Chiral Iridium-Based TLD-1433 Analogues: Exploration of Enantiomer-Dependent Behavior in Photodynamic Cancer Therapy.

Abstract

Metallodrug-based photodynamic therapy (PDT) agents have demonstrated significant superiority against cancers, while their different chirality-induced biological activities remain largely unexplored. In this work, we successfully developed a pair of enantiopure mononuclear Ir(III)-based TLD-1433 analogues, Δ-Ir-3T and Λ-Ir-3T, and their enantiomer-dependent anticancer behaviors were investigated. Photophysical measurements revealed that they display high photostability and chemical stability, strong absorption at 400 nm with high molar extinction coefficients (ε = 5.03 × 104 M-1 cm-1), and good 1O2 relative quantum yields (ΦΔ ≈ 47%). Δ- and Λ-Ir-3T showed potent efficacy against MCF-7 cancer cells, with a photocytotoxicity index of ≤44 238. This impressive result, to the best of our knowledge, represents the highest value among reported mononuclear Ir(III)-based PDT agents. Remarkably, Λ-Ir-3T tended to be more potent than Δ-Ir-3T when tested against SK-MEL-28, HepG2, and LO2 cells, with consistent results across multiple test repetitions.