Stepwise Assembly and Photodynamic Cancer Therapy of Homochiral Dinuclear Ir(III) Triple-Stranded Metallohelices

Rational design of chiral metallodrugs with precise stereochemical control and enhanced photodynamic performance is pivotal for advancing precision oncology. Herein, we report the stepwise assembly of homochiral dinuclear Ir(III) triple-stranded metallohelices (ΔΔ-/ΛΛ-Ha) via dynamic imine ligation followed by reductive stabilization, yielding configurationally stable amine-bridged helical architectures with locked chirality. While both enantiomers exhibit comparable dark toxicities, the ΔΔ-enantiomer demonstrates enhanced photodynamic activity against multiple cancer cell lines under white light irradiation. Mechanistic studies─including intracellular reactive oxygen species production, scavenger experiments, mitochondrial damage, apoptosis assays, ethidium bromide displacement, and DNA docking─link this enantioselectivity to chirality-dependent DNA recognition. The stronger DNA-binding affinity of the ΔΔ-enantiomer facilitates a more efficient spatial utilization of the generated singlet oxygen. This work provides a robust synthetic route to homochiral metallohelices and elucidates the critical role of molecular chirality in optimizing photodynamic therapeutics.

A pair of configurationally stable, amine-bridged homochiral dinuclear Ir(III) triple-stranded metallohelices with enantiomer-dependent photodynamic anticancer behavior were stepwise assembled through dynamic imine ligation followed by reductive stabilization.