Internal Abstraction of Dynemicin A: A QM/MM Approach

Enediynes exhibit promise as anti‐tumor drugs because of their ability to induce cell apoptosis. After undergoing Bergman cyclization, the enediyne is converted into para ‐benzyne, a diradical. These radicals are responsible for abstracting hydrogen from DNA, which causes the DNA to unravel, leading to cell death. Past research has shown that dynemicin A, an enediyne, easily binds to and abstracts hydrogen from DNA. However, the molecular mechanism through which this abstraction occurs is unknown. Following Bergman cyclization of the enediyne to form the diradical, we hypothesize two possible mechanisms for the subsequent reaction: 1.) the diradical directly abstracts hydrogen from DNA or 2.) the diradical moiety first abstracts a hydrogen from a proximate, intramolecular methyl group, and then the resulting methyl radical abstracts a hydrogen from the DNA. The Quantum Mechanics/Molecular Mechanics (QM/MM) package ONIOM available within Gaussian09 was used to investigate the energetics of these reactions.