Copper-Mediated Nuclease Activity of a Tambjamine Alkaloid

• Published in: Journal of the American Chemical Society 1998-05, Vol.120 (19), p.4557-4562
• Main Authors: Borah, Sumit, Melvin, Matt S, Lindquist, Niels, Manderville, Richard A
• Format: Article
• Language: English
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/ja9729746

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 (H2O2), but not superoxide dismutase (SOD), which converts the superoxide radical (O2 •-) into H2O2. 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 H2O2 to yield a copper−oxo species that initiates DNA cleavage.