Synthesis and properties of 4'-C-aminoalkyl-2'-fluoro-modified RNA oligomers

Bioorg Med Chem. 2018 Aug 15;26(15):4574-4582. doi: 10.1016/j.bmc.2018.08.001. Epub 2018 Aug 2.

Abstract

Synthesis and properties of double-stranded RNAs (dsRNAs) and small interfering RNAs (siRNAs) containing 4'-C-aminoethyl-2'-deoxy-2'-fluorouridine are described. Thermal denaturation studies showed that incorporation of 4'-C-aminoethyl-2'-fluoro analog improved the thermal stabilities of dsRNAs and siRNAs compared to the corresponding 4'-C-aminoethyl-2'-O-methyl analog. siRNA incorporating eight 4'-aminoethyl-2'-fluoro analogs in the passenger strand showed sufficient RNAi activity at 1 nM concentration, which was similar to that of the unmodified siRNA. Furthermore, the siRNA containing the 4'-C-aminoethyl-2'-fluoro analog exhibited high stability in a buffer containing 20% bovine serum. Forty-eight percent of the siRNA remained intact after 48 h of incubation. Thus, modification of siRNAs by the 4'-C-aminoethyl-2'-fluoro analog would be useful for the development of therapeutic siRNA molecules.

Keywords: 2′-Fluoro substituent; 4′-Aminoalkyl group; Nuclease resistance; RNA interference; Small interfering RNA; Thermal stability.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Fluorine / chemistry*
  • HeLa Cells
  • Humans
  • Nucleic Acid Denaturation
  • Plasmids / genetics
  • Plasmids / metabolism
  • RNA Interference
  • RNA, Double-Stranded / chemical synthesis
  • RNA, Double-Stranded / chemistry*
  • RNA, Small Interfering / chemical synthesis
  • RNA, Small Interfering / chemistry*
  • Transition Temperature
  • Uridine / analogs & derivatives
  • Uridine / chemical synthesis

Substances

  • RNA, Double-Stranded
  • RNA, Small Interfering
  • Fluorine
  • Uridine