Copper-Mediated Nuclease Activity of a Tambjamine Alkaloid

The marine natural product tambjamine E ( 5 ) has been found to efficiently bind DNA and carry out DNA cleavage in the presence of Cu(II) and molecular oxygen without addition of an external reducing agent . DNA cleavage studies utilizing supercoiled plasmid DNA showed that the cleavage is inhibited by the enzyme catalase, which lowers solution concentrations of hydrogen peroxide (H 2 O 2 ), but not superoxide dismutase (SOD), which converts the superoxide radical (O 2 • - ) into H 2 O 2 . The cleavage is also dependent on salt concentration and is not efficiently inhibited by hydroxyl radical scavengers. Evidence from UV−vis spectroscopy and electrospray mass spectrometry indicates that tambjamine E ( 5 ) binds Cu(II) to form a dimeric complex with 2:2 stoichiometry. Once bound to Cu(II), the bipyrrole nucleus of 5 is envisioned to reduce Cu(II) → Cu(I), while it is oxidized to a π-radical cation. Evidence in favor of this hypothesis was derived from the finding that generation of the dimeric copper complex of 5 in methanol was followed by dimerization of 5 to yield a tetrapyrrole derivative, (tambjamine E) 2 . Thus, Ci(I), generated through the intermediacy of the π-radical cation of tambjamine E, is envisioned to react with H 2 O 2 to yield a copper−oxo species that initiates DNA cleavage.