Improving the photodynamic activity of metallochlorins by combined computational design and experimental validation

Photodynamic therapy (PDT) is a minimally invasive cancer treatment that relies on photosensitizers activated by light to generate reactive oxygen species (ROS), primarily singlet oxygen ( 1 O 2 ). The efficiency of PDT depends largely on the photophysical properties of the PS, which can be tuned by structural modifications such as metal insertion. Here, we combined computational modeling and experimental validation to determine how coordinated metals influence the photodynamic activity of pyrrolidine-fused chlorin (CPy) derivatives. Density functional theory (DFT) calculations using the M06-L functional were employed to optimize ground- and excited- triplet spin state geometries and predict absorption spectra via Time-Dependent Density Functional Theory with the Tamm-Dancoff Approximation (TDDFT-TDA), while spin-orbit coupling (SOC) values were computed using relativistic zeroth-order regular approximation (ZORA) to assess intersystem crossing efficiency. Results indicated that heavy metal complexes, particularly Pt-based complexes, significantly enhance SOC and 1 O 2 generation, whereas complexes with low first triplet state energy (< 0.98 eV) showed negligible activity. These predictions were corroborated experimentally through the synthesis and characterization of the corresponding Pt, Ni, and Cu chlorin complexes. Photophysical measurements and 1 O 2 quantum yield determination using 1,3-diphenylisobenzofuran confirmed the computational trends: PtCPy exhibited high 1 O 2 production, while NiCPy and CuCPy were almost inactive, due to insufficient T 1 energy and paramagnetic nature, respectively. This study demonstrates that computational screening can predict PDT performance, helping to reduce experimental waste and supporting green chemistry principles.