title: Dideoxy fluoro-ketopyranosyl nucleosides as potent antiviral agents: synthesis and biological evaluation of 2,3- and 3,4-dideoxy-3-fluoro-4- and -2-keto-beta-d-glucopyranosyl derivatives of N(4)-benzoyl cytosine.
abstract: The synthesis of the dideoxy fluoro ketopyranonucleoside analogues, 1-(2,3-dideoxy-3-fluoro-6-O-trityl-beta-d-glycero-hexopyranosyl-4-ulose)-N(4)-benzoyl cytosine (7a), 1-(3,4-dideoxy-3-fluoro-6-O-trityl-beta-d-glycero-hexopyranosyl-2-ulose)-N(4)-benzoyl cytosine (13a) and their detritylated analogues 8a and 14a, respectively, is described. Condensation of peracetylated 3-deoxy-3-fluoro-D-glucopyranose (1) with silylated N(4)-benzoyl cytosine, followed by selective deprotection and isopropylidenation afforded compound 2. Routine deoxygenation at position 2', followed by a deprotection-selective reprotection sequence afforded the partially tritylated dideoxy nucleoside of cytosine 6, which upon oxidation of the free hydroxyl group at the 4'-position, furnished the desired tritylated 2,3-dideoxy-3-fluoro ketonucleoside 7a in equilibrium with its hydrated form 7b. Compound 2 was the starting material for the synthesis of the dideoxy fluoro ketopyranonucleoside 13a. Similarly, several subsequent protection and deprotection steps as well as routine deoxygenation at position 4', followed by oxidation of the free hydroxyl group at the 2'-position of the partially tritylated dideoxy nucleoside 12, yielded the desired carbonyl compound 13a in equilibrium with its hydrated form 13b. Finally, trityl removal from 7a/b and 13a/b provided the unprotected 2,3-dideoxy-3-fluoro-4-keto and 3,4-dideoxy-3-fluoro-2-ketopyranonucleoside analogues 8a and 14a, in equilibrium with their gem-diol forms 8b and 14b. None of the compounds showed inhibitory activity against a wide variety of DNA and RNA viruses at subtoxic concentrations, except 7a/b that was highly efficient against rotavirus infection. Nucleoside 7a/b also exhibited cytostatic activity against cells of various cancers. BrdU-cell cycle analysis revealed that the mechanism of cytostatic activity may be related to a delay in G1/S phase and initiation of programmed cell death.
authors.affiliation: Department of Biochemistry and Biotechnology, Laboratory of Organic Chemistry, University of Thessaly, 26 Ploutonos Str., 41221 Larissa, Greece.
authors.forename: Stella
authors.initials: S
authors.lastname: Manta
authors.forename: Evangelia
authors.initials: E
authors.lastname: Tsoukala
authors.forename: Niki
authors.initials: N
authors.lastname: Tzioumaki
authors.forename: Ales
authors.initials: A
authors.lastname: Goropevsek
authors.forename: Ravi Teja
authors.initials: RT
authors.lastname: Pamulapati
authors.forename: Avrelija
authors.initials: A
authors.lastname: Cencic
authors.forename: Jan
authors.initials: J
authors.lastname: Balzarini
authors.forename: Dimitri
authors.initials: D
authors.lastname: Komiotis
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D003596:Cytosine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D029822:Enterovirus B, Human / Q000187:drug effects; D006367:HeLa Cells; D018259:Herpesvirus 1, Human / Q000187:drug effects; D018258:Herpesvirus 2, Human / Q000187:drug effects; D006801:Humans; D008826:Microbial Sensitivity Tests; D008968:Molecular Conformation; D009705:Nucleosides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D012136:Respiratory Syncytial Viruses / Q000187:drug effects; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D014616:Vaccinia virus / Q000187:drug effects; D018116:Vesiculovirus / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D009705:Nucleosides; D003596:Cytosine