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 |
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| Institution: | 1. School of Pharmacy, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan;2. Nihon Pharmaceutical University, 10281 Komuro, Inamachi, Kita-adachi-gun, Saitama 362-0806, Japan;3. Yokohama College of Pharmacy, 601 Matano-cho, Totsuka-ku, Yokohama-shi, Kanagawa 245-0066, Japan;4. Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan;5. Department of Tumor Virology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Okayama 700-8558, Japan;6. Rega Institute for Medical Research, Katholieke Universiteit Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium;1. Department of Chemistry, Quaid-i-Azam University, Islamabad 45320, Pakistan;2. Centre for Advanced Drug Research, COMSATS Institute of Information Technology, Abbottabad 22060, Pakistan;3. Department of Life Science Informatics, B-IT, LIMES Program Unit Chemical Biology and Medicinal Chemistry, Rheinische Friedrich-Wilhelms-Universität, Dahlmannstr. 2, D-53113 Bonn, Germany;4. Department of Chemistry, University of Otago, PO Box 56, Dunedin 9054, New Zealand;5. Department of Pharmaceutical Sciences, COMSATS Institute of Information Technology, Abbottabad 22060, Pakistan;1. Laboratory of Biochemistry, Department of Bioscience and Biotechnology, Graduate School, Faculty of Agriculture, Kyushu University, Hakozaki 6-10-1, Higashi-ku, Fukuoka 812-8581, Japan;2. Laboratory of Structural Biology, Graduate School of Systems Life Sciences, Kyushu University, Hakozaki 6-10-1, Fukuoka 812-8581, Japan;3. Institute of Biophysics, Department of Bioscience and Biotechnology, Graduate School, Faculty of Agriculture, Kyushu University, Hakozaki 6-10-1, Fukuoka 812-8581, Japan;1. Department of Pediatric Surgery, Osaka University, Postgraduate School of Medicine, Osaka, Japan;2. Department of Pediatrics, Osaka University, Postgraduate School of Medicine, Osaka, Japan |
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| 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. |
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| Keywords: | Nucleoside Unsaturated sugar Fluorinated sugar Cordycepin Anti-HCV agent Molecular orbital calculation |
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