The enediynes are a class of natural products isolated from soil bacteria in the 1980s. They are among the most cytotoxic compounds currently known, affecting cell killing at low picomolar (10^-12 M) concentrations. These compounds bind in the minor groove of DNA and take advantage of a reaction known as a Bergman cyclization (shown above) to create a highly reactive 1,4-diradical species. In organic synthesis, the Bergman cyclization generally requires temperatures approaching 200 degrees Celsius. The enediynes; however, take advantage of a triggering reaction with a nucleophile, usually a thiol such as glutathione, to induce a conformational change in the molecule which makes the Bergman cyclization quite facile at physiological temperatures.
The 1,4 diradical produced by this cyclization reaction is well positioned to abstract a hydrogen from the deoxyribose sugar on each strand of the DNA duplex. These sugar-centered radicals are themselves highly reactive and undergo a series of reactions to generate a bistranded lesion. A “bistranded lesion” is a type of DNA damage which consists of two DNA lesions (damage sites), one on each opposing strand of the duplex, within close proximity to one another. The bistranded lesions generated by enediynes usually consist of either a double strand break or a single strand break with an opposing oxidized abasic lesion (oxidation of the sugar and loss of the nucleobase). Bistranded lesions are quite toxic to cells, which explains the high cytotoxicity of the endiynes. Unfortunately, this high potency has largely precluded the use of enediynes as clinical antitumor agents, as they show high toxicity in healthy cells and tumor cells alike. There has been some interest in using enediynes as part of antibody-drug conjugates to reduce their off-target effects, but these attempts have met with little success.
Pictured above: The Bergman cyclization for calicheamicin