Pierraffaele Barretta, Daniel Escudero, Gloria Mazzone
A combined mechanistic and photophysical investigation of the dual-function photosensitizer DANO and its photoproduct DAPS was carried out using DFT and TDDFT approaches. DANO acts as a light-activated nitric oxide (NO) donor, with NO release proceeding via the triplet excited state through a glutathione (GSH)-assisted hydrogen transfer. The reaction is thermodynamically and kinetically favored in the triplet state, with an activation barrier of 10.4 kcal mol-1 and an overall exergonicity of -3.1 kcal mol-1. In contrast, the ground-state pathway shows a significantly higher energy barrier (32.3 kcal mol-1), confirming the photo-induced nature of the NO release. Photophysical analysis of DANO revealed that the bright state S1 efficiently undergoes intersystem crossing (ISC) to either T2 (kISC = 1.22 × 106 s-1), eventually followed by internal conversion to T1, or T1 (kISC = 3.68 × 107 s-1), the state with the most pronounced dissociative character. Upon NO dissociation, the resulting species, DAPS, functions as an efficient type II photosensitizer. Excited-state analysis of the photoproduct suggests the intersystem crossing (ISC) process occurs via the S1 → T2 channel (kISC = 1.91 × 106 s-1), followed by internal conversion to T1. The populated triplet state exhibits a calculated lifetime of ≈5 µs, suggesting sufficient persistence for energy transfer to molecular oxygen. Although this value should be interpreted qualitatively because of the reduced computational model, it is compatible with the experimentally observed singlet oxygen generation. Computational analysis confirms also the feasibility of a free radical cascade initiated by DAPS for the formation of peroxynitrite and other highly reactive species, which is likely to enhance its photodynamic efficacy. These results support the DANO/DAPS system as a promising dual-action PDT agent, combining NO delivery and ROS generation.