Abstract
Since their discovery in naturally occurring compounds such as dynemicin and neocarzinostatin, enediyne-containing compounds have been investigated as potential chemotherapy drugs. When photoactivated, enediynes can undergo Bergman cyclization. The product of this reaction is a diradical capable of abstracting hydrogen atoms from DNA, which in turns leads to cleavage of the DNA strand and cell death. The utility of enediynes as an anticancer drug would be improved by their selective photoactivation in cancerous cells through the application of visible (as opposed to UV) light. In this study, time-dependent density functional theory (TD-DFT) calculations on a set of 53 structurally diverse enediyne compounds allowed characteristics to be identified which lead to longer absorption wavelengths. Among these were adding conjugated substituents to the alkyne termini, introducing heterocyclic supporting groups, and angling the enediyne relative to the supporting group. In order to determine if the electronic excitations associated with these absorptions would lead to Bergman cyclization, TD-DFT was used to directly study the electronic excited states resulting from the absorptions identified. Comparison of the geometric and electronic properties of the ground and electronic excited states has indicated several factors which can be correlated with the tendency of a particular photoexcitation to promote cyclization. Upon photoexcitation, an increase in the alkyne bond lengths along with a decrease in alkyne bond order, and a decrease in the C1-C6 distance are correlated with photocyclization reactivity. Additionally, by measuring the changes in the partial atomic charges between the excited state and ground state, the role of each region of the molecule in the electronic excitation can be quantified. Each of these factors can be incorporated into criteria to assess whether or not an enediyne will be more or less likely to photocyclize, allowing for the design of potential chemotherapy drugs. Three structures are proposed here as the basis for safer chemotherapy drug designs utilizing visible light.