Cyclometalated half-sandwich iridium(iii) and rhodium(iii) complexes as efficient agents against cancer stem-cell mammospheresd

Dana Josa, Piedad Herrera-Ramírez, Xiao Feng, Albert Gutiérrez, David Aguilà, Arnald Grabulosa, Manuel Martínez, Kogularamanan Suntharalingam  and  Patrick Gamez

Inorg Chem. Front., 2025, 12, 2404-2416.

Four cyclometalated complexes, namely [IrCl(η5-pentamethylcyclopendadienyl)(k2C-diphenyl(1-pyrenyl)phosphane)] (1) and [RhCl(η5-pentamethylcyclopendadienyl)(k2C-diphenyl(1-pyrenyl)phosphane)] (2), and their DMSO-coordinated counterparts [Ir(η5-pentamethylcyclopendadienyl)(kS-dmso)(k2C-diphenyl(1-pyrenyl)phosphane)]PF6 (1·DMSO) and [Rh(η5-pentamethylcyclopendadienyl)(kS-dmso)(k2C-diphenyl(1-pyrenyl)phosphane)]PF6 (2·DMSO), were synthesized and fully characterized, including their single-crystal X-ray structures. DNA-interacting 1 and 2 exhibits IC50 values in the range 0.53–0.79 μM against bulk breast cancer cells and breast cancer stem cells (CSCs), i.e., HMLER and HMLER-shEcad cells. The complexes are up to seven times more active than salinomycin and up to nine times more active than cisplatin. Moreover, 1 and 2 are very effective (in the micromolar range) against mammospheres obtained from single cell suspensions of HMLER-shEcad cells, 1 being thrice more toxic than 2 and up to 4.5-fold more potent than cisplatin and salinomycin. In depth mechanistic studies revealed that 1 induces necrosis, which is potentially dependent on necrosome formation and independent of ROS concentration. The efficacy of 1 against breast CSCs can be enhanced by co-treatment with PARP-1 inhibitors.

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Exploring the toxicity of mononuclear piano-stool Ru(II) anticancer agents: A comprehensive literature review

Martin Sojka  and  Patrick Gamez

Coord. Chem. Rev., 2025, 543, 216902.

Piano-stool Ru(II) complexes have emerged as a promising class of anticancer agents characterized by structural modularity and diverse cytotoxic activities. The present review consolidates over three decades of research, analyzing IC50 data for 1,449 mononuclear Ru(II) compounds across 151 cancer and healthy cell lines. The whole dataset reveals structure-activity relationships (SAR), emphasizing the role of multidentate ligands – particularly NN-, NO-, and OO-types – and ηn-rings in modulating the biological activity. Compounds with cyclopentadienyl groups often exhibit remarkable effectiveness, achieving sub-micromolar IC50 values and demonstrating efficacy against drug-resistant cancer lines. The bibliographic analysis highlights the versatility of certain ligand combinations, particularly triphenylphosphane with mono- and bidentate ligands, including bipyridine or thioacetamide motifs, which drive exceptional cytotoxic properties. Despite the extensive data set, some gaps remain as some cancer types are underrepresented, and the mechanism(s) of action of the Ru(II)-based cytotoxic agents is(are) not yet fully understood. Future possible research directions within this remarkable family of mononuclear half-sandwich Ru(II) complexes are given.

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