The enediyne antitumor antibiotics possess the unusual (Z)- 1 ,5-diyne-3-ene unit that rearranges in the presence of biological reducing equivalents to form a 1 ,4-phenyl diradical intermediate that performs double H-atom abstraction from cellular DNA. Upon discovery of these intriguing structures in the late 1980s, the pharmaceutical industry became interested in the potential use of enediynes as therapeutic antitumor agents. Unfortunately, after intense investigation by Eli Lilly, Wyeth-Ayerst, and Bristol Myers-Squibb, the compounds were determined to be too cytotoxic due to the inability to control their thermal reactivities effectively. Recent biomimetic enediyne studies have revealed that 1) the physical distance between the alkyne termini, and 2) the electronic structure and redox state of the enediyne chromophore adjacent to the reactive subunit are important factors that influence thermal enediyne reactivity. Additionally, the demonstration that the enediyne natural products can also be cyclized photochemically fostered questions regarding 3) the mechanism of photoactivated enediyne cyclization. Although the biologically relevant enediynes known to date are all organic compounds, transition metals routinely exert geometric and electronic influences on bound organic ligands. That is, they intricately poise ligand geometries, modulate electronic structures of bound ligands, and initiate thermal and photochemical redox reactions with bound organic substrates. For these reasons, metal ions are outstanding probes of enediyne reactivity. We have focused our research efforts on using metal ions to develop an understanding of the factors that control thermal and photochemical enediyne cyclization, and to incorporate this information into the design of synthetically accessible """"""""metalloenediynes"""""""" that exhibit controlled thermal and photochemical reactivities for potential biological applications. This proposal outlines studies designed to probe fundamental chemical questions regarding enediyne reactivity as well as initiating biological activity studies in cells.
Showing the most recent 10 out of 13 publications
