Design, Synthesis, and Evaluation of Anti-HBV Activity of Hybrid Molecules of Entecavir and Adefovir: Exomethylene Acycloguanine Nucleosides and Their Monophosphate Derivatives

Shuhei ImotoFaculty of Pharmaceutical Sciences, Sojo University, Nishi-ku, Kumamoto, Japan

Satoru KohgoDepartment of Pharmaceutical Sciences, Nihon Pharmaceutical University, Inamachi, Kita-adachi-gun, Saitama, Japan;Center for Clinical Sciences, National Center for Global Health and Medicine, Shinju-ku, Tokyo, Japan

Ryoh TokudaFaculty of Pharmaceutical Sciences, Sojo University, Nishi-ku, Kumamoto, Japan

Hiroki KumamotoSchool of Pharmacy, Showa University, Shinagawa-ku, Tokyo, Japan

Manabu AokiDepartment of Medical Technology, Kumamoto Health Science University, Kumamoto, Japan

Masayuki AmanoDepartments of Infectious Diseases and Hematology, Kumamoto University School of Medicine, Kumamoto, Japan

Nobuyo Kuwata-HigashiDepartments of Infectious Diseases and Hematology, Kumamoto University School of Medicine, Kumamoto, Japan

Hiroaki MitsuyaCenter for Clinical Sciences, National Center for Global Health and Medicine, Shinju-ku, Tokyo, Japan;Departments of Infectious Diseases and Hematology, Kumamoto University School of Medicine, Kumamoto, Japan;Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA

Kazuhiro HaraguchiDepartment of Pharmaceutical Sciences, Nihon Pharmaceutical University, Inamachi, Kita-adachi-gun, Saitama, JapanCorrespondence[email protected]

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Abstract

Exomethylene acycloguanine nucleosides 4, 6 and its monophosphate derivatives 5, 7, and 8 have been synthesized. Mitsunobu-type coupling of 2-N-acetyl-6-O-diphenylcarbamoylguanine (11) with primary alcohols proceeded regioselectively to furnish the desired N⁹-substituted products in moderate yield. Evaluation of 4-8 for anti-HBV activity in HepG2 cells revealed that the phosphonate derivative 8 was found to exhibit moderated activity (EC₅₀ value of 0.29 μM), but cytotoxicity (CC₅₀ value of 39 μM) against the host cells was also observed.

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Design, Synthesis, and Evaluation of Anti-HBV Activity of Hybrid Molecules of Entecavir and Adefovir: Exomethylene Acycloguanine Nucleosides and Their Monophosphate Derivatives

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Design, Synthesis, and Evaluation of Anti-HBV Activity of Hybrid Molecules of Entecavir and Adefovir: Exomethylene Acycloguanine Nucleosides and Their Monophosphate Derivatives

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