): 2009 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2011: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2010: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2009: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: ヌクレオシド / グリカール / チオ糖 / グリコシル化 / 抗ウイルス活性 / チオヌクレオシド / 求電子試剤 / 抗腫瘍活性

Research Abstract

Synthetic method for 4-thiofuranoid glycal having ethynyl or cyano group at the 4'-position has been developed. On the basis of electrophilic glycosidation between the glycals and nucleobase as a key step, the target 4'-ethynyl(or cyano)-2'-deoxy-4'-thionucleosides could be obtained. The antiviral evaluation revealed that 4'-ethynyl-2'-deoxy-4'-thioguanosine was found to be highly potent and less toxic NRTI. 4-Ethynyl-4-thioribose derived from 4-Thiofuranoid glycal derived served as gycosyl donor in Vorbruggen glycosidation to give the taget 4'-ehtynyl-4'-thiocytidine.

Research Products

• [Journal Article] Synthesis of 4 Ethynyl-2 deoxy-4 thioribonucleosides and discovery of a highly potent and less toxic NRTI (2011)
  • Author(s): Haraguchi, K.; Shimada, H.; Kimura, K.; Akutsu, G.; Tanaka, H., Abe, H.; Hamasaki, T.; Baba, M.; Gullen, E. A.; Dutschman, G. E.; Cheng, Y.-C.; Balzarini, Y.
  • Journal Title: ACS Med. Chem. Lett Volume: 2 Pages: 692-697
• [Journal Article] An access to the.-anomer of 4thio-C-ribonucleosides : hydrogoration of 1-C-Aryl-or 1-C-hetreoaryl-4-thiofuranoid glycals and its regiochemical outcome (2011)
  • Author(s): Haraguchi, K.; Horii, C.; Yoshimura, Y.; Ariga, F.; Tadokoro, A., Tanaka, H.
  • Journal Title: J. Org. Chem Volume: 76 Pages: 8608-8669
• [Journal Article] Phenylsulfanylation of 3 4unsaturated adenosine employing thiophenol-N-iodosuccinimide leads to 4phenylsulfanylcordycepin : synthesis of 4substituted cordycepins on the basis of substitution of the phenylsulfanyl leaving group (2011)
  • Author(s): Kubota, Y.; Ehara, M.; Haraguchi, K.; Tanaka, H.
  • Journal Title: J. Org. Chem Volume: 76 Pages: 8710-8717
• [Journal Article] エポキシ糖の反応性を利用する立体制御された分岐糖ヌクレオシドの合成研究:抗HIV活性を有するFestinavirの開発 (2011)
  • Author(s): 原口一広
  • Journal Title: 昭和大学薬学雑誌 Volume: 2 Pages: 15-29
  • NAID: 120006711012
• [Journal Article] Synthesis of 4'-Ethynyl-2'-deoxy-4'-thioribonucleosides and discovery of a highly potent and less toxic NRTI (2011)
  • Author(s): Kazuhiro Haraguchi
  • Journal Title: ACS Med.Chem.Lett Volume: 2 Issue: 9 Pages: 692-697
  • DOI: 10.1021/ml2001054
  • Peer Reviewed
• [Journal Article] An Access to the β-Anomer of 4'-Thio-C-ribonucleosides : Hydroboration of 1-C-Aryl- or 1-C-Heteroaryl-4-thiofuranoid Glycals and Its Regiochemical Outcome (2011)
  • Author(s): Haraguchi, K.; Horii, C.; Yoshimura, Y.: Ariga, F.; Tadokoro, A.; Tanaka, H.
  • Journal Title: J.Org.Chem. Volume: 76 Issue: 21 Pages: 8658-8669
  • DOI: 10.1021/jo201100n
  • Peer Reviewed
• [Journal Article] Phenylsulfanylation of 3', 4'-unsaturated adenosine employing thiophenol-N-iodosuccinimide leads to 4'-phenylsulfanylcordycepin : synthesis of 4'-substituted cordycepins on the basis of substitution of the phenylsulfanyl leaving group (2011)
  • Author(s): Kazuhiro Haraguchi
  • Journal Title: J.Org.Chem. Volume: 76 Issue: 21 Pages: 8710-8717
  • DOI: 10.1021/jo201246y
  • Peer Reviewed
• [Journal Article] Stereoselective preparation of 1-[5-O-(tert-butyldimethylsilyl)-2, 3-dideoxy-3-iodo-.-D-threo-pentofuranosyl] thymine from thymidine : an efficient entry to 3', 4'-unsaturated nucleoside (2010)
  • Author(s): Kubota, Y.; Nakamura, K.; Ishizaki, N.; Haraguchi, K.; Tanaka, H.
  • Journal Title: Syntheth. Commun Volume: 40 Pages: 1758-1764
• [Journal Article] Electrophilic glycosidation employing 3, 5-O-(di-tert-butylsilylene)-erythro-furanoid glycal leads to exclusive formation of theβ-anomer : synthesis of 2'-deoxynucleosides and its 1'-branched analogues (2010)
  • Author(s): Haraguchi, K.; Konno, K.; Yamada, K.; Kitagawa, Y.; Nakamura, K. T.; Tanaka, H.
  • Journal Title: Tetrahedron Volume: 66 Pages: 4587-4600
• [Journal Article] Synthesis and anti-HIV-1 evaluation of phosphonates which mimic the 5'-monophosphate of 4'-branched 2', 3'-didehydro-2', 3'-dideoxy nucleosides (2010)
  • Author(s): Kubota, Y.; Ishizaki, N.; Haraguchi, K.; Hamasaki, T.; Baba, M.; Tanaka, H.
  • Journal Title: Bioorg. Med. Chem Volume: 18 Pages: 7186-7192
• [Journal Article] A questionnaire survey of students who attempted the objective structured clinical examination(OSCE) at the School of Pharmacy, Showa University (2010)
  • Author(s): Kogo, M.; Saito, I.; Kurata, N.; Sasaki, K.; Ishii, M.; Haraguchi, K.; Kiuchi, Y.; Yamamoto, T.
  • Journal Title: The Showa University Journal of Pharmaceutical Sciences Volume: 1 Pages: 63-71
• [Journal Article] Preparation of 4benznensulfonyl-3deoxythymidine and its reaction with organoaluminum and organosilicon reagents (2010)
  • Author(s): Shimada, H.; Kikuchi, S.; Haraguchi, K.; Tanaka, H.
  • Journal Title: Carbohydr. Res Volume: 345 Pages: 2616-2622
• [Journal Article] Stereoselective preparation of 1-[5-0-(tert-butyldimethylsilyl)-2,3-dideoxy-3-iodo-β-D-threo-pentofuranosyl]thymine : an efficient entry to 3',4'-unsaturated nucleoside (2010)
  • Author(s): Kazuhiro Haraguchi
  • Journal Title: Synthetic.Commun. Volume: 40 Pages: 1758-1764
  • Peer Reviewed
• [Journal Article] Electrophilic glycosidation employing 3,5-0-(di-tert-butylsilylene)-erythro-furanoid glycals leads to exclusive formation of the β-Anomer: Synthesis of 2'-deoxynucleosides and its 1'-branched analogues (2010)
  • Author(s): Kazuhiro Haraguchi
  • Journal Title: Tetrahedron Volume: 66 Pages: 4587-4600
  • Peer Reviewed
• [Journal Article] Synthesis and anti-HIV-1 evaluation of phosphonate which mimics the 5'-monophosphate of 4'-branched 2',3'-didehydro-2',3'-dideoxy nucleoside (2010)
  • Author(s): Kazuhiro Haraguchi
  • Journal Title: Bioorg.Med.Chem. Volume: 18 Pages: 7186-7192
  • Peer Reviewed
• [Journal Article] Preparation of 4'-benzenesulfonyl-3'-deoxythymidine and its reaction with organoaluminum and organosilicon reagents (2010)
  • Author(s): Kazuhiro Haraguchi
  • Journal Title: Carbohydrate Research Volume: 345 Pages: 2616-2622
  • Peer Reviewed
• [Journal Article] Synthesis and antiviral evaluation of 4'-alkoxy analogues of 9-(-D-xylofuranosyl) adenine (2009)
  • Author(s): Kubota, Y.; Ishizaki, N.; Kaneda, Y.; Haraguchi, K.; Odanaka, Y.; Tanaka, H.; Kato, N.; Baba, M.; Balzarini, J.
  • Journal Title: Antiviral Chem. Chemother Volume: 19 Pages: 201-212
• [Journal Article] Additive Pummerer reaction of 3, 5-O-(di-t-butylsilylene)-4-thiofuranoid glycal : A high yield and.-selective entry to 4'-thioribonucleosides (2009)
  • Author(s): Haraguchi, K.; Matsui, H.; Takami, S.; Tanaka, H.
  • Journal Title: J. Org. Chem Volume: 74 Pages: 2616-2619
• [Journal Article] Solvent effect observed in nucleophilic substitution of 4'-(benzoyloxy) cordycepin with AlMe3 : stereochemical evidence for SNi mechanism (2009)
  • Author(s): Kubota, Y.; Kunikata, M.; Haraguchi, K.; Tanaka, H.
  • Journal Title: J. Org. Chem Volume: 74 Pages: 3402-3405
• [Journal Article] Nucleophilic substitution approach to 4'-substituted thymidines by employing 4'-benzenesulfonyl leaving group (2009)
  • Author(s): Shimada, H.; Kikuchi, S.; Okuda, S.; Haraguchi, K.; Tanaka, H.
  • Journal Title: Tetrahedron Volume: 65 Pages: 6008-6016
• [Journal Article] Synthesis of-(±)-4'-ethynyl-5', 5'-difluoro-2', 3'-didehydro-3'-deoxy-carbocyclic thymidine : a difluoromethylidene analogue of promising anti-HIV agent Ed4T (2009)
  • Author(s): Kumamoto, H.; Haraguchi, K.; Ida, M.; Nakamura, K. T.; Kitagawa, Y.; Hamasaki, T.; Baba, M.; Shimbara Matsubayashi, S.; Tanaka, H.
  • Journal Title: Tetrahedron Volume: 65 Pages: 7630-7636
• [Journal Article] Reaction of the 4'-benzenesulfonyl derivatives of thymidine with organosilicon and organoaluminum reagent (2009)
  • Author(s): Shimada, H.; Kikuchi, S.; Okuda, S.; Haraguchi, K.; Tanaka, H.
  • Journal Title: Nucleic Acids Symposium Series Volume: 53 Pages: 1-2
• [Journal Article] Synthesis and anti-HIV activity of 4'-C-ethynyl-2'-deoxy-4'-thionucleosides (2009)
  • Author(s): Haraguchi, K.; Shimada, H.; Akutsu, G.; Kimura, K.; Tanaka, H.; Hamasaki, T.; Baba, M.; Gullen, E. A.; Dutschman, G. E.; Cheng, Y.-C.; Balzalini, J.
  • Journal Title: Nucleic Acids Symposium Series Volume: 53 Pages: 97-98
• [Journal Article] Synthesis of 4'-substituted cordycepins via benzenesulfenylation at the 4'-position as a key step (2009)
  • Author(s): Kubota, Y. Ehara, M.; Shimada, H.; Haraguchi, K.; Tanaka, H.
  • Journal Title: Nucleic Acids Symposium Series Volume: 53 Pages: 99-100
• [Journal Article] Additive Pummerer Reaction of 3,5-o-(Di-t-butylsilylene)-4-thiofuranoid Glycal : A High Yield and β-Selective Entry to 4'-Thioribonucleosides (2009)
  • Author(s): Kazuhiro Haraguchi
  • Journal Title: J.Org.Chem. 74 Pages: 2616-2619
  • Peer Reviewed
• [Journal Article] Solvent Effect Observed in Nucleophilic Substitution of 4'-(Benzoyloxy)cordycepin with A1Me3 (2009)
  • Author(s): Kazuhiro Haraguchi
  • Journal Title: J.Org.Chem. 74 Pages: 3402-3405
  • Peer Reviewed
• [Journal Article] Nucleophilic Substitution Approach to 4'-Substituted Thymidines by Employing 4'-Benzenesulfonyl Leaving Group (2009)
  • Author(s): Kazuhiro Haraguchi
  • Journal Title: Tetrahedron 65 Pages: 6008-6016
  • Peer Reviewed
• [Presentation] Synthesis and anti-HIV-1 activity of 4'-ethynyl-2'-deoxy-4'-thionucleosides (2011)
  • Author(s): 原口一広
  • Organizer: the 2nd International Conference of Medchem 2011
  • Place of Presentation: 北京
  • Year and Date: 2011-08-10
• [Presentation] 糖部1'位にメチル基を有するジオキソラニルヌクレオシドの合成とその抗ウイルス活性 (2011)
  • Author(s): 窪田豊、金田有里、原口一広、加藤宣、馬場昌範、田中博道
  • Organizer: 第131年回
  • Place of Presentation: 静岡
• [Presentation] 長期投薬患者に対する薬剤師の電話による治療支援の有用性評価 (2011)
  • Author(s): 新田光代、原和夫、山本信夫、亀井美和子、木内祐二、原口一広
  • Organizer: 第131年回
  • Place of Presentation: 静岡
• [Presentation] 1'位にメチル基を有するジオキソラニルヌクレオシドの合成とその抗HCV活性 (2011)
  • Author(s): 窪田豊、金田有里、原口一広、加藤宣之、田中博道
  • Organizer: 第21回抗ウイルス療法研究会
  • Place of Presentation: 金沢
• [Presentation] Synthesis and anti-HIV-1 activity of 4'-ethynyl-2'-deoxy-4'-thionucleosides (2011)
  • Author(s): K. Haraguchi, H. Shimada, G. Akutsu, K. Kimura, H. Tanaka, H. Abe, T. Hamasaki, M. Baba, E. A. Gullen, G. E. Dutschman, Y.-C. Cheng, J. Balzalini
  • Organizer: The 2nd International Conference of Medchem 2011
  • Place of Presentation: Beijing, China
• [Presentation] A 1'-methyl substituted 4'-thiothymidine as promising inhibitor of orthopoxviruses in vitro and in vivo (2011)
  • Author(s): S. Duraffour, K. Haraguchi, K. Yamada, H. Tanaka, R. Snoeck, G. Andrei
  • Organizer: 6th European Meeting on Viral Zoonoses
  • Place of Presentation: Raphael, France
• [Presentation] 4'置換ヌクレオシド5'モノリン酸のミミックであるホスホネートの合成とその抗HIV活性 (2010)
  • Author(s): 原口一広
  • Organizer: 第29回メディシナルケミストリーシンポジウム
  • Place of Presentation: 京都
  • Year and Date: 2010-11-18
• [Presentation] Synthesis and anti-HIV-1 activity of 4'-C-ethynyl-2'-deoxy-4'-thioribonucleosides (2010)
  • Author(s): Kazuhiro Haraguchi
  • Organizer: the 19th International Round Table on Nucleosides, Nucleotides and Nucleic Acids
  • Place of Presentation: Lyon, France
  • Year and Date: 2010-08-29
• [Presentation] 糖部4'位に置換基を有するヌクレオシドホスホネート誘導体の合成とその抗ウイルス活性 (2010)
  • Author(s): 原口一広
  • Organizer: 第19回抗ウイルス療法研究会
  • Place of Presentation: 熊本
  • Year and Date: 2010-05-20
• [Presentation] 有機アルミニウム試剤を用いる糖部修飾ヌクレオシドの新規合成法の開発 (2010)
  • Author(s): 原口一広
  • Organizer: 第8回次世代を担う有機合成シンポジウム
  • Place of Presentation: 東京
  • Year and Date: 2010-05-13
• [Presentation] m-CPBAによるエリスロフラノイドグリカールのタンデム型エポキシ化/m-クロロベンゾイルオキシ化:psicofuranose誘導体の新規合成法の開発と糖供与体としての利用 (2010)
  • Author(s): 原口一広
  • Organizer: 日本薬学会第130年会
  • Place of Presentation: 岡山
  • Year and Date: 2010-03-29
• [Presentation] エポキシ糖の反応性を利用する立体制御された分岐糖ヌクレオシドの合成法の確立抗HIV活性を有するFestinavirの開発 (2010)
  • Author(s): 原口一広
  • Organizer: 日本薬学会第130年会
  • Place of Presentation: 岡山
  • Year and Date: 2010-03-29
• [Presentation] 糖部4'位に置換基を有するヌクレオシドホスホネート誘導体の合成とその抗ウイルス活性 (2010)
  • Author(s): 原口一広
  • Organizer: 日本薬学会第130年会
  • Place of Presentation: 岡山
  • Year and Date: 2010-03-29
• [Presentation] m-CPBAによるエリスロフラノイドグリカールのタンデム型エポキシ化/m-クロロベンゾイルオキシ化反応: psicofuranose誘導体の新規合成法の開発と糖供与体としての利用 (2010)
  • Author(s): 原口一広、紺野奇重、田中博道
  • Organizer: 第130年回
  • Place of Presentation: 岡山
• [Presentation] エポキシ糖の反応性を利用する立体制御された分岐糖ヌクレオシドの合成法の確立:抗HIV活性を有するFestinavirの開発 (2010)
  • Author(s): 原口一広
  • Organizer: 第130年回
  • Place of Presentation: 岡山
• [Presentation] 糖部4'位に置換基を有するヌクレオシドホスホネート誘導体の合成とその抗ウイルス活性 (2010)
  • Author(s): 窪田豊、石崎伸英、原口一広、田中博道
  • Organizer: 第130年回
  • Place of Presentation: 岡山
• [Presentation] 糖部4'位に置換基を有するヌクレオシドホスホネート誘導体の合成とその抗HIV活性 (2010)
  • Author(s): 窪田豊、石崎伸英、中村拡司、原口一広、田中博道、濱崎隆之、馬場昌範
  • Organizer: 第20回抗ウイルス療法研究会
  • Place of Presentation: 熊本
• [Presentation] Synthesis and anti-HIV activity of 4'-C-Ethynyl-2'-deoxy-4'-thionucleosides (2010)
  • Author(s): K. Haraguchi, H. Shimada, G. Akutsu, K. Kimura, H. Tanaka, T. Hamasaki, M. Baba, E. A. Gullen, G. E. Dutschman, Y.-C. Cheng, J. Balzalini
  • Organizer: XIX International Round Table on Nucleosides, Nucleotides and Nucleic Acids
  • Place of Presentation: Lyon, France
• [Presentation] Synthesis and Anti-HIV Activity of 4'-C-Ethynyl-2'-deoxy-4'-thionucleosides (2009)
  • Author(s): Kazuhiro Haraguchi
  • Organizer: Gordon Research Conference
  • Place of Presentation: Rhode Island
  • Year and Date: 2009-07-07
• [Presentation] フラノイドグリカールを利用する面選択的なグリコシル化反応:アノマー位が分岐したチミジン誘導体の合成研究 (2009)
  • Author(s): 原口一広、紺野奇重、田中博道
  • Organizer: 第129年回
  • Place of Presentation: 京都
• [Presentation] 糖部4'位のベンゼンスルフェニル化を鍵反応とする4'-置換コルジセピンの新規合成法の開発 (2009)
  • Author(s): 窪田豊、江原真理子、熊本浩樹、島田央、原口一広、田中博道
  • Organizer: 第129年回
  • Place of Presentation: 京都
• [Presentation] Synthesis and anti-HIV activity of 4'-C-ethynyl-2'-deoxy-4'-thionucleoside (2009)
  • Author(s): Haraguchi, K.; Shimada, H.; Akutsu, G.; Kimura, K.; Tanaka, H.; Hamasaki, T.; Baba, M.; Gullen, E. A.; Dutschman, G. E.; Cheng, Y.-C.; Balzalini, J
  • Organizer: 第36回核酸化学シンポジウム(第7回国際核酸化学シンポジウム)
  • Place of Presentation: 岐阜
• [Presentation] Reaction of the 4'-benzenesulfonyl derivatives of thymidine with organosilicon and organoaluminum reagent (2009)
  • Author(s): Shimada, H.; Kikuchi, S.; Okuda, S.; Haraguchi, K.; Tanaka, H.
  • Organizer: 第36回核酸化学シンポジウム(第7回国際核酸化学シンポジウム)
  • Place of Presentation: 岐阜
• [Presentation] Synthesis of 4'-substituted cordycepins via benzenesulfenylation at the 4'-position as a key step (2009)
  • Author(s): Kubota, Y. Ehara, M.; Shimada, H.; Haraguchi, K.; Tanaka, H.
  • Organizer: 第36回核酸化学シンポジウム(第7回国際核酸化学シンポジウム)
  • Place of Presentation: 岐阜
• [Presentation] 4'-C-エチニル-2'-デオキシ-4'-チオヌクレオシドの合成とその抗HIV活性 (2009)
  • Author(s): 原口一広、島田央、阿久津源太、木村圭吾、田中博道、濱崎隆之、馬場昌範、Elizabeth A. Gullen、Ginger E. Dutschman、Yung-Chi Cheng、Jan Balzarini
  • Organizer: 第19回抗ウイルス療法研究会
  • Place of Presentation: 東京
• [Presentation] Synthesis and anti-HIV activity of 4'-C-ethynyl-2'-deoxy-4'-thionucleosides (2009)
  • Author(s): K. Haraguchi, H. Shimada, G. Akutsu, K. Kimura, H. Tanaka, T. Hamasaki, M. Baba, E. A. Gullen, G. E. Dutschman, Y.-C. Cheng, J. Balzalini
  • Organizer: Gordon Research Conference on Purine, Pyrimidine and Related Substance
  • Place of Presentation: Rhode Island