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, N-4-benzoyl cytosine and N-6-benzoyl adenine

Abstract

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-glucopyramose (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. (C) 2009 Elsevier Masson SAS. All rights reserved.