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

<p dir="ltr">Four cyclometalated complexes, namely [IrCl(η5 -pentamethylcyclopendadienyl)(k2 C-diphenyl(1-pyrenyl) phosphane)] (1) and [RhCl(η5 -pentamethylcyclopendadienyl)(k2 C-diphenyl(1-pyrenyl)phosphane)] (2), and their DMSO-coordinated counterparts [Ir(η5 -pentamethylcyclopendadienyl)(kS-dmso)(k2 C-diphenyl(1- pyrenyl)phosphane)]PF6 (1·DMSO) and [Rh(η5 -pentamethylcyclopendadienyl)(kS-dmso)(k2 C-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.</p>