A Generator of Peroxynitrite Activatable with Red Light

The generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) as “unconventional” therapeutics with precise spatiotemporal control by using light stimuli may open entirely new horizons for innovative therapeutic modalities. Among ROS and RNS, peroxynitrite (ONOO-) plays a dominant role in chemistry and biology in view of its potent oxidizing power and cytotoxic action. We have designed and synthesized a molecular hybrid based on a benzophenothiazine as red light-harvesting antenna joint to an N-nitroso appendage through a flexible spacer. Red light excitation of this molecular construct triggers the release of nitric oxide (NO) and simultaneously produces superoxide anion (O2-). The diffusion-controlled reaction between these two radical species generates ONOO-, as confirmed by the using of the fluorescein-boronate as highly selective chemical probe. Besides, the red fluorescence of the hybrid allows its tracking in different types of cancer cells where it is well-tolerated in the dark but induces a remarkable cell mortality under irradiation with red light in a very low concentration range, with very low light doses (ca. 1 J cm-2). This is the first example of ONOO- generator regulated by the highly biocompatible and tissue penetrating red light and can open up intriguing prospects in biomedical research, where precise and spatiotemporally controlled concentrations of ONOO- are required.