Synthesis Metal Ion Binding and Biological Evaluation of New Anticancer 2-(2’-Hydroxyphenyl)benzoxazole Analogs of UK-1

摘要

UK-1 is a bis(benzoxazole) natural product displaying activity against a wide range of human cancer cell lines. A simplified analog of UK-1, 4-carbomethoxy-2-(2’-hydroxyphenyl)benzoxazole, was previously found to be almost as active as UK-1 against cancer cell lines, and similar to the natural product, formed complexes with variety of metal ions such as Mg²⁺ and Zn²⁺. A series 4-substituted-2-(2’-hydroxyphenyl)benzoxazole analogs of this “minimal pharmacophore” of UK-1 were prepared. The anti-cancer activity of these analogs was examined in breast and lung cancer cell lines. Spectrophotometric titrations in methanol were carried out in order to assess the ability of UK-1 and these analogs to coordinate with Mg²⁺ and Cu²⁺ ions. Although none of the new analogs were more cytotoxic than 4-carbomethoxy-2-(2’-hydroxyphenyl)benzoxazole, some analogs were identified that display similar cytotoxicity to this simplified UK-1 analog with improved water solubility. UK-1 and all of these new analogs bind Cu²⁺ ions better than Mg²⁺ ions, and the nature of the 4-substituent is important for the Mg²⁺ ion binding ability of these 2-(2’-hydroxyphenyl)benzoxazoles. Previous studies of a limited number of UK-1 analogs demonstrated a correlation between Mg²⁺ ion binding ability and cytotoxicity; however, within this series of 4-substituted-2-(2’-hydroxyphenyl)benzoxazoles the variations in cytotoxicity do not correlate with either Mg²⁺ or Cu²⁺ ion binding ability. These results, together with recent ESI-MS studies of Cu²⁺-mediated DNA binding by UK-1 and analogs, indicate that UK-1 and analogs may exert their cytotoxic effects by interaction with Cu²⁺ or other transition metal ions, rather than Mg²⁺, and that metal ion-mediated DNA binding, rather than metal ion binding affinity, is important for the cytotoxic effect of these compounds. The potential role of Cu²⁺ ions in the cytotoxic action of UK-1 is further supported by observation that UK-1 in the presence of Cu²⁺ displays enhanced cytotoxicity to MCF-7 and A549 cells when compared to UK-1 alone.