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

Hisashi Shimada, Kazuhiro Haraguchi, Kumi Hotta, Tomoko Miyaike, Yasuyuki Kitagawa, Hiromichi Tanaka, Ryutaro Kaneda, Hiroshi Abe, Satoshi Shuto, Kyoko Mori, Youki Ueda, Nobuyuki Kato, Robert Snoeck, Graciela Andrei, Jan Balzarini

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Upon reacting 3′,4′-unsaturated cytosine (8 and 9) and adenine nucleosides (13 and 14) with XeF2/BF3·OEt2, the respective novel 3′,4′-difluoro-3′-deoxyribofuranosyl nucleosides (10-12 and 15-18) could be obtained. Formation of anti-adducts (11, 16 and 18) revealed that the fluorination involved oxonium ions as incipient intermediates. TBDMS-protected 3′,4′-unsaturated adenosine provided the β-face adducts as sole stereoisomers whereas α-face-selectivity was observed with the TBDPS-protected adenosine 14. The evaluation of the novel 3′-deoxy-3′,4′-difluororibofuranosylcytosine-(19-21) and adenine nucleosides (22-25) against antitumor and antiviral activities revealed that 3′,4′-difluorocordycepin (24) was found to possess anti-HCV activity. The SI of 24 was comparable to that of the anti-HCV drug ribavirin. However, sofosbuvir, FDA-approved novel anti-HCV drug, showed better SI value. Our finding revealed that the introduction of the fluoro-substituent into the 4′-position of cordycepin derivatives decreased the cytotoxicity to the host cell with retention of the antiviral activity.

Original languageEnglish
Pages (from-to)6174-6182
Number of pages9
JournalBioorganic and Medicinal Chemistry
Volume22
Issue number21
DOIs
Publication statusPublished - Nov 1 2014

Fingerprint

Deoxyribonucleosides
Bioactivity
Nucleosides
Adenine
Adenosine
Antiviral Agents
Fluorination
Stereoisomerism
Ribavirin
Halogenation
Cytosine
Cytotoxicity
Pharmaceutical Preparations
Ions
Derivatives

Keywords

  • Anti-HCV agent Molecular orbital calculation
  • Cordycepin
  • Fluorinated sugar
  • Nucleoside
  • Unsaturated sugar

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry
  • Molecular Biology
  • Molecular Medicine
  • Organic Chemistry
  • Drug Discovery
  • Pharmaceutical Science
  • Medicine(all)

Cite this

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. / Shimada, Hisashi; Haraguchi, Kazuhiro; Hotta, Kumi; Miyaike, Tomoko; Kitagawa, Yasuyuki; Tanaka, Hiromichi; Kaneda, Ryutaro; Abe, Hiroshi; Shuto, Satoshi; Mori, Kyoko; Ueda, Youki; Kato, Nobuyuki; Snoeck, Robert; Andrei, Graciela; Balzarini, Jan.

In: Bioorganic and Medicinal Chemistry, Vol. 22, No. 21, 01.11.2014, p. 6174-6182.

Research output: Contribution to journalArticle

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, J 2014, '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', Bioorganic and Medicinal Chemistry, vol. 22, no. 21, pp. 6174-6182. https://doi.org/10.1016/j.bmc.2014.08.024
Shimada, Hisashi ; Haraguchi, Kazuhiro ; Hotta, Kumi ; Miyaike, Tomoko ; Kitagawa, Yasuyuki ; Tanaka, Hiromichi ; Kaneda, Ryutaro ; Abe, Hiroshi ; Shuto, Satoshi ; Mori, Kyoko ; Ueda, Youki ; Kato, Nobuyuki ; Snoeck, Robert ; Andrei, Graciela ; Balzarini, Jan. / 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. In: Bioorganic and Medicinal Chemistry. 2014 ; Vol. 22, No. 21. pp. 6174-6182.
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AU - Miyaike, Tomoko

AU - Kitagawa, Yasuyuki

AU - Tanaka, Hiromichi

AU - Kaneda, Ryutaro

AU - Abe, Hiroshi

AU - Shuto, Satoshi

AU - Mori, Kyoko

AU - Ueda, Youki

AU - Kato, Nobuyuki

AU - Snoeck, Robert

AU - Andrei, Graciela

AU - Balzarini, Jan

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