PRELIMINARY COMMUNICATION The Novel Bis(benzoxazole) Cytotoxic Natural Product UK-1 Is a Magnesium Ion-Dependent DNA Binding Agent and Inhibitor of Human Topoisomerase II

UK-1 is a novel, bis(benzoxazole) metabolite of Streptomyces sp. 517-02. UK-1 is cytotoxic to a variety of cancer cell lines, although it displays no antibacterial effects. We have investigated the metal ion coordination by UK-1 and find that UK-1 binds Zn2+ and Mg2+ to form stable complexes of overall 1:1 stoichiometry. Fe3+ metal ions are bound slightly less well by UK-1, and Ca2+ ions form weak complexes with this ligand. In contrast, potassium ions are not bound. The fluorescence spectrum of UK-1 displays a large Stokes shift, presumably as a result of the 2-(2′-hydroxyphenyl) benzoxazole chromophore present in this natural product. The intrinsic fluorescence of UK-1 was exploited in studying the interaction of this compound with DNA, along with changes in the UV/Vis spectrum of the compound and DNA melting studies. In the presence of Mg2+, UK-1 binds to double-stranded DNA 10 times more tightly than in the absence of Mg2+. Like the antitumor quinobenzoxazines, which also bind Mg2+ and bind to DNA in a magnesium ion-dependent fashion, UK-1 is an inhibitor of human topoisomerase II. Although these studies do not directly address the issue of the cellular target or targets responsible for UK-1 selective cytotoxicity, the similarities between UK-1 and the synthetic antitumor quinobenzoxazines indicate that UK-1 may exert its cytotoxic potential by targeting topoisomerase II.