Flavoplatins: Photoactivated platinum(IV) prodrugs bearing axial N-donors that trigger pyroptosis and reduce drug resistance

Abstract

Photoactivated Pt(IV) anticancer prodrugs derived from clinical Pt(II) drugs have garnered significant attention in recent years, with O-donor ligands being the most commonly used photosensitive axial ligands. N-donor ligands, however, such as N-heteroaromatics, offer the potential to enhance the ligand-to-metal charge transfer (LMCT) of Pt(IV) complexes, thereby improving their photochemical properties. Herein, we report a series of green-light activable Pt(IV) prodrugs bearing Ndonor axial ligands, designated flavoplatins, based on carboplatin and oxaliplatin. These prodrugs, functionalized with flavonol derivatives as photosensitive axial ligands, enabled rapid reduction under light irradiation to release Pt(II) drugs and the corresponding axial ligands. Flavoplatins 3a and 3b demonstrated exceptional photocytotoxicity, exhibiting at least a 27fold increase in effectiveness compared to carboplatin in both Pt-sensitive and Pt-resistant cancer cells. Additionally, both complexes efficiently accumulated in the endoplasmic reticulum and quickly induced pyroptosis via the NLRP-3/caspase-1/GSDMD pathway. This study underscores a promising alternative strategy for designing novel photoactivatable Pt(IV) prodrugs containing axial N-donors with enhanced therapeutic potential, particularly for targeting specific cellular pathways and reducing drug resistance.