An Activity‐Based Photosensitizer to Reverse Hypoxia and Oxidative Resistance for Tumor Photodynamic Eradication

Abstract Photodynamic therapy (PDT) has been a well‐accepted clinical treatment for malignant tumors owing to its noninvasiveness and high spatiotemporal selectivity. However, the treatment outcome of current PDT applications is hindered by hypoxia and intracellular oxidative resistance of solid tumors. Recent studies have shown that inhibiting histone deacetylases (HDACs) can induce cell ferroptosis, reverse hypoxia, and elevate oxidative status. Theoretically, the design and synthesis of activity‐based photosensitizers that target HDACs can address the bottlenecks of PDT. Herein, the concept of an activity‐based photosensitizer is presented for targeting HDACs, which is designed based on a quinoxalinone scaffold through a pharmacophore migration strategy. The developed activity‐based photosensitizer can inhibit HDACs, and overcome hypoxia and intracellular oxidative resistance, realizing the full potential of photosensitizers for malignant tumor treatment. The molecular design strategy proposed in this project should provide theoretical guidance for the development of ideal photosensitizers for practical applications.