In Silico Design of Anthraquinone-Based Two-Photon Photosensitizers for NIR-Activated Photodynamic Therapy in Hypoxic Tumors

A computational strategy is presented for the rational design of anthraquinone- based, heavy-atom–free photosensitizers optimized for two-photon photodynamic therapy in hypoxic tumors within NIR region. Twelve derivatives were evaluated for two-photon absorption, excited states dynamics, redox reactivity, and ADME properties. Four lead compounds— Oxz, Tdz, Prd, and Pmd— exhibited efficient Herzberg–Teller-enabled intersystem crossing, long triplet state lifetimes, and plausible phosphorescence quantum yields. The Redox Activity and Chemical Trends Map, validated against Marcus theory, distinguished distinct mechanistic profiles: Oxz favored Type I mechanism, Prd exhibited selective biomolecular oxidation (Type III), while Tdz and Pmd demonstrated broad- spectrum activity. Notably, Pmd retained reasonable phosphorescence rate despite concurrent processes, indicating sustained Type II reactivity under quenching. SwissADME analysis confirmed favorable permeability and synthetic accessibility. This integrative computational framework—though developed for anthraquinones—is generalizable to diverse scaffolds, enabling early-stage prioritization of oxygen-independent, multimodal two–photon PDT candidates for hypoxic cancer treatment.