Chemical Synthesis of Heterocyclic-Sugar Nucleoside Analogues

Today, a variety of nucleoside analogues have been discovered which expand the antiviral and anticancer spectrum and/or modify the pharmacological and/or pharmacokinetic properties of the parent compounds. Besides the hydroxymethyl group, which is necessary for the phosphorylation of the molecule by kinases, and the heterocyclic base moiety, which is implied in the recognition process of the nucleoside through specific hydrogen bonds, the key element which must be considered is the furanose ring, which in several instances seems to act as a spacer. A lot of structural modifications have been described, many of them having been successfully developed as therapeutic agents in medicine. Indeed, several compounds modified in the sugar and the base moiety have been developed as antiviral agents. Only variations on the substituents of the furanose ring were studied extensively and these, however, have several disadvantages, including chemical instability and clinical toxicity. With the aim of overcoming these drawbacks, several studies have been directed to analogues in which the furanose ring has been replaced by a different five-membered ring system. Among the several possibilities for heterocyclic nucleosides both only replacement of the oxygen atom of the furanose by a different heteroatom, like in thioanalogues and azanucleosides, and addition of a second heteroatom, as the case of isoxolanyl, oxathiolanyl, thiazolidinyl, oxazolidinyl, and isoxazolidinyl analogues, were considered. The chemistry of these nucleoside analogues will be described according to the heterocyclic ring acting as a spacer.