ABSTRACT
Of all the sugar scaffolds in nucleosides, the ribose ring provides a perfect template. This can be appreciated by the existence of two specific ribose conformational sections in the pseudorotational cycle characterized as North and South domains. The incorporation of fluorine on the ribose ring is able to induce a strong bias for either antipodal domain and provides an excellent tool with which to probe and demonstrate the existence of specific conformational preferences that are associated with the ability of enzymes (kinases and polymerases) to discriminate their substrates. Fluorine substitution at various positions of the sugar ring discriminated between active and inactive anti-HIV 2′,3′-dideoxynucleosides. Pivotal results in this chapter can be simply summarized as the “magic of fluorine,” which could optimize recognition and binding by the processing enzymes. Even in the cases where anti-HIV activity was absent, as in the case of the difluoro-β-d-lyxo uridine, the fluorine manifested its magic by providing some unexpected reactivity that mimicked the efficiency of an enzymatic reaction. The conformational preferences of individual fluorine-substituted nucleosides could be transmitted through the chain of the DNA helix and allows the synthesis of A-type and B-type oligomers.
