Four cyclometalated complexes,namely[IrCl(η₅-pentamethylcyclopendadienyl)(κ₂C-diphenyl(1-pyrenyl)phosphane)](1)and[RhCl(η₅-pentamethylcyclopendadienyl)(κ₂C-diphenyl(1-pyrenyl)phosphane)](2),and their DMSO-coordina...Four cyclometalated complexes,namely[IrCl(η₅-pentamethylcyclopendadienyl)(κ₂C-diphenyl(1-pyrenyl)phosphane)](1)and[RhCl(η₅-pentamethylcyclopendadienyl)(κ₂C-diphenyl(1-pyrenyl)phosphane)](2),and their DMSO-coordinated counterparts[Ir(η₅-pentamethylcyclopendadienyl)(κS-dmso)(κ₂C-diphenyl(1-pyrenyl)phosphane)]PF₆(1·DMSO)and[Rh(η₅-pentamethylcyclopendadienyl)(κS-dmso)(κ₂C-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 IC₅₀values in the range 0.53–0.79µM 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.展开更多
基金support from the Agència de Gestiódels Ajuts Univeristaris i de Recerca(project 2021-SGR-01107)Spanish Ministerio de Ciencia,Innovación y Universidades(projects PID2020-115537RB-I00,PID2020-115658GB-I00 and PCI2021-122027-2B,MCIU/AEI/10.13039/501100011033 and European Union NextGenerationEU/PRTR)+2 种基金the RSC(RSC Research Fund grant RF19-7147)is kindly acknowledged.P.G.thanks the Catalan Institution for Research and Advanced Studies(ICREA)supported by an EPSRC New Investigator Award(EP/S005544/1)the University of Leicester.We also thank the Advanced Imaging Facility(RRID:SCR_020967)at the University of Leicester for support.
文摘Four cyclometalated complexes,namely[IrCl(η₅-pentamethylcyclopendadienyl)(κ₂C-diphenyl(1-pyrenyl)phosphane)](1)and[RhCl(η₅-pentamethylcyclopendadienyl)(κ₂C-diphenyl(1-pyrenyl)phosphane)](2),and their DMSO-coordinated counterparts[Ir(η₅-pentamethylcyclopendadienyl)(κS-dmso)(κ₂C-diphenyl(1-pyrenyl)phosphane)]PF₆(1·DMSO)and[Rh(η₅-pentamethylcyclopendadienyl)(κS-dmso)(κ₂C-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 IC₅₀values in the range 0.53–0.79µM 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.
