title: Diastereoselective Synthesis of 6″-(Z)- and 6″-(E)-Fluoro Analogues of Anti-hepatitis B Virus Agent Entecavir and Its Evaluation of the Activity and Toxicity Profile of the Diastereomers.
abstract: A method for the diastereoselective synthesis of 6″-(Z)- and 6″-(E)-fluorinated analogues of the anti-HBV agent entecavir has been developed. Construction of the methylenecyclopentane skeleton of the target molecules has been accomplished by radical-mediated 5-exo-dig cyclization of the selenides 6 and 15 having the phenylsulfanylethynyl structure as a radical accepting moiety. In the radical reaction of the TBS-protected precursor 6, (Z)-anti-12 was formed as a major product. On the other hand, TIPS-protected 15 gave (E)-anti-12. The sulfur-extrusive stannylation of anti-12 furnished a mixture of geometric isomers of the respective vinylstannane, whereas benzoyl-protected 17 underwent the stannylation in the manner of retention of configuration. Following XeF2-mediated fluorination, introduction of the purine base and deoxygenation of the resulting carbocyclic guanosine gave the target (E)- and (Z)-3 after deprotection. Evaluation of the anti-HBV activity of 3 revealed that fluorine-substitution at the 6″-position of entecavir gave rise to a reduction in the cytotoxicity in HepG2 cells 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: Hiroki
authors.initials: H
authors.lastname: Kumamoto
authors.affiliation: School of Pharmacy, Showa University , 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan.
authors.forename: Misato
authors.initials: M
authors.lastname: Fukano
authors.affiliation: School of Pharmacy, Showa University , 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan.
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Nakano
authors.affiliation: School of Pharmacy, Showa University , 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan.
authors.forename: Keito
authors.initials: K
authors.lastname: Iwagami
authors.affiliation: School of Pharmacy, Showa University , 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan.
authors.forename: Chiaki
authors.initials: C
authors.lastname: Takeyama
authors.affiliation: Center for Clinical Sciences, National Center for Global Health and Medicine , 1-21-1 Toyama, Shinjuku, Tokyo 162-8655, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Kohgo
authors.affiliation: Faculty of Pharmaceutical Sciences, Sojo University , 4-22-1 Ikeda, Kumamoto 860-0082, Japan.
authors.forename: Shuhei
authors.initials: S
authors.lastname: Imoto
authors.affiliation: Department of Infectious Diseases and Hematology, Kumamoto University School of Medicine , Kumamoto 860-8556, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Amano
authors.affiliation: Department of Infectious Diseases and Hematology, Kumamoto University School of Medicine , Kumamoto 860-8556, Japan.
authors.forename: Nobuyo
authors.initials: N
authors.lastname: Kuwata-Higashi
authors.affiliation: Department of Medical Technology, Kumamoto Heath Science University , 325 Izumimachi, Kumamoto 861-5598, Japan.
authors.forename: Manabu
authors.initials: M
authors.lastname: Aoki
authors.affiliation: Department of Chemistry, Graduate School of Science, Nagoya University , Furo-cho, Chikusa-ku, Nagoya 464-8602, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Abe
authors.affiliation: Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health , Bethesda, Maryland 20892, United States.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Mitsuya
authors.affiliation: School of Pharmacy, Showa University , 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Fukuhara
authors.affiliation: Nihon Pharmaceutical University , 10281 Komuro, Inamachi, Kita-adachi-gun, Saitama 362-0806, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Haraguchi
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006147:Guanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006151:Guanosine / Q000737:chemistry*; D015497:HIV-1 / Q000187:drug effects*; D056945:Hep G2 Cells / Q000737:chemistry*; D006515:Hepatitis B virus / Q000187:drug effects; D006801:Humans; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000998:Antiviral Agents; D006151:Guanosine; C413685:entecavir; D006147:Guanine