title: Synthesis and biological evaluation of unsaturated keto and exomethylene D-arabinopyranonucleoside analogs: novel 5-fluorouracil analogs that target thymidylate synthase.
abstract: The synthesis of pyrimidine unsaturated keto and exomethylene arabinopyranonucleoside analogs as potential antitumor and antiviral agents is described. Commercially available 1,2,3,4-tetra-O-acetyl-D-arabinopyranose (1) was condensed with silylated thymine, uracil, 5-fluorouracil, N(4)-benzoyl cytosine and 5-(trifluoromethyl)uracil, respectively, deacetylated and acetylated to afford 1-(3,4-O-isopropylidene-α-D-arabinopyranosyl)pyrimidine analogs 4. Two different synthetic routes were investigated for the conversion of compounds 4 into the new 1-(2,3,4-trideoxy-2-methylene-α-pent-3-enopyranosyl)nucleoside derivatives of thymine (10a), uracil (10b), 5-fluorouracil (10c) and N(4)-benzoyl cytosine (10d). Only the first approach could afford derivative 10d. Debenzoylation of 10d afforded 1-(2,3,4-trideoxy-2-methylene-α-pent-3-enopyranosyl)cytosine (10f). The first approach resulted also to the 2-keto-3,4-unsaturated analogs 9. The new analogs did not show inhibition of DNA and RNA virus replication in cell culture. The 2'-ketonucleoside derivatives 9 were found to be more cytostatic than the corresponding 2'-exomethylene nucleosides 10. The 5-fluorouracil unsaturated keto derivative 9c and the exomethylene derivatives 10c and 13c showed antiproliferative activity in the lower micromolar range. Experimental evidence revealed that 9c, 10c and 13c may act as novel types of 5-fluorouracil releasing prodrugs, and points to thymidylate synthase as target for their cytostatic action.
authors.affiliation: Department of Biochemistry and Biotechnology, Laboratory of Organic Chemistry, University of Thessaly, 26 Ploutonos Str, 41221 Larissa, Greece.
authors.forename: Niki
authors.initials: N
authors.lastname: Tzioumaki
authors.forename: Stella
authors.initials: S
authors.lastname: Manta
authors.forename: Evangelia
authors.initials: E
authors.lastname: Tsoukala
authors.forename: Johan
authors.initials: J
authors.lastname: Vande Voorde
authors.forename: Sandra
authors.initials: S
authors.lastname: Liekens
authors.forename: Dimitri
authors.initials: D
authors.lastname: Komiotis
authors.forename: Jan
authors.initials: J
authors.lastname: Balzarini
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D005472:Fluorouracil / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D009705:Nucleosides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013379:Substrate Specificity; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014543:Uridine Phosphorylase / Q000037:antagonists & inhibitors / Q000378:metabolism; D014780:Viruses / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D009705:Nucleosides; D013940:Thymidylate Synthase; D014543:Uridine Phosphorylase; D005472:Fluorouracil