Mechanism of action of an Ir(III) Complex Bearing a Boronic Acid Active as H2O2-Responsive Photosensitizer: ROS Generation and Quinone Release for GSH Scavenging

A DFT-based theoretical investigation is reported here to clarify the mechanism of action of a recently synthesized Ir(III) complex, Ir-B(OH)2, characterized by the presence of an aryl boronic acid moiety on one bidentate ligand that can detect H2O2 in cancer cells. The H2O2-mediated oxidation of boronic acids under physiological conditions affords the active complex for PDT application, Ir-OH, and a quinone methide (QM) as a by-product, which in turn can scavenge glutathione (GSH) compromising one of the most powerful cellular defence against the ROS produced by PDT treatments. The most plausible reaction mechanism for the oxidation of the aryl boronic acid by H2O2 is described. The formation of the products, namely the PS Ir-OH and the QM, is achieved overcoming an energy barrier of 33 kcal mol−1 and with a considerable energy gain. The description of the subsequent GSH scavenging mechanism by the released QM evidences that the reaction occurs with a low energy expense. Moreover, the computation of the photophysical properties, needed for evaluating the occurrence of type I and type II processes, of the prodrug Ir-B(OH)2 and the active PS Ir-OH suggests that they are both able to generate the singlet molecular oxygen, 1O2, while other ROS cannot be achieved. Moreover, the MOs involved in the excited states population, both singlet and triplet, unravel the key role of the metal centre in the ISC process.