Glutathione (GSH) is the most abundant thiol in mammalian cells and plays a crucial role in maintaining redox cellular homeostasis. The thiols of two GSH molecules can be oxidized to the disulfide GSSG. The cytosolic GSH/GSSG ratio is very high (>100), and its reduction can lead to apoptosis or necrosis, which are of interest in cancer research. Cu^II ions are very efficient oxidants of thiols, but with an excess of GSH, Cu^I_n(GS)_m clusters are formed, in which Cu^I is very slowly reoxidized by O₂ at pH 7.4 and even more slowly at lower pH. Here, the aerobic oxidation of GSH by Cu^II was investigated at different pH values in the presence of the anticancer thiosemicarbazone Dp44mT, which accumulates in lysosomes and induces lysosomal membrane permeabilization in a Cu-dependent manner. The results showed that Cu^II-Dp44mT catalyzes GSH oxidation faster than Cu^II alone at pH 7.4 and hence accelerates the production of very reactive hydroxyl radicals. Moreover, GSH oxidation and hydroxyl radical production by Cu^II-Dp44mT were accelerated at the acidic pH found in lysosomes. To decipher this unusually faster thiol oxidation at lower pH, density functional theory (DFT) calculations, electrochemical and spectroscopic studies were performed. The results suggest that the acceleration is due to the protonation of Cu^II-Dp44mT on the hydrazinic nitrogen, which favors the rate-limiting reduction step without subsequent dissociation of the Cu^I intermediate. Furthermore, preliminary biological studies in cell culture using the proton pump inhibitor bafilomycin A1 indicated that the lysosomal pH plays a role in the activity of Cu^II-Dp44mT.

Organometallic complexes with novel activation mechanisms are attractive anticancer drug candidates. Here, we show that half-sandwich iodido cyclopentadienyl iridium(III) azopyridine complexes exhibit potent antiproliferative activity towards cancer cells, in most cases more potent than cisplatin. Despite their inertness towards aquation, these iodido complexes can undergo redox activation by attack of the abundant intracellular tripeptide glutathione (GSH) on the chelated azopyridine ligand to generate paramagnetic intermediates, and hydroxyl radicals, together with thiolate-bridged dinuclear iridium complexes, and liberate reduced hydrazopyridine ligand. DFT calculations provided insight into the mechanism of this activation. GS⁻ attack on the azo bond facilitates the substitution of iodide by GS⁻, and leads to formation of GSSG and superoxide if O₂ is present as an electron-acceptor, in a largely exergonic pathway. Reactions of these iodido complexes with GSH generate Ir-SG complexes, which are catalysts for GSH oxidation. The complexes promoted elevated levels of reactive oxygen species (ROS) in human lung cancer cells. This remarkable ligand-centred activation mechanism coupled to redox reactions adds a new dimension to the design of organoiridium anticancer prodrugs.

The novel hetero‐dinuclear complex trans,trans,trans‐[Pt^IV(py)₂(N₃)₂(OH)(μ‐OOCCH₂CH₂CONHCH₂‐bpyMe)Ir^III(ppy)₂]Cl (Pt‐Ir), exhibits charge transfer between the acceptor photochemotherapeutic Pt(IV) (Pt‐OH) and donor photodynamic Ir(III) (Ir‐NH₂) fragments. It is stable in the dark, but undergoes photodecomposition more rapidly than the Pt(IV) parent complex (Pt‐OH) to generate Pt(II) species, an azidyl radical and ¹O₂. The Ir(III)* excited state, formed after irradiation, can oxidise NADH to NAD⋅ radicals and NAD⁺. Pt‐Ir is highly photocytotoxic towards cancer cells with a high photocytotoxicity index upon irradiation with blue light (465 nm, 4.8 mW/cm²), even with short light‐exposure times (10–60 min). In contrast, the mononuclear Pt‐OH and Ir‐NH₂ subunits and their simple mixture are much less potent. Cellular Pt accumulation was higher for Pt‐Ir compared to Pt‐OH. Irradiation of Pt‐Ir in cancer cells damages nuclei and releases chromosomes. Synchrotron‐XRF revealed ca. 4× higher levels of intracellular platinum compared to iridium in Pt‐Ir treated cells under dark conditions. Luminescent Pt‐Ir distributes over the whole cell and generates ROS and ¹O₂ within 1 h of irradiation. Iridium localises strongly in small compartments, suggestive of complex cleavage and excretion via recycling vesicles (e.g. lysosomes). The combination of PDT and PACT motifs in one molecule, provides Pt‐Ir with a novel strategy for multimodal phototherapy.

The effects of Mg, Zn, Cd, and Pd dications on the photophysical properties of the tetraphenylporphyrin ligand have been explored, considering the corresponding complexes and by using the density functional theory and its time-dependent extension. Results show that absorption wavelengths do not change significantly when the metal ion changes contrary to what happens to the singlet–triplet energy gaps (ΔE_S−T) and the spin-orbit matrix elements ΨSnHsoΨTm. The most probable intersystem spin crossing (ISC) pathways for the population of the lowest triplet states have been explored. Our findings can contribute to rationalize the available experimental data and promote the potential therapeutic use of these compounds as photosensitizers in photodynamic therapy (PDT).