The research activity in the general area of modified oligonucleotides and their dephospho analogues is summarized. The general criteria for the design of oligomers with altered backbones, namely charge, hydration and conformational freedom of the internucleosidyl linkage, are described. The flexible and semi-rigid polyamide linkages are emphasized which are best suited to adapt to the solid phase synthetic methodologies, at the same time satisfying the necessary physical requirements for optimum binding to form a duplex or triplex. A novel approach is described which takes advantage of the established peptide chemistry in the synthesis of oligonucleosides with an amino acid backbone. A discussion of the future direction for the synthesis and application of these polymers is included. 1. Introduction 2. Alternative Phosphate-Containing Linkages 2.1. Phosphorothioates 2.1.1. Phosphorodithioates 2.2. Methylphosphonates 2.3. Phosphoramidates 2.4. Phosphate Esters 2.5. The Contradiction Suggested by the Modified Phosphate Oligonucleotides: Influence of Backbone Charge and Hydration 3. Phosphate-Free Backbones 3.1. Carbonate Linkages 3.2. Carboxymethyl Linkages 3.3. Acetamidate Linkages 3.4. Carbamate Linkages 3.5. The Polyamide Linkages 3.5.1. The Semi-Rigid Polyamide Linkages 3.6. General Criteria for Altered Oligomer Design 3.6.1. Conformational Freedom 3.6.2. Backbone Charge 3.6.3. Backbone Hydration 3.7. Sulfur-Based Linkages 3.7.1. Thioether Linkages 3.7.2. Sulfonate, Sulfonamide and Sulfamate Linkages 3.7.3. Sulfide, Sulfoxide and Sulfone Linkages 3.8. Miscellaneous Linkages 3.8.1. Formacetal and Thioformacetal Linkages 3.8.2. Methylhydroxylamine Linkages 3.8.3. N-Cyanoguanidine Linkage 3.9. Alkylsilyl Linkages 4. Conclusion
