Biomimetic Iron Complex Achieves TET Enzyme Reactivity

The epigenetic marker 5‐methyl‐2′‐deoxycytidine (5mdC) is the most prevalent modification to DNA. It is removed inter alia via an active demethylation pathway: oxidation by Ten‐Eleven Translocation 5‐methyl cytosine dioxygenase (TET) and subsequent removal via base excision repair or direct demodification. Recently, we have shown that the synthetic iron(IV)‐oxo complex [Fe(IV)(O)(Py(5)Me(2)H)](2+) (1) can serve as a biomimetic model for TET by oxidizing the nucleobase 5‐methyl cytosine (5mC) to its natural metabolites. In this work, we demonstrate that nucleosides and even short oligonucleotide strands can also serve as substrates, using a range of HPLC and MS techniques. We found that the 5‐position of 5mC is oxidized preferably by 1, with side reactions occurring only at the strand ends of the used oligonucleotides. A detailed study of the reactivity of 1 towards nucleosides confirms our results; that oxidation of the anomeric center (1′) is the most common side reaction.