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.

p-Sulfonatocalix[n]arenes have shown excellent potential for accommodating chemotherapeutic drugs through host–guest complexation and enhancing their anticancer activity. Betaine has been reported to exert an anticancer effect at high concentrations. In order to increase its concentration in cancer cells, we have complexed it with p-SC4, which releases its content in an acidic environment typical of cancer tissue. In this work, a host–guest complex of the chemically stable, natural, and safe active methyl donor (betaine) and p-sulfonatocalix[4]arenes (p-SC4) was designed and characterized using ¹H NMR, UV, Job's plot analysis, DFT calculations, and molecular modeling for use in cancer therapeutics. The peak amplitude of the prepared host–guest complexes was linearly proportional to the concentration of betaine in the range of 1.0 × 10⁻⁵ M⁻¹ to 2.5 × 10⁻⁴ M⁻¹. The reaction stoichiometry between p-SC4 and betaine in the formed complex was 1 : 1. The stability constant for the complex is 8.9 × 10⁴ M⁻¹ which corresponds to a complexation free energy of −6.74 kcal mol⁻¹. Complexation between betaine and p-SC4 was found to involve the insertion of the trimethylammonium group of betaine into the p-SC4 cavity, as supported by the experimental data. The complex displayed enhanced cytotoxic activities against breast adenocarcinoma cells (MCF-7) and cervical cancer cells (HeLa) compared to free betaine. In conclusion, the host–guest complexation of betaine with p-SC4 increases its concentration in cancer cells, which warrants further investigation for cancer therapy.

P-sulfonatocalix[n]arenes have demonstrated a great potential for encapsulation of therapeutic drugs via host-guest complexation to improve solubility, stability, and bioavailability of encapsulated drugs. In this work, guest-host complexes of a third-generation anticancer drug (oxaliplatin) and p-4-sulfocalix[n]arenes (n = 4 and 6; p-SC4 and p-SC6, respectively) were prepared and investigated, using ¹H NMR, UV, Job’s plot analysis, and DFT calculations, for use as cancer therapeutics. The peak amplitude of the prepared host-guest complexes was linearly proportional to the concentration of oxaliplatin in the range of 1.0 × 10⁻⁵ M⁻¹ to 2.1 × 10⁻⁴ M⁻¹. The reaction stoichiometry between either p-SC4 or p-SC6 and oxaliplatin in the formed complexes was 1:1. The stability constants for the complexes were 5.07 × 10⁴ M⁻¹ and 6.3 × 10⁴ M⁻¹. These correspond to complexation free energy of −6.39 and −6.52 kcal/mol for p-SC4 and p-SC6, respectively. Complexation between oxaliplatin and p-SC4 or p-SC6 was found to involve hydrogen bonds. Both complexes exhibited enhanced biological and high cytotoxic activities against HT-29 colorectal cells and MCF-7 breast adenocarcinoma compared to free oxaliplatin, which warrants further investigation for cancer therapy.

DFT calculations on a conjugate of ferrocene to an octahedral Pt(iv) complex reveal Fe-to-Pt charge transfer, promoting longer-wavelength photoactivation, enhanced cellular accumulation, potent anticancer activity, and cell death via ferroptosis.

Para-sulfocalix[n]arenes are promising host molecules that can accommodate various chemotherapeutic drugs. Pt(IV)-based complexes, including satraplatin and asplatin, are promising alternatives that overcome the shortcomings of Pt(II) complexes. In this study, asplatin has been synthesized by fusing acetylsalicylic acid (aspirin) and cisplatin. Furthermore, it has been characterized using ¹H NMR, mass spectrometry, elemental analysis, and UHPLC. A host-guest complex of asplatin and p-sulfocalix[4]arene (PSC4) has been developed and characterized using UV, Job’s plot analysis, HPLC, and density functional theory (DFT) calculations. The experimental and computational investigations propose that a 1:1 complex between asplatin and PSC4 is formed. The stability constant of the designed complex has been determined using Job’s plot and UHPLC and computed to be 9.1 × 10⁴ M^–1 and 8.7 × 10⁴ M⁻¹, which corresponds to a free energy of complexation of −6.8 kcal mol^–1, while the calculated value for the inclusion free energy is −13.2 kcal mol⁻¹. Both experimentally and theoretically estimated complexation free energy show that a stable host-guest complex can be formed in solution. The in vitro drug release study displayed the ability of the complex to release its cargo at a cancerous pH (pH of 5.5). Additionally, the asplatin/PSC4 complex is shown to be biocompatible when tested on human skin fibroblast noncancerous cells, demonstrating the highest in vitro cytotoxic activity against (MCF-7), cervical (HeLa), and lung cancer cells (A-549), with IC₅₀ values of 0.75, 2.15, and 3.60 µg/mL, respectively. This is as compared to either cisplatin (IC₅₀ of 5.47, 5.94 and 9.61 µg/mL, respectively) or asplatin (IC₅₀ of 1.54, 5.05 and 3.91 µg/mL, respectively). On the other hand, the free asplatin exhibited higher cytotoxicity on cancerous cells and lower toxicity on noncancerous cells. The outcomes of the present joint theoretical and experimental investigation reinforce the interest in platinum-based anticancer therapeutics when they are protected from undesired interactions and suggest the use of the PSC4 macromolecule as a promising carrier for Pt(IV) anticancer drugs. The formed asplatin/PSC4 inclusion complex may represent an effective chemotherapeutic agent.