title: 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.
abstract: Upon reacting 3',4'-unsaturated cytosine (8 and 9) and adenine nucleosides (13 and 14) with XeF(2)/BF3 · OEt(2), 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.
authors.affiliation: School of Pharmacy, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan.
authors.forename: Hisashi
authors.initials: H
authors.lastname: Shimada
authors.affiliation: Nihon Pharmaceutical University, 10281 Komuro, Inamachi, Kita-adachi-gun, Saitama 362-0806, Japan. Electronic address: harakazu@nichiyaku.ac.jp.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Haraguchi
authors.affiliation: School of Pharmacy, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan.
authors.forename: Kumi
authors.initials: K
authors.lastname: Hotta
authors.affiliation: School of Pharmacy, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Miyaike
authors.affiliation: Yokohama College of Pharmacy, 601 Matano-cho, Totsuka-ku, Yokohama-shi, Kanagawa 245-0066, Japan.
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Kitagawa
authors.affiliation: School of Pharmacy, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan.
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Tanaka
authors.affiliation: Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan.
authors.forename: Ryutaro
authors.initials: R
authors.lastname: Kaneda
authors.affiliation: Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Abe
authors.affiliation: Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Shuto
authors.affiliation: Department of Tumor Virology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Okayama 700-8558, Japan.
authors.forename: Kyoko
authors.initials: K
authors.lastname: Mori
authors.affiliation: Department of Tumor Virology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Okayama 700-8558, Japan.
authors.forename: Youki
authors.initials: Y
authors.lastname: Ueda
authors.affiliation: Department of Tumor Virology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Okayama 700-8558, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Kato
authors.affiliation: Rega Institute for Medical Research, Katholieke Universiteit Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium.
authors.forename: Robert
authors.initials: R
authors.lastname: Snoeck
authors.affiliation: Rega Institute for Medical Research, Katholieke Universiteit Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium.
authors.forename: Graciela
authors.initials: G
authors.lastname: Andrei
authors.affiliation: Rega Institute for Medical Research, Katholieke Universiteit Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium.
authors.forename: Jan
authors.initials: J
authors.lastname: Balzarini
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D002460:Cell Line; D003839:Deoxyadenosines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D003853:Deoxyribonucleosides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D054879:Halogenation; D016174:Hepacivirus / Q000187:drug effects*; D006526:Hepatitis C / Q000188:drug therapy; D006801:Humans; D013329:Structure-Activity Relationship
chemical_list: D000998:Antiviral Agents; D003839:Deoxyadenosines; D003853:Deoxyribonucleosides; C058120:cordycepin
keywords: Anti-HCV agent; Cordycepin; Fluorinated sugar; Molecular orbital calculation; Nucleoside; Unsaturated sugar