The natural product shown above, UK-1, was first isolated by Taniguchi and co-workers from a strain of Streptomyces, a soil microbe. We became interested in this natural product for two reasons. First, we were intrigued with the reports that UK-1 displayed anticancer activity in cell culture, but lacked any antibacterial or antifungal activity. This sort of selectivity for killing cancer cells versus prokaryotes or even other eukaryotes is very unusual in natural product chemistry. Second, we recognized in the structure of UK-1 a potential metal ion binding motif: the 2(ortho-hydrophenyl)benzoxaole core, shown in red above. Our interest in metal ion binding anticancer agents stemmed from our work on antibacterial fluoroquinolones and quinobenzoxazines, fluoroquinolone analogs with antitumor activity, both of which bind metal ions to form 2:2 dimers which interact with DNA.

We secured gram amounts of UK-1 by total synthesis, and verified that this natural product is selectively cytotoxic to cancer cells versus bacteria. We also found that UK-1 binds magnesium ions, as well as other di- and tri-valent metal ions, with micromolar affinity. Furthermore, in analogy with the quinobenzoxazines, UK-1 binds to double-stranded DNA as the magnesium complex.

We are preparing analogs of UK-1 in order to understand the structural features that give rise to the selective cytotoxicity. We are also carrying out studies to identify the target(s) of this natural product. Recently, we have found that a simple analog that we call TOP-027, shares with UK-1 all of the following features: High-affinity Magnesium ion binding, metal ion-dependent DNA binding, and selective cytotoxicity to cancer cells. TOP-027 represents the "minimal pharmacophore" for UK-1. In collaboration with the group of Prof. Jennifer Brodbelt in the Department of Chemistry, ESI-MS is being employed to further probe the nature of the metal ion binding and metal ion-dependent DNA binding by UK-1 and analogs. ESI-MS observed metal versus non-metal-mediated DNA binding, as well as the specificity of DNA binding (i.e., double-stranded versus single-stranded), is correlated with the biological activities of these analogues.

For more information on UK-1 and other metal ion-dependent DNA binding agents, see the following publications:

Reynolds, M. B.; DeLuca, M. R.; Kerwin, S. M. "The Novel Bis(benzoxazole) Cytotoxic Natural Product UK-1 is a Magnesium Ion-Dependent DNA Binding Agent and Inhibitor of Human Topoisomerase II" Bioorg. Chem. 1999, 27, 326-337.

Yu, H.; Kwok, Y.; Hurley, L. H.; Kerwin, S. M. "Efficient, Mg2+-Dependent Photochemical Cleavage of DNA by the Anticancer Quinobenzoxazine (S)-A-62176" Biochemistry 2000, 38, 10236-10246.

Reyzer, M. L.; Brodbelt, J. S.; Kumar, D.; Kerwin, S. M. "Evaluation of Complexation of Metal Mediated DNA Binding Drugs to Oligonucleotides via Electrospray Ionization Mass Spectrometry" Nucl. Acids Res. 2001 29, u9-u20.

Kumar, D., Jacob, M.; Reynolds, M.; Kerwin, S. M. "Synthesis and Evaluation of Anticancer Benzoxazoles and Benzimidazoles related to UK-1" Bioorg. Med. Chem., 2002, 10, 3997-4004.

Oehlers, L.; Mazzitelli, C.; Rodriguez, M.; Kerwin, S. M.; Brodbelt, J. "Evaluation of Complexes of DNA Duplexes and Novel Benzoxazoles and Benzimidazoles by Electrospray Ionization Mass Spectrometry" J. Am. Soc. Mass Spec., 2004, 15, 1593-1603.

College of Pharmacy at UT Austin