Mechanistic Studies on RNA Strand Scission from a C2′-Radical

The C2′-carbon–hydrogen bond in ribonucleotides is significantly weaker than other carbohydrate carbon–hydrogen bonds in RNA or DNA. Independent generation of the C2′-uridine radical (<b>1</b>) in RNA oligonucleotides via Norrish type I photocleavage of a ketone-substituted nucleotide yields direct strand breaks via cleavage of the β-phosphate. The reactivity of <b>1</b> in different sequences and under a variety of conditions suggests that the rate constant for strand scission is significantly greater than 10⁶ s^–1 at pH 7.2. The initially formed C2′-radical (<b>1</b>) is not trapped under a variety of conditions, consistent with computational studies (Chem.Eur. J. 2009, 15, 2394) that suggest that the barrier to strand scission is very low and that synchronous proton transfer from the 2′-hydroxyl to the departing phosphate group facilitates cleavage. The C2′-radical could be a significant contributor to RNA strand scission by the hydroxyl radical, particularly under anaerobic conditions where <b>1</b> can be produced from nucleobase radicals