Phototoxicity of Half-Sandwich Rhodium(III) Complexes with Anthracene and Biphenyl Substituents toward Mammalian Cancer Cells and Multicellular Tumor Spheroids

We report the synthesis and characterization of three half-sandwich rhodium(III) complexes incorporating anthracene and biphenyl moieties to investigate their photobiological activity. Complexes 1 and 2, bearing anthracene-based Schiff base ligand, displayed pronounced phototoxicity upon blue-light irradiation, with complex 2 achieving a phototoxicity index of 144 in A375 melanoma cells. In contrast, complex 3, lacking the anthracene unit, was photoinactive. Photoactivation of complexes 1 and 2 induced −N═CH– Schiff bond cleavage, releasing anthracene-9-carbaldehyde, as confirmed by UV–vis and mass spectrometry. Blue light also enabled catalytic oxidation of NADH to NAD⁺. Mechanistic studies revealed oncosis-like cell death mediated by reactive oxygen species. Both complexes retained activity in 3D tumor spheroids, demonstrating efficient tissue penetration. These results identify anthracene-functionalized rhodium(III) complexes as promising candidates for photodynamic therapy and provide, to our knowledge, the first detailed mechanistic insight into photopotentiation in half-sandwich rhodium systems.