The platinum(Ⅳ)prodrug trans,trans,trans-[Pt(N3)2(OH)2(py)2](1)is stable and non-toxic in the dark,but potently cytotoxic to cancer cells when irradiated by visible light,including cisplatin-resistant cells.On irradi...The platinum(Ⅳ)prodrug trans,trans,trans-[Pt(N3)2(OH)2(py)2](1)is stable and non-toxic in the dark,but potently cytotoxic to cancer cells when irradiated by visible light,including cisplatin-resistant cells.On irradiation with visible light,it generates reactive Pt(Ⅱ)species which can attack DNA,and produces reac-tive oxygen species(ROS)and reactive nitrogen species(RNS)which exert unusual effects on biochemical pathways.We now show that its novel mechanism of action includes induction of immunogenic cell death(ICD).Treatment of cancer cells with 1 followed by photoirradiation with visible light induces calre-ticulin(CRT)expression at the surface of dying cancer cells.This is accompanied by release of high mobi-lity group protein-1B(HMGB1)and the secretion of ATP.Autophagy appears to play a key role in this che-motherapeutically-stimulated ICD.The observed uneven distribution of ecto-CRT promotes phagocyto-sis,confirmed by the observation of engulfment of photoirradiated CT26 colorectal cancer cells treated with 1 by J774.A1 macrophages.The photoactivatable prodrug 1 has a unique mechanism of action which distinguishes it from other platinum drugs due to its immunomodulating properties,which may enhance its anticancer efficacy.展开更多
Diazido Pt(Ⅳ)complexes with a general formula[Pt(N_(3))_(2)(L)(L’)(OR)(OR’)]are a new generation of anticancer prodrugs designed for use in photoactivated chemotherapy.The potencies of these complexes are affected ...Diazido Pt(Ⅳ)complexes with a general formula[Pt(N_(3))_(2)(L)(L’)(OR)(OR’)]are a new generation of anticancer prodrugs designed for use in photoactivated chemotherapy.The potencies of these complexes are affected by the cis/trans geometry configuration,the non-leaving ligand L/L’and derivatisation of the axial ligand OR/OR’.展开更多
Mono-axial functionalised octahedral diazido Pt(IV)complexes trans,trans,trans-[Pt(py)_(2)(N_(3))_(2)(OR_(1))(OR_(2))](OR_(1)=OH and OR_(2)=anticancer agent coumarin-3 carboxylate(cou,2a),pyruvate dehydrogenase kinase...Mono-axial functionalised octahedral diazido Pt(IV)complexes trans,trans,trans-[Pt(py)_(2)(N_(3))_(2)(OR_(1))(OR_(2))](OR_(1)=OH and OR_(2)=anticancer agent coumarin-3 carboxylate(cou,2a),pyruvate dehydrogenase kinase(PDK)inhibitors 4-phenylbutyrate(PhB,2b)or dichloroacetate(DCA,2c)),and their di-axial functionalised analogues with OR_(1)=DCA and OR_(2)=cou(3a),PhB(3b),or DCA(3c)have been synthesised and characterised,including the X-ray crystal structures of complexes 2a,3a,3b and 3c.These complexes exhibit dark stability and have the potential to generate cytotoxic Pt(II)species and free radicals selectively in cancer cells when irradiated.Mono-functionalised complexes 2a-2c showed higher aqueous solubility and more negative reduction potentials.Mono-and di-functionalised complexes displayed higher photocytotoxicity with blue light(1 h,465 nm,4.8 mW cm^(-2))than the parent dihydroxido complex 1(OR_(1)=OR_(2)=OH)in A2780 human ovarian(IC_(50)0.9-2.9μM for 2a-2c;0.11-0.39μM for 3a-3c)and A549 human lung cancer cells(5.4-7.8μM for 2a-2c;1.2-2.6μM for 3a-3c)with satisfactory dark stability.Notably,no apparent dark cytotoxicity was observed in healthy lung MRC-5 fibroblasts for all complexes(IC_(50)>20μM).Significantly higher platinum cellular accumulation and photo-generated ROS levels were observed for the di-functionalised complexes compared with their mono-functionalised analogues when cancer cells were treated under the same concentrations.展开更多
The organoiridium(III)anticancer complex[(η^(5)-Cp^(xbiph))Ir(phpy)py](Cp^(xbiph)=biphenyltetramethylcyclopentadienyl,phpy=phenylpyridine,py=pyridine)unexpectedly reacts with the tripeptide glutathione in the presenc...The organoiridium(III)anticancer complex[(η^(5)-Cp^(xbiph))Ir(phpy)py](Cp^(xbiph)=biphenyltetramethylcyclopentadienyl,phpy=phenylpyridine,py=pyridine)unexpectedly reacts with the tripeptide glutathione in the presence of coenzyme NADH to give glutathione sulfenate(Ir–S(O)G)and sulfinate(Ir–S(O)_(2)G)complexes.These new adducts may play a role in the anticancer activity of such organoiridium complexes.展开更多
The synthesis of nanoparticles of conjugates of caffeic acid-modified chitosan with ruthenium arene complexes is described.The chemical structure and physical properties of the nanoparticles were characterised by elec...The synthesis of nanoparticles of conjugates of caffeic acid-modified chitosan with ruthenium arene complexes is described.The chemical structure and physical properties of the nanoparticles were characterised by electronic absorption spectroscopy(UV-vis),Fourier transform infrared spectroscopy(FT-IR),1H NMR spectroscopy,dynamic light scattering(DLS),transmission electron microscopy(TEM),X-ray powder diffraction(XRD),and circular dichroism(CD)analysis.The multi-spectral results revealed that caffeic acid is covalently bound to chitosan and chelates to{Ru(p-cymene)Cl}+.The DLS studies indicated that the Ru-caffeic acid modified chitosan nanoparticles are well-defined and of nanometre size.Such well-defined nanocomposites of chitosan and metal complexes might find a range of applications,for example in drug delivery.展开更多
Transition metal complexes are often prodrugs which undergo activation by ligand exchange and redox reactions before they interact with target sites.It is therefore important to understand the roles of both the metal ...Transition metal complexes are often prodrugs which undergo activation by ligand exchange and redox reactions before they interact with target sites.It is therefore important to understand the roles of both the metal and the ligands in their activation,especially in cells.Here we use a combination of synchrotron nanoprobe X-ray fluorescence(XRF)from Os L_(3)M_(5)and Br KL_(3)emissions and inductively coupled plasmamass spectrometry(ICP-MS)detection of^(189)Os,^(79)Br,and^(127)I,to investigate the time-dependent accumulation and localization of osmium as well as the monodentate ligand and the chelated phenylazopyridine in A2780 human ovarian cancer cells treated with the potent anticancer complexes[Os(η^(6)-pcymene)(4-R_(2)-phenyl-azopyridine-5-R_(1))X]PF_(6),with R_(2)=NMe_(2)or OH,R_(1)=H or Br,and X=Cl or I.The data confirm that the relatively inert iodido complexes are activated rapidly in cancer cells by release of the iodido ligand,probably initiated by attack by the intracellular tripeptide glutathione(γ-L-Glu-l-Cys-Gly)on the azo double bond.The bond between osmium and the azopyridine appears to remain stable in cells for ca.24 h,although some release of the chelated ligand is observed.Interestingly,the complexes seem to be degraded more rapidly in normal human cells,perhaps providing a possible mechanism for selective cytotoxicity towards cancer cells.展开更多
Specific interactions between the macrocycle backbone,solvent and counter anions control configurational interconversions of novel organoruthenium(Ⅱ)metallamacrocycles[Ru(η^(6)-p-cymene)(μ_(2)-m-bitmb)Cl]_(2)·...Specific interactions between the macrocycle backbone,solvent and counter anions control configurational interconversions of novel organoruthenium(Ⅱ)metallamacrocycles[Ru(η^(6)-p-cymene)(μ_(2)-m-bitmb)Cl]_(2)·2X,m-bitmb=1,3,5-trimethyl-2,4-di(imidazole-1-ylmethyl)benzene,X=Cl^(-)(1.2Cl),NO_(3)^(-)(1-2NO_(3)),CF_(3)SO_(3)^(-)(1.2CF_(3)SO_(3)),PF_6^(-)(1.2PF_(6)),or BF_(4)^(-)(1.2BF_(4)).X-ray crystal structures reveal 1.2Cl in boat and chair conformations,1.2NO_(3)in twist-boat and chair conformations,and 1.2CF_(3)SO_(3)in a chair conformation.Chair/boat isomers of mono-and bis-DMSO adducts from 1.2Cl,1.2CF_(3)SO_(3)or 1.2NO_(3)in DMSO/H_(2)O were separated and characterized.Slow anion-dependent interconversion of configurational isomers was observed in solution.Ligand field molecular mechanics and density functional theory calculations suggest an unusual macrochelate ring-opening isomerization mechanism.Such dynamic stimuliresponsive configurational changes offer scope for design of metallocycles for induced-fit recognition of biological targets.展开更多
Chloride is the most abundant anion in living systems.Most natural or synthetic chloride anionophores function via hydrogen-bonding interactions.However,dynamic metal-anion coordination can also be an efficient way of...Chloride is the most abundant anion in living systems.Most natural or synthetic chloride anionophores function via hydrogen-bonding interactions.However,dynamic metal-anion coordination can also be an efficient way of transporting chloride across membranes.Here,we investigate anion transport by manganese(Ⅲ)meso-tetraphenylporphyrin chloride{[Mn(TPP)Cl],TPP=meso-tetraphenylporphyrin}complex that exhibits labile axial coordination.[Mn(TPP)Cl]showed high chloride transport activity in a bilayer vesicle model with an EC_(50) value of 4.42×10^(−3) mol%.In living cells,[Mn(TPP)Cl]induced rapid chloride influx and autophagy.The release of Ca^(2+)and adenosine 5′-triphosphate(ATP),as well as the relocation of calreticulin,revealed that[Mn(TPP)Cl]caused immunogenic cell death.Proteomic analysis indicated that[Mn(TPP)Cl]impaired several physiological processes,including DNA synthesis,transcription,mitochondrial respiration,RNA translation,and immune response.Our study suggests that dynamic metal-anion interactions across membranes might provide a practical strategy for the interference of chloride homeostasis.展开更多
基金supported by the Czech Science Foundation(Grant 18-09502S)the Wellcome Trust(Grant 209173/Z/17/Z,Fellowship for C.I.)+1 种基金EPSRC(Grants EP/F034210/1 and EP/P030572/1)Anglo American Platinum Mike and Enfys Bagguley(PhD Studentship for H.E.B).
文摘The platinum(Ⅳ)prodrug trans,trans,trans-[Pt(N3)2(OH)2(py)2](1)is stable and non-toxic in the dark,but potently cytotoxic to cancer cells when irradiated by visible light,including cisplatin-resistant cells.On irradiation with visible light,it generates reactive Pt(Ⅱ)species which can attack DNA,and produces reac-tive oxygen species(ROS)and reactive nitrogen species(RNS)which exert unusual effects on biochemical pathways.We now show that its novel mechanism of action includes induction of immunogenic cell death(ICD).Treatment of cancer cells with 1 followed by photoirradiation with visible light induces calre-ticulin(CRT)expression at the surface of dying cancer cells.This is accompanied by release of high mobi-lity group protein-1B(HMGB1)and the secretion of ATP.Autophagy appears to play a key role in this che-motherapeutically-stimulated ICD.The observed uneven distribution of ecto-CRT promotes phagocyto-sis,confirmed by the observation of engulfment of photoirradiated CT26 colorectal cancer cells treated with 1 by J774.A1 macrophages.The photoactivatable prodrug 1 has a unique mechanism of action which distinguishes it from other platinum drugs due to its immunomodulating properties,which may enhance its anticancer efficacy.
基金supported by the MRC(grant G0701062)EPSRC(grants EP/G006792,EP/F034210/1,EP/P030572/1 to PJS),ERC(grant 247450 to PJS)a Chancellor’s International PhD Scholarship from the University of Warwick(for HS),and the Wellcome Trust(209173/Z/17/Z,Sir Henry Wellcome Fellowship for CI).
文摘Diazido Pt(Ⅳ)complexes with a general formula[Pt(N_(3))_(2)(L)(L’)(OR)(OR’)]are a new generation of anticancer prodrugs designed for use in photoactivated chemotherapy.The potencies of these complexes are affected by the cis/trans geometry configuration,the non-leaving ligand L/L’and derivatisation of the axial ligand OR/OR’.
基金support from the EPSRC(EP/G006792,EP/F034210/1 for PJS)University of Warwick(Chancellor’s International PhD Scholarship for HS)Anglo-American Platinum(HS)and Wellcome Trust(grant no 209173/Z/17/Z,Sir Henry Wellcome Fellowship for CI).
文摘Mono-axial functionalised octahedral diazido Pt(IV)complexes trans,trans,trans-[Pt(py)_(2)(N_(3))_(2)(OR_(1))(OR_(2))](OR_(1)=OH and OR_(2)=anticancer agent coumarin-3 carboxylate(cou,2a),pyruvate dehydrogenase kinase(PDK)inhibitors 4-phenylbutyrate(PhB,2b)or dichloroacetate(DCA,2c)),and their di-axial functionalised analogues with OR_(1)=DCA and OR_(2)=cou(3a),PhB(3b),or DCA(3c)have been synthesised and characterised,including the X-ray crystal structures of complexes 2a,3a,3b and 3c.These complexes exhibit dark stability and have the potential to generate cytotoxic Pt(II)species and free radicals selectively in cancer cells when irradiated.Mono-functionalised complexes 2a-2c showed higher aqueous solubility and more negative reduction potentials.Mono-and di-functionalised complexes displayed higher photocytotoxicity with blue light(1 h,465 nm,4.8 mW cm^(-2))than the parent dihydroxido complex 1(OR_(1)=OR_(2)=OH)in A2780 human ovarian(IC_(50)0.9-2.9μM for 2a-2c;0.11-0.39μM for 3a-3c)and A549 human lung cancer cells(5.4-7.8μM for 2a-2c;1.2-2.6μM for 3a-3c)with satisfactory dark stability.Notably,no apparent dark cytotoxicity was observed in healthy lung MRC-5 fibroblasts for all complexes(IC_(50)>20μM).Significantly higher platinum cellular accumulation and photo-generated ROS levels were observed for the di-functionalised complexes compared with their mono-functionalised analogues when cancer cells were treated under the same concentrations.
基金the ERC(grant no.247450),Science City(AWM/ERDF),and EPSRC for support,and members of EC COST Action CM1105 for stimulating discussions.
文摘The organoiridium(III)anticancer complex[(η^(5)-Cp^(xbiph))Ir(phpy)py](Cp^(xbiph)=biphenyltetramethylcyclopentadienyl,phpy=phenylpyridine,py=pyridine)unexpectedly reacts with the tripeptide glutathione in the presence of coenzyme NADH to give glutathione sulfenate(Ir–S(O)G)and sulfinate(Ir–S(O)_(2)G)complexes.These new adducts may play a role in the anticancer activity of such organoiridium complexes.
基金the National Natural Science Foundation of China(Project No.21571154)the Jiangsu Overseas Research&Training Program for University Prominent Young&Middle-aged Teachers and Presidents,Leverhulme Trust(Early Career Fellowship No.ECF-2013-414 to NPEB)+2 种基金the ERC(Grant No.247450 to PJS)EPSRC(EP/F034210/1 to PJS)Science City(AWM/ERDF)for support,and EU COST Action CM1105 for stimulating discussions.
文摘The synthesis of nanoparticles of conjugates of caffeic acid-modified chitosan with ruthenium arene complexes is described.The chemical structure and physical properties of the nanoparticles were characterised by electronic absorption spectroscopy(UV-vis),Fourier transform infrared spectroscopy(FT-IR),1H NMR spectroscopy,dynamic light scattering(DLS),transmission electron microscopy(TEM),X-ray powder diffraction(XRD),and circular dichroism(CD)analysis.The multi-spectral results revealed that caffeic acid is covalently bound to chitosan and chelates to{Ru(p-cymene)Cl}+.The DLS studies indicated that the Ru-caffeic acid modified chitosan nanoparticles are well-defined and of nanometre size.Such well-defined nanocomposites of chitosan and metal complexes might find a range of applications,for example in drug delivery.
基金the Engineering and Physical Sciences Research Council(EPSRC grant no.EP/P030572/1)Anglo American Platinum for funding+2 种基金Gipuzkoa Foru Aldundia(Gipuzkoa Fellows program,grant number 2019-FELL-000018-01/62/2019)for financial supportthe Maria de Maeztu Units of Excellence Programme-Grant No.MDM-2017-0720 Ministry of Science,Innovation and Universitiesthe I14 Beamline(DLS,Oxford)under experiment numbers MG-19838 and SP-20548。
文摘Transition metal complexes are often prodrugs which undergo activation by ligand exchange and redox reactions before they interact with target sites.It is therefore important to understand the roles of both the metal and the ligands in their activation,especially in cells.Here we use a combination of synchrotron nanoprobe X-ray fluorescence(XRF)from Os L_(3)M_(5)and Br KL_(3)emissions and inductively coupled plasmamass spectrometry(ICP-MS)detection of^(189)Os,^(79)Br,and^(127)I,to investigate the time-dependent accumulation and localization of osmium as well as the monodentate ligand and the chelated phenylazopyridine in A2780 human ovarian cancer cells treated with the potent anticancer complexes[Os(η^(6)-pcymene)(4-R_(2)-phenyl-azopyridine-5-R_(1))X]PF_(6),with R_(2)=NMe_(2)or OH,R_(1)=H or Br,and X=Cl or I.The data confirm that the relatively inert iodido complexes are activated rapidly in cancer cells by release of the iodido ligand,probably initiated by attack by the intracellular tripeptide glutathione(γ-L-Glu-l-Cys-Gly)on the azo double bond.The bond between osmium and the azopyridine appears to remain stable in cells for ca.24 h,although some release of the chelated ligand is observed.Interestingly,the complexes seem to be degraded more rapidly in normal human cells,perhaps providing a possible mechanism for selective cytotoxicity towards cancer cells.
基金funded by the Original Exploration Program and General program of National Natural Science Foundation of China(Nos.22350001,21977052,22077066)Anglo American and EPSRC(No.EP/P030572/1)for funding platinum group metals(PGM)research in his laboratorythe Natural Science Foundation of Anhui Higher Education Institutions(No.2022AH051716)。
文摘Specific interactions between the macrocycle backbone,solvent and counter anions control configurational interconversions of novel organoruthenium(Ⅱ)metallamacrocycles[Ru(η^(6)-p-cymene)(μ_(2)-m-bitmb)Cl]_(2)·2X,m-bitmb=1,3,5-trimethyl-2,4-di(imidazole-1-ylmethyl)benzene,X=Cl^(-)(1.2Cl),NO_(3)^(-)(1-2NO_(3)),CF_(3)SO_(3)^(-)(1.2CF_(3)SO_(3)),PF_6^(-)(1.2PF_(6)),or BF_(4)^(-)(1.2BF_(4)).X-ray crystal structures reveal 1.2Cl in boat and chair conformations,1.2NO_(3)in twist-boat and chair conformations,and 1.2CF_(3)SO_(3)in a chair conformation.Chair/boat isomers of mono-and bis-DMSO adducts from 1.2Cl,1.2CF_(3)SO_(3)or 1.2NO_(3)in DMSO/H_(2)O were separated and characterized.Slow anion-dependent interconversion of configurational isomers was observed in solution.Ligand field molecular mechanics and density functional theory calculations suggest an unusual macrochelate ring-opening isomerization mechanism.Such dynamic stimuliresponsive configurational changes offer scope for design of metallocycles for induced-fit recognition of biological targets.
基金supported by the National Natural Science Foundation of China(grant nos.22022707,21778078,21877057,91953117,21837006,and 21773314)the innovative team of Ministry of Education(grant no.IRT_17R111)+3 种基金the Fundamental Research Funds for the Central Universitiesthe Guangdong Natural Science Funds for Distinguished Young Scholar(2019B151502017)EPSRC(no.EP/P030572/1)Chinese Scholarship Council(to F.-X.W.).
文摘Chloride is the most abundant anion in living systems.Most natural or synthetic chloride anionophores function via hydrogen-bonding interactions.However,dynamic metal-anion coordination can also be an efficient way of transporting chloride across membranes.Here,we investigate anion transport by manganese(Ⅲ)meso-tetraphenylporphyrin chloride{[Mn(TPP)Cl],TPP=meso-tetraphenylporphyrin}complex that exhibits labile axial coordination.[Mn(TPP)Cl]showed high chloride transport activity in a bilayer vesicle model with an EC_(50) value of 4.42×10^(−3) mol%.In living cells,[Mn(TPP)Cl]induced rapid chloride influx and autophagy.The release of Ca^(2+)and adenosine 5′-triphosphate(ATP),as well as the relocation of calreticulin,revealed that[Mn(TPP)Cl]caused immunogenic cell death.Proteomic analysis indicated that[Mn(TPP)Cl]impaired several physiological processes,including DNA synthesis,transcription,mitochondrial respiration,RNA translation,and immune response.Our study suggests that dynamic metal-anion interactions across membranes might provide a practical strategy for the interference of chloride homeostasis.
