Tuning the Optical Properties of Phenanthriplatin: Towards New Photoactivatable Analogues

The activity of traditional bifunctional platinum-based drugs is based on a double binding attack of DNA strands that eventually damages the genetic code. Unfortunately, such therapy comes with severe side effects, which drastically limit its efficiency and more importantly, its large-scale applicability. One emerging alternative is the use of monofunctional platinum complexes based on phenanthriplatin, a new molecule that develops a potent toxicity in tumorous cells by reacting with one DNA base only. Herein, we use theoretical tools to assess the optical properties of phenanthriplatin as well as a series of analogues in an effort to pave the way to their use in photoactivated chemotherapy. In a first step, the absorption signatures of both isolated and DNA-embedded drugs are predicted through abinitio calculations. Two nitro derivatives are shown to activate a charge transfer from the DNA to the drug and might consequently initiate a cascade of photodamage events. In a second step, we performed molecular dynamics simulations that reveal that such structural change is enough to perturb the DNA-binding mode. The biological implications of these results in the framework of the design of novel photoactivatable drugs are discussed