Light-induced synthesis of organic molecules has attracted vast attention since the early 20th century. Electronic excitation provides a viable route for activating ground state reactions that are otherwise unfavorable due to large activation energies. Light-induced photomedicine is an especially promising field and has made huge advancements in the treatment of cancers. In general, light-irradiation of a stable drug leads to the formation of an intermediate molecule, which is reactive towards a given biochemical process. In the present case, we are interested in the photo-activity of the cyclopropenone-containing enediyne photoprecursor shown in structure (1) in the reaction scheme below. Previous experimental studies have confirmed the light-induced elimination of CO from (1) to form the corresponding enediyne (2), which then undergoes a Bergman cycloaromatization rearrangement to form the biradical (3). This reactive biradical may then undergo reaction with DNA. Using high-level electronic structure and time-dependent dynamics methods, the first part of our contribution reveals the details of the ground and excited state reaction paths associated with the reaction scheme below. In particular, we show the hitherto unrecognized involvement of conical intersections and spin-flipping processes in the eventual formation of (3). Our results reveal that the formation of (3) may occur directly from (1), without branching into the intermediate minimum (2). In the second part of our contribution, the resulting biradical (3) is intercalated within DNA so as to explore the effect of the biradical on genomic DNA. Molecular dynamics simulations and mixed QM/MM electronic structure computations show that biradical (3) intercalates well with DNA. The dominant reaction involves H-atom abstraction from proximal nucleobases and the sugar-phosphate backbone, which induce nucleobase release and backbone-cleavage, respectively. The broader impacts of this work show that this type of mechanism could allow for the destruction of cells, which could eventually be used as a treatment for cancer. Future endeavors will extend to studies of the ways in which such drugs can be selectively targeted towards cancerous cells.

Photochemical mechanisms of light-activated drug molecules for potential cancer therapy

2019 Spring National Meeting

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