Theoretical Insights into the Switching Off/On of 1 O 2 Photosensitization in Chemicontrolled Photodynamic Therapy

Density Functional Theory and time‐dependent (TD) DFT calculations were carried out for recently reported 4,4‐difluoro‐4‐bora‐3 a ,4 a ‐diaza‐ s ‐indacene (BODIPY)‐based photosensitizers (PSs) that could be activated by reactive oxygen species (ROS) to generate 1 O 2 specifically in target tissues. To assess the applicability of the compounds as activatable PSs (a‐PSs) in photodynamic therapy, absorption wavelengths; singlet–triplet energy gaps; and spin–orbit matrix elements for the radiationless transition, S n →T m , were investigated. A TD‐DFT qualitative analysis indicated that only a Br‐substituted BODIPY derivative with the chromanol ring of α‐tocopherol linked by methylene functioned as an a‐PS. The chromanol ring promotes photoinduced electron transfer to the BODIPY unit that reduces the probability of intersystem crossing and triplet‐state population, and can turn off 1 O 2 photosensitization. Therefore, 1 O 2 photosensitization can be switched on only in target cells in which the chromanol ring is oxidized by ROS. The oxidation reaction pathways of the most promising derivative, by either 1 O 2 or cumyloxyl radical as typical ROS, have been examined to reveal that oxidation by the cumyloxyl radical is more effective than that by 1 O 2 .