Nonionic Analogs of RNA with Dimethylene Sulfone Bridges

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 itin the presence of
secondary
hydroxyl groupsto 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.