title: Efficient synthesis of exomethylene- and keto-exomethylene-d-glucopyranosyl nucleoside analogs as potential cytotoxic agents.
abstract: A novel series of exomethylene- and keto-exomethylene-d-glucopyranonucleosides with thymine, uracil, and 5-fluorouracil as heterocyclic bases have been designed and synthesized. Wittig condensation of the 3-keto glucoside 1 gave the corresponding 1,2:5,6-di-O-isopropylidene-3-deoxy-3-methylene-d-glucofuranose (2), which after hydrolysis and acetylation led to the precursor 1,2,4,6-tetra-O-acetyl-3-deoxy-3-methylene-d-glucopyranose (4). Compound 4 was condensed with silylated thymine, uracil, and 5-fluorouracil, respectively, deacetylated and acetalated to afford 1-(3'-deoxy-4',6'-O-isopropylidene-3'-methylene-β-d-glucopyranosyl)pyrimidines 7a-c. Oxidation of the free hydroxyl group in the 2'-position of the sugar moiety led to the formation of the labile 1-(3'-deoxy-4',6'-O-isopropylidene-3'-methylene-β-d-glucopyranosyl-2'-ulose)pyrimidines 8a-c. Finally, deisopropylidenation of the resulted derivatives 8a-c afforded the diol nucleosides 9a-c. The target keto-exomethylene analogs 9a-c were more cytostatic against a variety of tumor cell lines than the corresponding saturated-hydroxy-exomethylene derivatives 6. In particular, the 5-fluorouracil derivative 9c was highly cytostatic at an IC(50) (50% inhibitory concentration) ranging between 0.56 and 9.4 microg/mL, which was comparable to the free parental 5-fluorouracil base.
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: Evangelia
authors.initials: E
authors.lastname: Tsoukala
authors.forename: Stella
authors.initials: S
authors.lastname: Manta
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: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003603:Cytotoxins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005472:Fluorouracil / Q000737:chemistry; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D009705:Nucleosides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013941:Thymine / Q000737:chemistry; D014498:Uracil / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D003603:Cytotoxins; D009705:Nucleosides; D014498:Uracil; D013941:Thymine; D005472:Fluorouracil