Nonionic Analogs of RNA with Dimethylene Sulfone Bridges

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Abstract

Analogs of RNA have been synthesized where each of the phosphodiester linking groups is replaced by dimethylene sulfone units (sulfone-linked nucleic acid analogs of RNA, or “rSNAs”). These are the first fully nonionic analogs of RNA to be prepared as oligomers. Sequences leading to the octamer 5‘-r(ASO2USO2GSO2GSO2USO2CSO2ASO2U)-3‘ have been prepared from 3‘,5‘-bishomo-β-ribonucleoside derivatives as building blocks prepared from diacetone d-glucose, and their chemistry has been explored. Coupling was performed in solution via SN2 reactions between a thiol from one fragment and a bromide from the other, oxidation of the resulting thioether to the sulfone, and deprotection of a terminal primary hydroxyl group and regioselective conversion of itin the presence of secondary hydroxyl groupsto an active group (thiol or bromide) to yield another fragment for coupling. Base-labile protecting groups were used for the nucleobases, and one-step full deprotection was achieved using 1 M NaOH. The target octamer and each isolated intermediate were characterized by NMR, UV spectroscopy, and mass spectrometry. While chemical reactions involving longer rSNAs were in several cases retarded relative to analogous reactions with monomers, some rates were enhanced. In water, the rSNA octamer displayed a thermal transition in the UV spectrum above 65 °C with a large hyperchromicity. The behaviors of rSNAs suggest roles for the polyanionic backbone in DNA and RNA beyond its role in conferring aqueous solubility. The repeating anionic charges in natural oligonucleotides evidently also control the potent molecular recognition properties of these richly functionalized molecules, direct strand−strand interactions to the part of the biopolymer distant from the backbone (the Watson−Crick edge of the nucleobases), cause the polymer to favor an extended conformation, and ensure that the physical properties of the oligonucleotide are largely independent of its sequence. This suggests structural features that must be built into nonionic oligonucleotide analogs generally.

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