Synthesis, Hypoxia-Selective Anti-Oral Cancer Activity and Mechanism of a CA IX-Targeting Platinum(II) Complex Based on Pyridoxal 4-Sulfamoylphenylhydrazone

Tumor-mediated hypoxia resistance severely limits the therapeutic efficacy of conventional platinum-based drugs against oral cancer. Targeting carbonic anhydrase IX (CA IX), which is specifically overexpressed in hypoxic tumor cells, represents an effective strategy to reverse chemoresistance. In this work, a novel CA IX-targeting platinum(II) complex was synthesized using pyridoxal 4-sulfamoylphenylhydrazone as the ligand. Single-crystal X-ray diffraction reveals its stable square-planar coordination geometry in the solid state. Enzymatic assays revealed that the complex exhibited negligible inhibition toward the normal CA II isoform and displayed potent inhibitory activity against CA IX (Ki = 26.5 nM), superior to the ligand and the positive control compound U-104. Molecular docking suggests its stable binding to the active pocket of CA IX. In vitro assays exhibited notable hypoxia-selective cytotoxicity against oral cancer HSC-2 cells, with an IC50 value of 3.7 ± 0.2 μM under hypoxic conditions. Mechanistic investigations suggest that the complex may induce oral cancer cell death partly by elevating intracellular reactive oxygen species (ROS) levels and activating the mitochondrial-mediated apoptotic pathway. It should be noted that the solution-state behavior, aquation, and hydrolysis of this platinum complex have not been experimentally explored in the present study; thus, the biologically active platinum-containing species remains uncharacterized, and the observed bioactivity cannot be unequivocally assigned to the intact solid-state complex. This study provides new insights and experimental support for the development of hypoxia-responsive platinum-based agents targeting CA IX against oral cancer.