title: Sugar-modified derivatives of cytostatic 7-(het)aryl-7-deazaadenosines: 2'-C-methylribonucleosides, 2'-deoxy-2'-fluoroarabinonucleosides, arabinonucleosides and 2'-deoxyribonucleosides.
abstract: A series of novel sugar-modified derivatives of cytostatic 7-hetaryl-7-deazaadenosines (2'-C-methylribonucleosides, 2'-deoxy-2'-fluoroarabinonucleosides, arabinonucleosides and 2'-deoxyribonucleosides) was prepared and screened for biological activity. The synthesis consisted of preparation of the corresponding sugar-modified 7-iodo-7-deazaadenine nucleosides and their aqueous-phase Suzuki-Miyaura cross-coupling reactions with (het)arylboronic acids or Stille couplings with hetarylstannanes in DMF. The synthesis of 7-iodo-7-deazaadenine nucleosides was based on a glycosidation of 6-chloro-7-iodo-7-deazapurine with a suitable sugar synthon or on an interconversion of 2'-OH stereocenter (for arabinonucleosides). Several examples of 2'-C-Me-ribonucleosides showed moderate anti-HCV activities in a replicon assay accompanied by cytotoxicity. Several 7-hetaryl-7-deazaadenine fluoroarabino- and arabinonucleosides exerted moderate micromolar cytostatic effects. The most active was 7-ethynyl-7-deazaadenine fluoroarabinonucleoside which showed submicromolar antiproliferative activity. However, all the sugar-modified derivatives were less active than the parent ribonucleosides.
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Gilead Sciences & IOCB Research Center, Flemingovo nam. 2, CZ-16610 Prague 6, Czech Republic.
authors.forename: Petr
authors.initials: P
authors.lastname: Nauš
authors.forename: Pavla
authors.initials: P
authors.lastname: Perlíková
authors.forename: Aurelie
authors.initials: A
authors.lastname: Bourderioux
authors.forename: Radek
authors.initials: R
authors.lastname: Pohl
authors.forename: Lenka
authors.initials: L
authors.lastname: Slavětínská
authors.forename: Ivan
authors.initials: I
authors.lastname: Votruba
authors.forename: Gina
authors.initials: G
authors.lastname: Bahador
authors.forename: Gabriel
authors.initials: G
authors.lastname: Birkuš
authors.forename: Tomáš
authors.initials: T
authors.lastname: Cihlář
authors.forename: Michal
authors.initials: M
authors.lastname: Hocek
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001087:Arabinonucleosides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002241:Carbohydrates / Q000737:chemistry*; D003853:Deoxyribonucleosides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D018922:HL-60 Cells; D006367:HeLa Cells; D016174:Hepacivirus / Q000187:drug effects*; D006801:Humans; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D000998:Antiviral Agents; D001087:Arabinonucleosides; D002241:Carbohydrates; D003853:Deoxyribonucleosides