Oligodeoxyribonucleotide analogues with bridging dimethylene sulfide, sulfoxide, and sulfone groups. Toward a second-generation model of nucleic acid structure.
Short DNA analogues with bridging dimethylene sulfide, sulfoxide, and sulfone groups replacing the phosphate diesters (S-DNAs) were synthesized from building blocks prepared via two routes, both starting from D-glucose. Building blocks for RNA analogues were prepared by stereoselective introduction of nucleobase into a 2'-acylated ribose analogue. The ribose analogues were converted to deoxyribose analogues by replacement of a 3''-OH group by a thioacetyl unit, followed by photolytic deoxygenation or radical-based 2'-deoxygenation. DNA analogues joined via CH(2)(-)S-CH(2) units were prepared by S(N)2 displacement of a 6'-mesyl group on one building block using a thiolate nucleophile of another. 4,4'-Dimethoxytrityl protection and deprotection schemes were established for both the thiol and hydroxyl groups. The corresponding sulfoxide DNA analogues were obtained by oxidation with hydrogen peroxide. Sulfone DNA analogues were obtained by oxidation of the sulfide DNA with persulfate or hydrogen peroxide in the presence of a titanium silicate catalyst. The physical properties of several representative oligonucleotide analogues were examined, and interpreted in light of a "second-generation" model for DNA strand-strand recognition, a model that emphasizes the role of the polyanionic backbone in diminishing unwanted tendencies of highly functionalized molecules to form "structure" in solution. Even short sulfide-linked DNA analogues displayed association properties different from those displayed by standard DNA molecules. Complex formation observed with sulfide-linked tetramers by HPLC study in different solvents suggested that the complex is formed using hydrogen bonding. Sulfone-linked dinucleotides display Watson-Crick behavior; the tetramer, however, displayed self-structure. Self-structure and self-aggregation become more prominent as the length of the oligonucleotide analogues increases. The tendency to self-aggregate can be decreased by adding a charged sulfonate group to the 3''-end of the DNA analogue. Features of the second-generation model are important for many areas of nucleic acid chemistry, from the design of nucleic acid therapeutic agents to the search for life on other planets.
Huang
Zhen
Z
Department of Chemistry, University of Florida, Gainesville 32611, USA.
Benner
Steven A
SA
D002384:Catalysis; D002851:Chromatography, High Pressure Liquid; D002855:Chromatography, Thin Layer; D004247:DNA / Q000737:chemistry*; D005947:Glucose / Q000031:analogs & derivatives* / Q000737:chemistry*; D006860:Hydrogen Bonding; D046911:Macromolecular Substances; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D015394:Molecular Structure; D009690:Nucleic Acid Conformation; D009693:Nucleic Acid Hybridization; D009838:Oligodeoxyribonucleotides / Q000737:chemistry*; D012313:RNA / Q000737:chemistry; D013237:Stereoisomerism; D013457:Sulfur Compounds / Q000737:chemistry*
D046911:Macromolecular Substances; D009838:Oligodeoxyribonucleotides; D013457:Sulfur Compounds; D012313:RNA; D004247:DNA; D005947:Glucose