title: Norbornane-based nucleoside and nucleotide analogues locked in North conformation.
abstract: We report on the synthesis of novel conformationally locked nucleoside and nucleotide derivatives, which are structurally closely related to clinically used antivirals such as didanosine and abacavir. As a suitable conformationally rigid substitute of the sugar/pseudosugar ring allowing a permanent stabilization of the nucleoside in North conformation we employed bicyclo[2.2.1]heptane (norbornane) substituted in the bridgehead position with a hydroxymethyl group and in the C-3 position with a nucleobase. Prepared nucleoside derivatives were also converted into appropriate phosphoramidate prodrugs (ProTides) in order to increase delivery of the compounds in the cells. All target compounds were evaluated in a broad antiviral and cytostatic assay panel.
authors.affiliation: Gilead Sciences & IOCB Research Centre, Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i., 166 10 Prague 6, Czech Republic.
authors.forename: Milan
authors.initials: M
authors.lastname: Dejmek
authors.affiliation: Gilead Sciences & IOCB Research Centre, Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i., 166 10 Prague 6, Czech Republic.
authors.forename: Michal
authors.initials: M
authors.lastname: Šála
authors.affiliation: Gilead Sciences & IOCB Research Centre, Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i., 166 10 Prague 6, Czech Republic.
authors.forename: Hubert
authors.initials: H
authors.lastname: Hřebabecký
authors.affiliation: Gilead Sciences & IOCB Research Centre, Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i., 166 10 Prague 6, Czech Republic.
authors.forename: Martin
authors.initials: M
authors.lastname: Dračínský
authors.affiliation: Gilead Sciences & IOCB Research Centre, Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i., 166 10 Prague 6, Czech Republic.
authors.forename: Eliška
authors.initials: E
authors.lastname: Procházková
authors.affiliation: Gilead Sciences & IOCB Research Centre, Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i., 166 10 Prague 6, Czech Republic.
authors.forename: Dominika
authors.initials: D
authors.lastname: Chalupská
authors.affiliation: Gilead Sciences & IOCB Research Centre, Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i., 166 10 Prague 6, Czech Republic.
authors.forename: Martin
authors.initials: M
authors.lastname: Klíma
authors.affiliation: Gilead Sciences & IOCB Research Centre, Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i., 166 10 Prague 6, Czech Republic.
authors.forename: Pavla
authors.initials: P
authors.lastname: Plačková
authors.affiliation: Gilead Sciences & IOCB Research Centre, Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i., 166 10 Prague 6, Czech Republic.
authors.forename: Miroslav
authors.initials: M
authors.lastname: Hájek
authors.affiliation: Rega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, BE-3000 Leuven, Belgium.
authors.forename: Graciela
authors.initials: G
authors.lastname: Andrei
authors.affiliation: Rega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, BE-3000 Leuven, Belgium.
authors.forename: Lieve
authors.initials: L
authors.lastname: Naesens
authors.affiliation: Rega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, BE-3000 Leuven, Belgium.
authors.forename: Pieter
authors.initials: P
authors.lastname: Leyssen
authors.affiliation: Rega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, BE-3000 Leuven, Belgium.
authors.forename: Johan
authors.initials: J
authors.lastname: Neyts
authors.affiliation: Rega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, BE-3000 Leuven, Belgium.
authors.forename: Jan
authors.initials: J
authors.lastname: Balzarini
authors.affiliation: Gilead Sciences & IOCB Research Centre, Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i., 166 10 Prague 6, Czech Republic.
authors.forename: Evzen
authors.initials: E
authors.lastname: Boura
authors.affiliation: Gilead Sciences & IOCB Research Centre, Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i., 166 10 Prague 6, Czech Republic.
authors.forename: Radim
authors.initials: R
authors.lastname: Nencka
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis*; D006801:Humans; D009636:Norbornanes / Q000138:chemical synthesis / Q000737:chemistry*; D009690:Nucleic Acid Conformation; D009705:Nucleosides / Q000138:chemical synthesis / Q000737:chemistry*; D009711:Nucleotides / Q000138:chemical synthesis / Q000737:chemistry*; D013237:Stereoisomerism
chemical_list: D000998:Antiviral Agents; D009636:Norbornanes; D009705:Nucleosides; D009711:Nucleotides
keywords: Antiviral; Carbocyclic nucleosides; Norbornane; PI4KIIα; Purines