Metalloenediynes: advances in the design of thermally and photochemically activated diradical formation for biomedical applications.

The remarkable discovery of the enediyne antitumor antibiotics almost two decades ago has led to significant developments in the systematic design and study of simple synthetic enediyne constructs and their Bergman cyclization reactivities. Advances in understanding both the geometric and electronic factors that are important in influencing the activation barrier to formation of the potent 1,4-phenyl diradical intermediate in simple organic enediynes have been made as a first step to the development of synthetic agents for biomedical uses. Progress in these areas has also served as a benchmark and guideline for a new wave of inorganic metalloenediyne constructs that display variable and wide-ranging reactivity or stability depending upon the geometric or electronic structure of the resulting complex. In general, metal sites offer additional structural flexibilities over their carbocyclic or acyclic organic analogues, which contributes greatly to their intriguing Bergman cyclization reactivities. This is true not only for thermal cyclization of metal-bound enediyne ligands in which the metal acts as a scaffold or Lewis acid, but also for photoelectronic or photothermal Bergman cyclization which can be achieved via metal-ligand charge transfer excited states. These reactivity developments parallel new protein targeting strategies for simple enediynes constructs, suggesting that a combined approach of controlled initiation and site specific targeting may allow enediynes to truly reach their full potential in biomedical applications.