After nearly 20 years of research on the use of ruthenium in the fight against cancer, only two Ru(III) coordination complexes have advanced to clinical trials. During this time, the field has produced excellent candidate drugs with outstanding in vivo and in vitro activity; however, we have yet to find a ruthenium complex that would be a viable alternative to platinum drugs currently used in the clinic. We aimed to explore what we have learned from the most prominent complexes in the area, and to challenge new concepts in chemical design. Particularly relevant are studies involving NKP1339, NAMI-A, RM175, and RAPTA-C, which have paved the way for current research. We explored the development of the ruthenium anticancer field considering that the mechanism of action of complexes no longer focuses solely on DNA interactions, but explores a diverse range of cellular targets involving multiple chemical strategies.

A photoactivatable dopamine-conjugated platinum(IV) anticancer complex (Pt-DA) has been incorporated into G-quadruplex G₄K⁺ borate hydrogels by using borate ester linkages (Pt-G₄K⁺B hydrogel). These were characterized by ¹¹B NMR, attenuated total reflection Fourier transform infrared spectroscopy, circular dichroism, scanning electron microscopy and transmission electron microscopy. Microscopy investigations revealed the transformation of an extended fiber assembly into discrete flakes after incorporation of Pt-DA. Pt-DA showed photocytotoxicity against cisplatin-resistant A2780Cis human ovarian cancer cells (IC₅₀ 74 μM, blue light) with a photocytotoxic index <2, whereas Pt-G₄K⁺B hydrogels exhibited more potent photocytotoxicity (IC₅₀ 3 μM, blue light) with a photocytotoxic index >5. Most notably, Pt-DA and Pt-G₄K⁺B hydrogels show selective phototoxicity for cancer cells versus normal fibroblast cells (MRC5).

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.

Mitochondria generate energy but malfunction in many cancer cells, hence targeting mitochondrial metabolism is a promising approach for cancer therapy. Here we have designed cyclometallated iridium(III) complexes, containing one TEMPO (2,2,6,6-tetramethylpiperidine-1-oxyl) spin label [C₄₃H₄₃N₆O₂Ir₁·PF₆]˙ (Ir-TEMPO1) and two TEMPO spin labels [C₅₂H₅₈N₈O₄Ir₁·PF₆]˙ (Ir-TEMPO2). Electron paramagnetic resonance (EPR) spectroscopy revealed spin–spin interactions between the TEMPO units in Ir-TEMPO2. Both Ir-TEMPO1 and Ir-TEMPO2 showed bright luminescence with long lifetimes (ca. 35–160 ns); while Ir-TEMPO1 displayed monoexponential decay kinetics, the biexponential decays measured for Ir-TEMPO2 indicated the presence of more than one energetically-accessible conformation. This observation was further supported by density functional theory (DFT) calculations. The antiproliferative activity of Ir-TEMPO2 towards a range of cancer cells was much greater than that of Ir-TEMPO1, and also the antioxidant activity of Ir-TEMPO2 is much higher against A2780 ovarian cancer cells when compared with Ir-TEMPO1. Most notably Ir-TEMPO2 was particularly potent towards PC3 human prostate cancer cells (IC₅₀ = 0.53 μM), being ca. 8× more active than the clinical drug cisplatin, and ca. 15× more selective towards cancer cells versus normal cells. Confocal microscopy showed that both Ir-TEMPO1 and Ir-TEMPO2 localise in the mitochondria of cancer cells.