Configuration and Molecular Flexibility Regulated Reactive Oxygen Species Type and Efficiency for Potent Anticancer Performance: A BODIPY-Pt(II) Complex Case.

Regulating type-I and type-II photochemistry is essential for anticancer photodynamic therapy. Type-I pathways generate hydroxyl and superoxide radicals, whereas type-II produces singlet oxygen. We tuned reactive oxygen species (ROS) generation by varying Pt(II) configuration and ligand flexibility. Among the four complexes, rigid cis-configured c-Pt-BDP showed maximal •OH production and photocytotoxicity, with light-IC50 values of 0.89 μM in Panc02 and 0.93 μM in A549 cells. Flexible cis-configured c-Pt-CH2-BDP favored 1O2 and showed moderate activity (light-IC50: >2.42 and 1.77 μM, respectively). Rigid trans-configured t-Pt-BDP produced •O2-, whereas flexible t-Pt-CH2-BDP generated negligible ROS; both showed poor activity (light-IC50 > 50 μM). Computational predictions explained the ROS profiles through kinetic and energetic differences. Fe2+ accumulation, lipid peroxidation, and GSH depletion supported ferroptotic cell death. In A549 xenografts, irradiated intratumoral c-Pt-BDP achieved 88.42% tumor growth inhibition under the tested conditions. Thus, Pt(II) geometry and ligand flexibility provide design parameters for controlling ROS generation in metal-coordinated photosensitizers.