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

• Published in: Bioorganic & medicinal chemistry Vol. 26; no. 15; pp. 4574 - 4582
• Main Authors: Kano, Toshifumi, Katsuragi, Yui, Maeda, Yusuke, Ueno, Yoshihito
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 15-08-2018
• Subjects: 2′-Fluoro substituent; 4′-Aminoalkyl group; Fluorine - chemistry; HeLa Cells; Humans; Nuclease resistance; 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; Small interfering RNA; Thermal stability; Transition Temperature; Uridine - analogs & derivatives; Uridine - chemical synthesis; 4′-Aminoalkyl group; Small interfering RNA; 2′-Fluoro substituent; Nuclease resistance; RNA interference; Thermal stability
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2018.08.001

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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.