Structural design and in flow synthesis of aromatic endoperoxides as oxygen releasing agents at physiological conditions

Hypoxia occurs in different pathological settings as a consequence of poor vascularization and it results in reduced efficacy of current nosocomial treatments i.e. chemotherapy and photodynamic therapy. In order to overcome these boundaries, aromatic endoperoxides (EPOs) have been studied and proposed as oxygen-releasing agents (ORAs) due to their ability to reversibly bind molecular oxygen (O2), liberating it upon suitable triggering. DFT calculation of the dissociation energy (Ediss) of the intramolecular O-O bridge and structural crystallographic data of synthesized and studied EPOs drove the design of an array of 9,10-disubstituted anthracenes among which three candidates were carefully selected. Once optimized the synthesis of the aromatic substrates, for the first time the corresponding EPOs have been produced under continuous flow irradiation in the presence of a sub-stoichiometric amount of a photosensitizer in organic solvents. The release of O2 could be obtained straightforwardly at 37.5 °C by thermolysis. In accordance with the calculated Ediss = 3.2 kcal mol-1, 3,3'-(anthracene-9,10-diyl)bis(prop-2-yn-1-ol) (DIPA) resulted as the best candidate for the sustained release of O2 in biocompatible and physiologically relevant conditions. The exploitation of these optimized EPOs as ORAs to relieve hypoxia will be further evaluated and described in due course.