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

• Published in: Bioorganic & medicinal chemistry Vol. 22; no. 21; pp. 6174 - 6182
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.11.2014; Elsevier
• Subjects: Anti-HCV agent; Antiviral Agents - chemical synthesis; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Biochemistry & Molecular Biology; Cell Line; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Cordycepin; Deoxyadenosines - chemical synthesis; Deoxyadenosines - chemistry; Deoxyadenosines - pharmacology; Deoxyribonucleosides - chemical synthesis; Deoxyribonucleosides - chemistry; Deoxyribonucleosides - pharmacology; Fluorinated sugar; Halogenation; Hepacivirus - drug effects; Hepatitis C - drug therapy; Humans; Life Sciences & Biomedicine; Molecular orbital calculation; Nucleoside; Pharmacology & Pharmacy; Physical Sciences; Science & Technology; Structure-Activity Relationship; Unsaturated sugar; Nucleoside; Molecular orbital calculation; Fluorinated sugar; Unsaturated sugar; Cordycepin; Anti-HCV agent; SUBSTITUTION; NUCLEOSIDES
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2014.08.024

[Display omitted] 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.