title: Synthesis and cytostatic and antiviral activities of 2'-deoxy-2',2'-difluororibo- and 2'-deoxy-2'-fluororibonucleosides derived from 7-(Het)aryl-7-deazaadenines.
abstract: A series of sugar-modified derivatives of cytostatic 7-heteroaryl-7-deazaadenosines (2'-deoxy-2'-fluororibo- and 2'-deoxy-2',2'-difluororibonucleosides) bearing an aryl or heteroaryl group at position 7 was prepared and screened for biological activity. The difluororibonucleosides were prepared by non- stereoselective glycosidation of 6-chloro-7-deazapurine with benzoyl-protected 2-deoxy-2,2-difluoro-D-erythro-pentofuranosyl-1-mesylate, followed by amination and aqueous Suzuki cross-couplings with (het)arylboronic acids. The fluororibo derivatives were prepared by aqueous palladium-catalyzed cross-coupling reactions of the corresponding 7-iodo-7-deazaadenine 2'-deoxy-2'-fluororibonucleoside 20 with (het)arylboronic acids. The key intermediate 20 was prepared by a six-step sequence from the corresponding arabinonucleoside by selective protection of 3'- and 5'-hydroxy groups with acid-labile groups, followed by stereoselective SN 2 fluorination and deprotection. Some of the title nucleosides and 7-iodo-7-deazaadenine intermediates showed micromolar cytostatic or anti-HCV activity. The most active were 7-iodo and 7-ethynyl derivatives. The corresponding 2'-deoxy-2',2'-difluororibonucleoside 5'-O-triphosphates were found to be good substrates for bacterial DNA polymerases, but are inhibitors of human polymerase α.
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Gilead Sciences & IOCB Research Center, Flemingovo nam. 2, 16610 Prague 6, Czech Republic.
authors.forename: Pavla
authors.initials: P
authors.lastname: Perlíková
authors.forename: Ludovic
authors.initials: L
authors.lastname: Eberlin
authors.forename: Petra
authors.initials: P
authors.lastname: Ménová
authors.forename: Veronika
authors.initials: V
authors.lastname: Raindlová
authors.forename: Lenka
authors.initials: L
authors.lastname: Slavětínská
authors.forename: Eva
authors.initials: E
authors.lastname: Tloušťová
authors.forename: Gina
authors.initials: G
authors.lastname: Bahador
authors.forename: Yu-Jen
authors.initials: YJ
authors.lastname: Lee
authors.forename: Michal
authors.initials: M
authors.lastname: Hocek
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000737:chemistry*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D054697:Cytostatic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D018922:HL-60 Cells; D006367:HeLa Cells; D056945:Hep G2 Cells; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D019384:Nucleic Acid Synthesis Inhibitors; D012263:Ribonucleosides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D000998:Antiviral Agents; D054697:Cytostatic Agents; D019384:Nucleic Acid Synthesis Inhibitors; D012263:Ribonucleosides; D004259:DNA-Directed DNA Polymerase; D000225:Adenine