Structure-Based Design and in-Flow Synthesis of Aromatic Endoperoxides Acting as Oxygen Releasing Agents

Hypoxia occurs in different pathological settings as a consequence of poor vascularization, and it results in reduced efficacy of some 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 and an experimental t1/2=40 minutes, 3,3′-(anthracene-9,10-diyl)bis(prop-2-yn-1-ol) resulted as the best candidate for the sustained release of O2 under physiologically relevant conditions. Its exploitation as ORA to relieve hypoxia will be evaluated and described in due course.