Unsaturated dideoxy fluoro-ketopyranosyl nucleosides as new cytostatic agents: a convenient synthesis of 2,6-dideoxy-3-fluoro-4-keto-beta-D-glucopyranosyl analogues of uracil, 5-fluorouracil, thymine, N4-benzoyl cytosine and N6-benzoyl adenine.
The beta-protected nucleosides of uracil (2a), 5-fluorouracil (2b), thymine (2c), N(4)-benzoyl cytosine (2d) and N(6)-benzoyl adenine (2e) were synthesized by condensation of the peracetylated 3-deoxy-3-fluoro-D-glucopyranose (1) with the corresponding silylated bases. The nucleosides were deacetylated and several subsequent protection and deprotection steps afforded the partially acetylated analogues 6a-e. Selective iodination followed by hydrogenation gave the acetylated dideoxy analogues of uracil (8a), 5-fluorouracil (8b), thymine (8c), N(4)-benzoyl cytosine (8d) and N(6)-benzoyl adenine (8e), respectively. Finally, direct oxidation of the free hydroxyl group at the 4'-position of 8a-e, and simultaneous elimination reaction of the beta-acetoxyl group, afforded the desired unsaturated 2,6-dideoxy-3-fluoro-4-keto-beta-D-glucopyranosyl derivatives 9a-e. The new analogues were evaluated for antiviral and cytostatic activity. Compounds 9a-e were not active against a broad panel of DNA and RNA viruses at subtoxic concentrations. However, they were markedly cytostatic against a variety of tumor cell lines. The compounds should be regarded as potential new lead compounds to be further investigated for anticancer therapy.
Manta
Stella
S
Department of Biochemistry and Biotechnology, Laboratory of Organic Chemistry, University of Thessaly, 26 Ploutonos Street, 41221 Larissa, Greece.
Tzioumaki
Niki
N
Tsoukala
Evangelia
E
Panagiotopoulou
Aggeliki
A
Pelecanou
Maria
M
Balzarini
Jan
J
Komiotis
Dimitri
D
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D054697:Cytostatic Agents / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D009705:Nucleosides / Q000737:chemistry* / Q000494:pharmacology; D014780:Viruses / Q000187:drug effects
D000970:Antineoplastic Agents; D000998:Antiviral Agents; D054697:Cytostatic Agents; D009705:Nucleosides