title: Synthesis of 4,6-dideoxy-3-fluoro-2-keto-beta-D-glucopyranosyl analogues of 5-fluorouracil, N6-benzoyl adenine, uracil, thymine, N4-benzoyl cytosine and evaluation of their antitumor activities.
abstract: The synthesis of the unsaturated 4,6-dideoxy-3-fluoro-2-keto-beta-d-glucopyranosyl nucleosides of 5-fluorouracil (6a), N(6)-benzoyl adenine (6b), uracil (6c), thymine (6d) and N(4)-benzoyl cytosine (6e), is described. Monoiodination of compounds 1a,b, followed by acetylation, catalytic hydrogenation and finally regioselective 2'-O-deacylation afforded the partially acetylated dideoxynucleoside analogues of 5-fluorouracil (5a) and N(6)-benzoyl adenine (5b), respectively. Direct oxidation of the free hydroxyl group at the 2'-position of 5a,b, with simultaneous elimination reaction of the beta-acetoxyl group, afforded the desired unsaturated 4,6-dideoxy-3-fluoro-2-keto-beta-D-glucopyranosyl derivatives 6a,b. Compounds 1c-e were used as starting materials for the synthesis of the dideoxy unsaturated carbonyl nucleosides of uracil (6c), thymine (6d) and N(4)-benzoyl cytosine (6e). Similarly a protection-selective deprotection sequence followed by oxidation of the free hydroxyl group at the 2'-position of the dideoxy benzoylated analogues 9c-e with simultaneous elimination reaction of the beta-benzoyl group, gave the desired nucleosides 6c-e. None of the compounds was inhibitory to a broad spectrum of DNA and RNA viruses at subtoxic concentrations. The 5-fluorouracil derivative 6a was more cytostatic (50% inhibitory concentration ranging between 0.2 and 12 microM) than the other compounds.
authors.affiliation: Department of Biochemistry and Biotechnology, Laboratory of Organic Chemistry, University of Thessaly, 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: Christos
authors.initials: C
authors.lastname: Kiritsis
authors.forename: Jan
authors.initials: J
authors.lastname: Balzarini
authors.forename: Dimitri
authors.initials: D
authors.lastname: Komiotis
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000633:toxicity; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D045744:Cell Line, Tumor; D003596:Cytosine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000633:toxicity; D004354:Drug Screening Assays, Antitumor; D005472:Fluorouracil / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000633:toxicity; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D009705:Nucleosides / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D013237:Stereoisomerism; D013941:Thymine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000633:toxicity; D014498:Uracil / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000633:toxicity
chemical_list: D000970:Antineoplastic Agents; D009705:Nucleosides; D014498:Uracil; D003596:Cytosine; D000225:Adenine; D013941:Thymine; D005472:Fluorouracil