Encouraging results obtained for modulation of gene expression by antisense oligonucleotides and their analogues have kindled hopes for a new generation of therapeutics against viral infections, cancer, and many other diseases. Among such analogues, oligo(nucleoside phosphorothioate)s (Oligo‐S) have generally shown the highest efficacy in inhibiting the biosynthesis of “unwanted” proteins. The first clinical trials of antisense agents are now in progress using Oligo‐S against genital warts and acute myeloid leukemia, and tests of Oligo‐S against AIDS should follow soon. Nevertheless, their mechanism of action, internalization, cellular trafficking, subcellular localization, and interaction with cellular proteins is still poorly understood. It is assumed a priori that application involves rapid and efficient molecular recognition of target RNA by Oligo‐S; however, the effects of the chirality of Oligo‐S have so far been unappreciated, because Oligo‐S has not yet been synthesized with stereocontrol. Indeed, the diastereomeric composition of Oligo‐S has never been determined, primarily because of the lack of appropriate analytical methods. Since each of the diastereomers is a stereochemically unique chemical entity, questions arise as to which diastereomer is responsible for an observed biological response, including positive (curative) or possibly negative (toxic) side effects. In this review we intend provide a perhaps somewhat speculative assessment of the problems associated with the stereo‐controlled synthesis of Oligo‐S and to discuss the state‐of‐the‐art in this field including strategies that may lead to Oligo‐S of predetermined chirality. This article is not intended to discourage researchers from further studies of dia‐steromeric mixtures of Oligo‐S as potential pharmaceuticals. Throughout the history of medicinal chemistry numerous useful medicines were discovered, developed, and employed without the detailed knowledge of their structure. Indeed, the composition of the vaccines discovered by Pasteur is a subject of vigorous study still today.

Wild mixtures of stereoisomers are usually formed in the synthesis of oligo(nucleoside phosphorothioate)s owing to the stereogenic phosphorus centers. Is the preparation of isomers with defined configuration at each phosphorus atom feasible, and if so, how far off is the stereoselective synthesis? In this review the problems of the stereoselective preparation of these compounds are outlined, and new synthetic methods are discussed. Oligo(nucleoside phosphorothioate)s have potential as “antisense therapeutics” for treatment of viral infections, cancer, and possibly even AIDS. But medical applications require stereochemically uniform compounds.

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