Dideoxy fluoro-ketopyranosyl nucleosides as potent antiviral agents: Synthesis and biological evaluation of 2,3- and 3,4-dideoxy-3-fluoro-4-and -2-keto-β-D-glucopyranosyl derivatives of N4-benzoyl cytosine

The synthesis of the dideoxy fluoro ketopyranonucleoside analogues, 1-(2,3-dideoxy-3-fluoro-6- O -trityl-β- d -glycero-hexopyranosyl-4-ulose)- N 4 -benzoyl cytosine ( 7a ), 1-(3,4-dideoxy-3-fluoro-6- O -trityl-β- d -glycero-hexopyranosyl-2-ulose)- N 4 -benzoyl cytosine ( 13a ) and their detritylated analogues 8a and 14a , respectively, is described. Condensation of peracetylated 3-deoxy-3-fluoro- d -glucopyranose ( 1 ) with silylated N 4 -benzoyl cytosine, followed by selective deprotection and isopropylidenation afforded compound 2 . Routine deoxygenation at position 2′, followed by a deprotection-selective reprotection sequence afforded the partially tritylated dideoxy nucleoside of cytosine 6 , which upon oxidation of the free hydroxyl group at the 4′-position, furnished the desired tritylated 2,3-dideoxy-3-fluoro ketonucleoside 7a in equilibrium with its hydrated form 7b . Compound 2 was the starting material for the synthesis of the dideoxy fluoro ketopyranonucleoside 13a . Similarly, several subsequent protection and deprotection steps as well as routine deoxygenation at position 4′, followed by oxidation of the free hydroxyl group at the 2′-position of the partially tritylated dideoxy nucleoside 12 , yielded the desired carbonyl compound 13a in equilibrium with its hydrated form 13b . Finally, trityl removal from 7a / b and 13a / b provided the unprotected 2,3-dideoxy-3-fluoro-4-keto and 3,4-dideoxy-3-fluoro-2-ketopyranonucleoside analogues 8a and 14a , in equilibrium with their gem-diol forms 8b and 14b . None of the compounds showed inhibitory activity against a wide variety of DNA and RNA viruses at subtoxic concentrations, except 7a / b that was highly efficient against rotavirus infection. Nucleoside 7a / b also exhibited cytostatic activity against cells of various cancers. BrdU-cell cycle analysis revealed that the mechanism of cytostatic activity may be related to a delay in G1/S phase and initiation of programmed cell death. A synthesis of the novel dideoxy fluoro ketopyranonucleoside analogues of N 4 -benzoyl cytosine ( 7a , 8a and 13a , 14a ) in equilibrium with their hydrated forms ( 7b , 8b and 13b , 14b ) is reported. 7a / b was highly efficient against rotavirus infection and exhibited high and selective antitumor activity against cells of various cancers as compared with other compounds, AZT or 5FU respectively. BrdU-cell cycle analysis revealed that the mechanism of antitumor activity may be related to a delay in G1/S phase and prog