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[reaction: see text] Zinc(II) and copper(II) complexes of prodigiosin (1) have been characterized. All N-atoms of 1 bind Cu(II) to generate 5: the complex exhibits regiospecific oxidation of the C-pyrrole. In contrast, coordination by Zn(II) to 1 produces Zn(1)(2) (8), a 4-coordinate tetrahedral complex. The influence of these binding geometries on Cu-mediated double-strand (ds) DNA cleavage by 1 is discussed.

The 4-methoxypyrrolic natural products contain a common 4-methoxy-2,2'-bipyrrole chromophore and exhibit promising anticancer, antimicrobial, and immunosuppressive activities. Herein, the ability of two representative members, tambjamine E (1) and prodigiosin (2), to bind calf thymus DNA (CT-DNA), polyd[G-C](2), and polyd[A-T](2) has been characterized using absorption and fluorescence spectroscopy. Scatchard plots showed that 1 occupies a site size (n) of ca. three base pairs and possesses affinity constants (K) ranging from 1 to 0.1 x 10(5) M(-)(1). Prodigiosin (2) binds DNA by mixed modes, as isobestic points were not evident in titration experiments. The neutral aldehyde precursor 4 was found to possess no measurable DNA binding affinity, indicating that the enamine structure of 1 and the pyrromethene of 2 are essential elements for DNA binding affinity. The enamine of 1 was found to undergo hydrolysis to 4 with a half-life (t(1/2)) of 14.5 h at pH 7.4 and 37.5 degrees C. For the B-ring nitrogen atom of 1, a pK(a) value of 10.06 was also established. From fluorescence spectroscopy it was found that 1, 2, and 4 possess weak emission spectra in water that is increased in nonaqueous solvents. For 1 and 2, DNA binding also increased the emission yield. Energy-transfer measurements suggested an intercalative binding mode, with preference for AT sites. The ability of distamycin to displace 1 and 2 from the helix also suggested that they intercalate from the minor-groove. This specificity differs from other unfused aromatic cations that bind by a minor-groove mode at AT sequences and intercalate at GC sites. Reasons for the specificity displayed by 1 and 2, as well as the implications of our findings to their biological properties are discussed.

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.