title: Synthesis and biological evaluation of conformationally restricted adenine bicycloribonucleosides.
abstract: We prepared a novel series of conformationally restricted bicyclonucleosides and nucleotides. The synthetic approach employed a ring closing metathesis to provide access to both 6 and 7 membered saturated and unsaturated rings linking the 3' to 5' methylene groups of the sugar. The bicyclonucleosides were also transformed to the corresponding phosphoramidate prodrugs by an innovative one-pot protocol of boronate ester protection, coupling of the phosphoryl chloridate and deprotection of the boronate. A similar strategy was also employed for the synthesis of the corresponding monophosphates as crucial intermediates for the synthesis of selected triphosphates. The biological properties of the nucleosides and monophosphate prodrugs were assessed for antiviral and cytostatic activities in cell based assays whilst the triphosphates were evaluated in enzymatic assays. The lack of significant effects suggests that the linkage of the 3' to 5'via a ring system and the subsequent conformational restriction of the ribose ring to the South conformation are incompatible with the kinases and polymerases that recognize nucleosides and their metabolites.
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i., Gilead Sciences & IOCB Research Centre, 166 10 Prague 6, Czech Republic. nencka@uochb.cas.cz.
authors.forename: Hubert
authors.initials: H
authors.lastname: Hřebabecký
authors.forename: Eliška
authors.initials: E
authors.lastname: Procházková
authors.forename: Michal
authors.initials: M
authors.lastname: Šála
authors.forename: Pavla
authors.initials: P
authors.lastname: Plačková
authors.forename: Eva
authors.initials: E
authors.lastname: Tloušťová
authors.forename: Ona
authors.initials: O
authors.lastname: Barauskas
authors.forename: Yu-Jen
authors.initials: YJ
authors.lastname: Lee
authors.forename: Yang
authors.initials: Y
authors.lastname: Tian
authors.forename: Richard
authors.initials: R
authors.lastname: Mackman
authors.forename: Radim
authors.initials: R
authors.lastname: Nencka
mesh_terms: D000225:Adenine / Q000737:chemistry*; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D002236:Carbohydrate Conformation; D045744:Cell Line, Tumor; D060326:Chemistry Techniques, Synthetic; D015195:Drug Design; D016174:Hepacivirus / Q000187:drug effects; D006801:Humans; D008958:Models, Molecular; D009711:Nucleotides / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D011355:Prodrugs / Q000378:metabolism
chemical_list: D000998:Antiviral Agents; D009711:Nucleotides; D011355:Prodrugs; D000225:Adenine