In this work,we designed and synthesised a new cyclometallated iridium(Ⅲ)nitrone complex[Ir(bpz)2(bpy-nitrone)](PF_(6))(1)(Hbpz=benzo[a]phenazine;bpy-nitrone=4-((methyl(oxido)imino)methyl)-4’-methyl-2,2’-bipyridine...In this work,we designed and synthesised a new cyclometallated iridium(Ⅲ)nitrone complex[Ir(bpz)2(bpy-nitrone)](PF_(6))(1)(Hbpz=benzo[a]phenazine;bpy-nitrone=4-((methyl(oxido)imino)methyl)-4’-methyl-2,2’-bipyridine)as a bioorthogonally activatable phototheranostic agent.Complex 1 displayed very weak emission and singlet oxygen(^(1)O_(2))photosensitisation in solutions due to the quenching nitrone moiety.However,upon the strain-promoted alkyne–nitrone cycloaddition(SPANC)reaction with bicyclo[6.1.0]non-4-yne(BCN),which converted the nitrone unit to a non-quenching isoxazoline derivative,the complex exhibited a substantial increase in emission intensity in the near-infrared region and^(1)O_(2)generation efficiency.Given that mitochondria are a crucial target in cancer therapy,we prepared a series of BCN-functionalised phosphonium cations(BCN-Phos-n),each bearing different substituents,to serve as mitochondrial-targeting vectors for delivering complex 1 to the mitochondria via the bioorthogonal SPANC reaction.Notably,complex 1 exhibited more significant emission turn-on upon reaction with BCN-Phos-5 and BCN-Phos-6(I/I_(o)=24.7 and 14.1,respectively),attributed to their increased hydrophobicity resulting from the methylation or methoxylation of the phenyl rings on the phosphonium cation.Live-cell confocal imaging and flow cytometric analyses revealed that complex 1 showed larger emission enhancement in HeLa cells pretreated with BCN-Phos-5 or BCN-Phos-6 compared to other BCN-Phosn analogues.Co-staining experiments confirmed that the resultant luminescent isoxazoline cycloadducts predominantly accumulated in the mitochondria.Additionally,both dark and light-induced cytotoxicity of complex 1 increased upon pretreatment of the cells with BCN-Phos-5 or BCN-Phos-6.Our results demonstrate that the theranostic potential of transition metal nitrone complexes can be significantly enhanced via strategic structural manipulation of their bioorthogonal reaction partners.展开更多
文摘In this work,we designed and synthesised a new cyclometallated iridium(Ⅲ)nitrone complex[Ir(bpz)2(bpy-nitrone)](PF_(6))(1)(Hbpz=benzo[a]phenazine;bpy-nitrone=4-((methyl(oxido)imino)methyl)-4’-methyl-2,2’-bipyridine)as a bioorthogonally activatable phototheranostic agent.Complex 1 displayed very weak emission and singlet oxygen(^(1)O_(2))photosensitisation in solutions due to the quenching nitrone moiety.However,upon the strain-promoted alkyne–nitrone cycloaddition(SPANC)reaction with bicyclo[6.1.0]non-4-yne(BCN),which converted the nitrone unit to a non-quenching isoxazoline derivative,the complex exhibited a substantial increase in emission intensity in the near-infrared region and^(1)O_(2)generation efficiency.Given that mitochondria are a crucial target in cancer therapy,we prepared a series of BCN-functionalised phosphonium cations(BCN-Phos-n),each bearing different substituents,to serve as mitochondrial-targeting vectors for delivering complex 1 to the mitochondria via the bioorthogonal SPANC reaction.Notably,complex 1 exhibited more significant emission turn-on upon reaction with BCN-Phos-5 and BCN-Phos-6(I/I_(o)=24.7 and 14.1,respectively),attributed to their increased hydrophobicity resulting from the methylation or methoxylation of the phenyl rings on the phosphonium cation.Live-cell confocal imaging and flow cytometric analyses revealed that complex 1 showed larger emission enhancement in HeLa cells pretreated with BCN-Phos-5 or BCN-Phos-6 compared to other BCN-Phosn analogues.Co-staining experiments confirmed that the resultant luminescent isoxazoline cycloadducts predominantly accumulated in the mitochondria.Additionally,both dark and light-induced cytotoxicity of complex 1 increased upon pretreatment of the cells with BCN-Phos-5 or BCN-Phos-6.Our results demonstrate that the theranostic potential of transition metal nitrone complexes can be significantly enhanced via strategic structural manipulation of their bioorthogonal reaction partners.
