Uracil condenses specifically with trifluoroacetaldehyde and hexafluoroacetone at C-5 to form derivatives containing perfluoro alcohols at this critical position. Uracil also reacts specifically with bis(perfluoroalkanoyl)peroxides under radical conditions to give perfluoroalkyl derivatives at the same position. The latter compounds lose two fluorine atoms readily at pH 8-9 to form perfluoroalkyl ketones, which exist preferentially as their hydrates or tetrahedral nucleophilic adducts. Since the half-life for loss of fluorine is ca. 20 min at pH 8, these compounds are potential irreversible affinity labels for pyrimidine recognition sites in vivo. Under the same reaction conditions, the perfluoroalkypyrimidines are 3-5 times as reactive as trifluoromethylpyrimidines, whose strong antiviral properties have been thoroughly demonstrated. The same radical perfluoroalkylation can be achieved with uridines. Although the carbon-fluorine bond is significantly more stable in the nucleoside series, conversion to ketones can also be achieved in basic media, particularly with sulfhydryl catalysis. These ketones are reducible to secondary alcohols with sodium borohydride. The inductive effects of multiple fluorine atoms renders the alcohols highly acidic and readily capable of forming strong internal hydrogen bonds with a carbonyl or amino group at C-4. We anticipate that such hydrogen bonding will interfere with the intermolecular hydrogen bonding needed for effective base pairing in polynuclear strands and, thus, expect that such compounds may block cell division and may act as antiviral and anticancer agents. Furthermore, hydrogen bonding in this position in purines and pyrimidines has been found essential for the action of PRPP synthetase. By increasing the length of the perfluoroalkyl chain, lipophilicity can be correspondingly increased to meet the needs for effective transport across membranes. The nucleophile at C-4 in uridine or cytidine is also capable of displacing a fluorine atom adjacent to the ketone to form novel bicyclic pyrimidine nucleosides. All of these compounds also have the potential of acting as inhibitors of cytidine deaminase.
