title: Synthesis and anti-HIV activity of conformationally restricted bicyclic hexahydroisobenzofuran nucleoside analogs.
abstract: A chiral synthesis of a series of hexahydroisobenzofuran (HIBF) nucleosides has been accomplished via glycosylation of a stereo-defined (syn-isomer) sugar motif 16 with the appropriate silylated bases. All nucleoside analogs were obtained in 52-71% yield as a mixture of alpha- and beta-anomeric products increasing the breadth of the novel nucleosides available for screening. The structure of the novel bicyclic HIBF nucleosides was established by a single crystal X-ray structure of the beta-HIBF thymine analog 22b. Furthermore, the sugar conformation for these nucleosides was established as N-type. Among the novel HIBF nucleosides synthesized, twenty-five compounds were tested as inhibitor of HIV-1 in human peripheral blood mononuclear (PBM) cells and seven were found to be active (EC(50) = 12.3-36.2 microM). Six of these compounds were purine analogs with beta-HIBF inosine analog 22o being the most potent (EC(50) = 12.3 microM) among all compounds tested. The striking resemblance between didanosine (ddI) and 22o may explain the potent anti-HIV activity.
authors.affiliation: Departamento de Química Orgánica e Inorgánica and Instituto Universitario de Biotecnología de Asturias, Universidad de Oviedo, 33006-Oviedo (Asturias), Spain.
authors.forename: Alba
authors.initials: A
authors.lastname: Díaz-Rodríguez
authors.forename: Yogesh S
authors.initials: YS
authors.lastname: Sanghvi
authors.forename: Susana
authors.initials: S
authors.lastname: Fernández
authors.forename: Raymond F
authors.initials: RF
authors.lastname: Schinazi
authors.forename: Emmanuel A
authors.initials: EA
authors.lastname: Theodorakis
authors.forename: Miguel
authors.initials: M
authors.lastname: Ferrero
authors.forename: Vicente
authors.initials: V
authors.lastname: Gotor
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001572:Benzofurans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001643:Bridged Bicyclo Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002522:Chlorocebus aethiops; D018360:Crystallography, X-Ray; D006031:Glycosylation; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D008968:Molecular Conformation; D009705:Nucleosides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D014709:Vero Cells
chemical_list: D019380:Anti-HIV Agents; D001572:Benzofurans; D001643:Bridged Bicyclo Compounds; D009705:Nucleosides; C540211:hexahydroisobenzofuran