Contrasting effects of ethylene and propylene linkers on the kinetic stability of water-soluble near-infrared-absorbing diradical-PtII complexes

Diradical-Pt^II complexes with o-phenylenediamine ligands exhibit intense near-infrared (NIR) absorption, making them applicable as photothermal agents for cancer imaging and therapy. However, their NIR-absorbing properties can be deactivated by ligand exchange with cellular substances such as glutathione (GSH). To improve the kinetic stability of diradical-Pt^II complexes, we synthesized two novel tetradentate ligands, 4,4′-(ethane-1,2-diylbis(azanediyl))bis(3-aminobenzenesulfonate) (EABS) and 4,4′-(propane-1,3-diylbis(azanediyl))bis(3-aminobenzenesulfonate) (PABS), in which two 3,4-diaminobenzenesulfonate (DABS) units are connected by an ethylene or propylene linker, respectively. Contrary to the expectation that the resulting chelate ring will enhance stability, [Pt(EABS)]²⁻ readily released its linker to form [Pt(DABS)₂]²⁻ owing to its bent and twisted coordination structure. In contrast, [Pt(PABS)]²⁻ was stable owing to its less distorted structure and exhibited an intense absorption peak at 723 nm (8.7 × 10⁴ M⁻¹ cm⁻¹) in aqueous solution. Kinetic analysis of the ligand exchange reaction with GSH showed that the half-life of [Pt(PABS)]²⁻ under intracellular conditions ([GSH] = 1.0 × 10^–2 M) is 27 h, approximately 1300 and 16 000 times longer than those of [Pt(DABS)₂]²⁻ (72 s) and [Pt(EABS)]²⁻ (5.9 s), respectively. Thus, the linker chain length significantly influences molecular structure and kinetic stability against GSH, with the propylene linker effectively enhancing the stability of diradical-Pt^II complexes. Additionally, ligand oxidation gradually extinguished the NIR absorption of aqueous [Pt(PABS)]²⁻, which would prevent unpredictable photothermal damage to healthy tissues after treatment. The ligand design of [Pt(PABS)]²⁻ is expected to enable efficient imaging and therapy for cancer with minimal side effects.