Optically Pure Double-Stranded Dinuclear Ir(III) Metallohelices Enabled Chirality-Induced Photodynamic Responses

Investigation on the interactions between enantiomers of chiral drugs and biomolecules can help precisely understand their biological behaviors in vivo and provide insights into the design of new drugs. Herein, we designed and synthesized a pair of optically pure, cationic, double-stranded dinuclear Ir­(III)-metallohelices (Λ2 R 4-H and Δ2 S 4-H), and their dramatic enantiomer-dependent photodynamic therapy (PDT) responses were thoroughly studied in vitro and in vivo. Compared to the mononuclear enantiomeric or racemic [Ir­(ppy)2(dppz)]­[PF6] (Λ-/Δ-Ir, rac-Ir) that with high dark toxicity and low photocytotoxicity index (PI) values, both of the optically pure metallohelices displayed negligible toxicity in the dark while exhibiting very distinctive light toxicity upon light irradiation. The PI value of Λ2 R 4-H was approximately 428, however, Δ2 S 4-H significantly reached 63,966. Interestingly, only Δ2 S 4-H was found to migrate from mitochondria to nucleus after light irradiation. Further proteomic analysis verified that Δ2 S 4-H activated the ATP-dependent migration process after light irradiation, and subsequently inhibited the activities of the nuclear proteins such as superoxide dismutase 1 (SOD1) and eukaryotic translation initiation factor 5A (EIF5A) to trigger the accumulation of superoxide anions and downregulate mRNA splicing processes. Molecular docking simulations suggested that the interactions between metallohelices and nuclear pore complex NDC1 dominated the migration process. This work presents a new kind of Ir­(III) metallohelices-based agent with the highest PDT efficacy, highlights the importance of metallohelices’ chirality, and provides inspirations for the future design of chiral helical metallodrugs.