COPPER-MEDIATED NUCLEASE ACTIVITY OF A TAMBJAMINE ALKALOID

The marine natural product tambjamine E (5) has been found to efficien tly bind DNA and carry out DNA cleavage in the presence of Cu(II) and molecular oxygen without addition of an external reducing agent. DNA c leavage studies utilizing supercoiled plasmid DNA showed that the clea vage is inhibited by the enzyme catalase, which lowers solution concen trations of hydrogen peroxide (H2O2), but not superoxide dismutase (SO D), which converts the superoxide radical (O-2(.-)) into H2O2. The cle avage is also dependent on salt concentration and is not efficiently i nhibited by hydroxyl radical scavengers. Evidence from UV-vis spectros copy 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 pi-radical cation, Evidence in favor of this hypothesis was derived from the finding that generati on of the dimeric copper complex of 5 in methanol was followed by dime rization of 5 to yield a tetrapyrrole derivative, (tambjamine E)(2). T hus, Ci(I), generated through the intermediacy of the pi-radical catio n of tambjamine E, is envisioned to react with H2O2 to yield a copper- oxo species that initiates DNA cleavage.