The Cleavage of RNA Model Compounds: The Interplay Between the Nucleophile and the Leaving Group

Abstract

Hydrolytic reactions of phosphodiester bonds of RNA have been extensively studied over several decades. Information on the factors that affect the reactivity of phosphodiester bonds in biomolecules is important for the development of new nucleic acid‐related therapeutics. Furthermore, the development of artificial nucleases requires efficient catalytic entities, and rational design of catalysts requires detailed understanding of the catalytic mechanisms. In the present article, we concentrate on the interplay between the nucleophile and leaving group both in the absence and in the presence of metal ion catalysts. The effect of the nucleophile on the reactivity of RNA model compounds has been studied with 2‐hydroxypropyl and uridine 3′‐aryl phosphates as well as with bis‐(p‐nitrophenyl)phosphate as substrates. pH‐rate profiles for three different 2‐hydroxypropyl arylphosphates were compared with those obtained with a uridine 3′‐alkyl and aryl phosphates. The observations are discussed in terms of the relative goodness/poorness of the nucleophile and the leaving group. Metal complex‐dependent reactions were studied in the presence of well‐known and robust CuTerPy and CuBiPy complexes. The results show that CuTerPy and CuBiPy favour different types of phosphodiesters as substrates, depending on the properties of the nucleophile and leaving group, and suggest that the complexes utilize different catalysis mechanisms, which may depend also on the structure of the substrate. The results obtained further the understanding on the basic principles of metal complex‐promoted cleavage of RNA and model compounds, help to assess the relevance of data obtained with model compounds and support the design of artificial enzymes for phosphodiester cleavage.