Unsaturated dideoxy fluoro-ketopyranosyl nucleosides as new cytostatic agents: A convenient synthesis of 2,6-dideoxy-3-fluoro-4-keto-β-d-glucopyranosyl analogues of uracil, 5-fluorouracil, thymine, N4-benzoyl cytosine and N6-benzoyl adenine
| Autor: | Niki Tzioumaki, Dimitri Komiotis, Evangelia Tsoukala, Stella Manta, Aggeliki Panagiotopoulou, Maria Pelecanou, Jan Balzarini |
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| Rok vydání: | 2009 |
| Předmět: |
Pharmacology
Cell Survival Stereochemistry Organic Chemistry Halogenation Antineoplastic Agents Nucleosides Uracil General Medicine Cytostatic Agents Antiviral Agents Chemical synthesis Thymine chemistry.chemical_compound Elimination reaction chemistry Cell Line Tumor Viruses Drug Discovery Animals Humans Nucleoside DNA Cytosine |
| Zdroj: | European Journal of Medicinal Chemistry. 44:4764-4771 |
| ISSN: | 0223-5234 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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