Nucleosides. 123. Synthesis of antiviral nucleosides: 5-substituted 1-(2-deoxy-2-halogeno-.beta.-D-arabinofuranosyl)cytosines and -uracils. Some structure-activity relationships

Abstract

The syntheses of several 2''-halogeno-5-substituted-arabinofuranosylcytosines and -uracils are described, and relationships of structure to anti-herpesvirus activity in vitro were examined. Those arabinonucleosides containing the 2''-fluoro function exhibit, generally, more potent anti-herpesvirus (HSV) activity than do their 2''-chloro or 2''-bromo analogs. The importance of the fluoride in the 2''-up (arabino) configuration for enhancement of antiviral effectiveness is demonstrated by the superior activity of 2''-fluoro-5-iodo-ara-C [2''-fluoro-5-iodo-1-.beta.-araabinofuranosyl cytosine, FIAC] to that of 2''-fluoro-5-iodo-cytosine. Of all the nucleosides tested, FIAC exhibited the most potent in vitro activity against HSV. 2''-Chloro-5-iodo- and 5-methyl-ara-C were 37 to more than 500 times more effective in vitro against HSV type 2 than against type 1, suggesting that these latter derivatives might serve clinically as useful probes to distinguish between HSV types 1 and 2 in the diagnosis of HSV infections in man.