Year: 2024
Type: article
Abstract: Nowadays, nucleic acid derivatives capable of modulating gene expression at the RNA level gained widespread recognition as promising therapeutic agents. A suitable degree of biological stability of oligonucleotide therapeutics that is required for in vivo application can be most expeditiously achieved by chemical modification of the internucleotidic phosphate group, which may also affect their cellular uptake, tissue distribution and pharmacokinetics. Our group has previ-ously developed a strategy for the chemical modification of the phosphate group via Staudinger reaction on solid phase of the intermediate dinucleoside phosphite triester and a range of, pref-erably, electron deficient organic azides such as sulfonyl azides during automated solid-phase DNA synthesis according to the conventional β-cyanoethyl phosphoramidite scheme. Polyfluoro compounds are characterized by unique properties that prompted their extensive application both in industry and in scientific research. We report herein the synthesis and isolation of novel oligodeoxyribonucleotides incorporating internucleotidic perfluoro-1-octanesulfonyl phospho-ramidate or 2,2,2-trifluoroethanesulfonyl phosphoramidate groups. In addition, novel oligonu-cleotide derivatives with fluorinated zwitterionic phosphate mimics were synthesized by a tan-dem methodology, which involved: (a) introduction of a carboxylic ester group at the internu-cleotidic position via a Staudinger reaction with methyl 2,2-difluoro-3-azidosulfonylacetate; and (b) treatment with an aliphatic diamine, e.g. 1,1-dimethylethylenediamine or 1,3-diaminopropane. It was further shown that the polyfluoro oligonucleotides obtained were able to form comple-mentary duplexes with either DNA or RNA, which were not significantly differing in stability from the natural counterparts. Long-chain perfluoroalkyl oligonucleotides were taken up into cultured human cells in the absence of a transfection agent. It may be concluded that the polyfluoro oligonucleotides described here can represent a useful platform for designing oligonucleotide therapeutics.
DOI: 10.3390/ijms26010300
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,296
OpenAlex ID: W4405926437