Unsaturated fluoro-ketopyranosyl nucleosides: synthesis and biological evaluation of 3-fluoro-4-keto-beta-d-glucopyranosyl derivatives of N(4)-benzoyl cytosine and N(6)-benzoyl adenine

• Published in: European journal of medicinal chemistry 2008-02, Vol.43 (2), p.420-428
• Main Authors: Manta, Stella, Agelis, George, Botić, Tanja, Cencic, Avrelija, Komiotis, Dimitri
• Format: Article
• Language: English
• Subjects: Adenine - analogs & derivatives; Adenine - chemical synthesis; Adenine - pharmacology; Antiviral Agents - chemical synthesis; Antiviral Agents - pharmacology; Cell Line, Tumor; Cytosine - analogs & derivatives; Cytosine - chemical synthesis; Cytosine - pharmacology; Humans; Magnetic Resonance Spectroscopy; Microbial Sensitivity Tests; Rotavirus - drug effects; Spectrometry, Mass, Electrospray Ionization
• ISSN: 0223-5234
• DOI: 10.1016/j.ejmech.2007.04.001

The protected beta-nucleosides 1-(2,4,6-tri-O-acetyl-3-deoxy-3-fluoro-beta-d-glucopyranosyl)-N(4)-benzoyl cytosine (2a) and 9-(2,4,6-tri-O-acetyl-3-deoxy-3-fluoro-beta-d-glucopyranosyl)-N(6)-benzoyl adenine (2b), were synthesized by the coupling of peracetylated 3-deoxy-3-fluoro-d-glucopyranose (1) with silylated N(4)-benzoyl cytosine and N(6)-benzoyl adenine, respectively. The nucleosides were deacetylated and several subsequent protection and deprotection steps afforded the partially acetylated nucleosides of cytosine 7a and adenine 7b, respectively. Finally, direct oxidation of the free hydroxyl group at 4'-position of 7a and 7b, and simultaneous elimination reaction of the beta-acetoxyl group, afforded the desired unsaturated 3-fluoro-4-keto-beta-d-glucopyranosyl derivatives. These newly synthesized compounds were evaluated for their potential antitumor and antiviral activities. Compared to 5FU, the newly synthesized derivatives showed to be more efficient as antitumor growth inhibitors and they exhibited direct antiviral effect toward rotavirus.