ABSTRACT
Two mitochondria-localized Ru(ii) complexes with photo-labile ligands were reported to exert one- and two-photon activatable anticancer activity through a dual-function mechanism, i.e. mitochondrial DNA covalent binding after photo-induced ligand dissociation and photo-catalyzed NADH depletion, thus displaying good activity towards cisplatin-resistant cancer cells under both normoxic and hypoxic conditions.
Subject(s)
Antineoplastic Agents/pharmacology , Coordination Complexes/pharmacology , DNA, Mitochondrial/drug effects , NAD/antagonists & inhibitors , Nitrogen Dioxide/metabolism , Ruthenium/pharmacology , A549 Cells , Antineoplastic Agents/chemistry , Antineoplastic Agents/metabolism , Coordination Complexes/chemistry , Coordination Complexes/metabolism , DNA Damage , DNA, Mitochondrial/metabolism , Humans , Ligands , Molecular Structure , NAD/analysis , NAD/metabolism , Photochemical Processes , Photons , Ruthenium/chemistry , Ruthenium/metabolismABSTRACT
In this work, the simple modification of a pyrene group on the labile ligand gives the resultant complex 1 versatility, for example, "turn-on" fluorescence after photo-dissociation, dual PDT and PACT activity, and a large two-photon absorption cross section.
ABSTRACT
The electronic effect of the substituent has been fully leveraged to improve the activity of molecular water reduction catalysts (WRCs). However, the steric effect of the substituents has received less attention. In this work, a steric hindrance effect was observed in a quinoline-involved polypyridyl Co complex-based water reduction catalyst (WRC), which impedes the formation of Co(iii)-H from Co(i), two pivotal intermediates for H2 evolution, leading to significantly impaired electrocatalytic and photocatalytic activity with respect to its parent complex, [Co(TPA)Cl]Cl (TPA = tris(2-pyridinylmethyl)-amine). In sharp contrast, two isoquinoline-involved polypyridyl Co complexes exhibited significantly improved H2 evolution efficiencies compared to [Co(TPA)Cl]Cl, benefitting mainly from the more basic and conjugated features of isoquinoline over pyridine. The dramatically different influences caused by the replacement of a pyridine group in the TPA ligand by quinoline and isoquinoline fully demonstrates the important roles of both the electronic and steric effects of a substituent. Our results may provide novel insights for designing more efficient WRCs.
ABSTRACT
Three new isomeric cobalt complexes of TPA (tris(2-pyridylmethyl)amine) based on methoxy substitution at the ortho, meta and para positions, respectively, were constructed and their photocatalytic proton reduction efficiencies were compared. It was found that there are good linear correlations with the Hammett constants of the substituents for the computed Co-N bond lengths, redox potentials of CoII/I and CoI/0 events, and the photocatalytic activities of the complexes. The ortho-substituted Co complex distinguished itself from the others remarkably in all these comparisons, demonstrating the presence of a steric effect besides the electronic effect. For other examined complexes, a stronger electron-donating substituent may lead to a higher hydrogen evolution efficiency, suggesting that the formation of a Co(iii) hydride intermediate is the rate-limiting step.
ABSTRACT
A two-photon excited "Ping-Pong" type energy transfer process is for the first time disclosed in a pyrene-modified Ir(iii) cyclometalated complex. The energy transfer, from the singlet excited state of the 4-(pyren-1-yl)-tpy (tpy-py) unit to the Ir(iii) moiety and then back again to the triplet excited state of the tpy-py unit, enhances both the two-photon absorption cross sections and singlet oxygen quantum yield of the complex, and dramatically boosts its two-photon photodynamic activity both in vitro and in 3D multicellular spheroids.
ABSTRACT
Cholesterol (CHOL) is an indispensable component of liposomes. Incorporation of 7-dehydrocholesterol (7-DHC) instead of CHOL can efficiently enhance the anticancer activity of photosensitizer-encapsulated liposomes upon irradiation, yielding an IC50 value about half of that of CHOL-based controls. The photo-oxidation of 7-DHC into its endoperoxide form by singlet oxygen may account for the enhanced therapeutic effect, realizing an efficient combination of photodynamic therapy (PDT) and photoactivated chemotherapy.
Subject(s)
Antineoplastic Agents/pharmacology , Dehydrocholesterols/pharmacology , Liposomes/pharmacology , Photosensitizing Agents/pharmacology , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Dehydrocholesterols/chemistry , Drug Screening Assays, Antitumor , Humans , Liposomes/chemistry , Optical Imaging , Particle Size , Photochemotherapy , Photosensitizing Agents/chemistry , Reactive Oxygen Species/analysis , Reactive Oxygen Species/metabolismABSTRACT
Three chloromethyl-modified Ru(ii) complexes were designed and synthesized as mitochondria targeting photosensitizers, which can generate carbon radicals in the presence of NADH under visible light irradiation, cause DNA cleavage and covalent binding in Ar-saturated solutions, and lead to apoptosis of human ovarian carcinoma SKOV-3 cells under hypoxic conditions (3% O2), demonstrating a new mode of type I mechanism to overcome the limitation of hypoxia in photodynamic therapy (PDT).
Subject(s)
Coordination Complexes/chemistry , Mitochondria/metabolism , NAD/metabolism , Ruthenium/chemistry , Apoptosis/drug effects , Cell Hypoxia , Cell Line, Tumor , Coordination Complexes/pharmacology , Coordination Complexes/therapeutic use , DNA Cleavage/drug effects , Humans , Light , Membrane Potential, Mitochondrial/drug effects , Mitochondria/drug effects , Neoplasms/drug therapy , Neoplasms/pathology , PhotochemotherapyABSTRACT
Photoacid generators (PAGs) are finding increasing applications in spatial and temporal modulation of biological events in vitro and in vivo. In these applications, large pH jumps at low PAG concentrations are of great importance to achieve maximal expected manipulation but minimal unwanted interference. To this end, both high photoacid quantum yield and capacity are essential, where the capacity refers to the proton number that a PAG molecule can release. Up to now, most PAGs only produce one proton for each molecule. In this work, the hydrolysis reaction of benzyl chlorides was successfully leveraged to develop a novel type of PAG. Upon visible light irradiation, Ru(ii) polypyridyl complexes modified with chloromethyl groups can undergo full hydrolysis with photoacid quantum yield as high as 0.6. Depending on the number of the chloromethyl groups, the examined Ru(ii) complexes can release multiple protons per molecule, leading to large pH jumps at very low PAG concentrations, a feature particularly favorable for bio-related applications.
ABSTRACT
In this work, we demonstrate for the first time that [Ru(bpy)2(R-OQN)](+) complexes (bpy = 2,2'-bipyridine, R-OQN = 5-chloro-8-oxyquinolate or 5-bromo-8-oxyquinolate) are able to generate hydroxyl radicals and cleave DNA effectively upon visible light irradiation. The potent electron-donating ability of the R-OQN-based non-innocent ligands gives the complexes a high reducing capability, favoring the generation of superoxide anion radicals from which hydroxyl radicals may be generated. More interestingly, halogen substitution plays an important role. When the 5-Cl- or 5-Br-8-oxyquinolate ligand is replaced by 8-oxyquinolate or 5-CH3-8-oxyquinolate, the corresponding complexes lose their hydroxyl radical-generation and DNA photocleavage abilities. These findings open new applications for the non-innocent ligand-based Ru(II) complexes in the fields of biology and medicine, such as in photodynamic therapy (PDT).
Subject(s)
Coordination Complexes/chemistry , DNA Cleavage/radiation effects , DNA, Superhelical/chemistry , Ruthenium/chemistry , Acetonitriles/chemistry , Dimethyl Sulfoxide/chemistry , Hydroxyl Radical/chemistry , Ligands , Light , Reactive Oxygen Species/chemistryABSTRACT
[Cu(TMPA)Cl]Cl (1) and [Cu(Cl-TMPA)Cl2] (2) exhibited efficient photocatalytic H2 evolution with a TON of 6108 and 10014 (6 h), respectively, in CH3CN/H2O solution (9 : 1, v/v) containing an Ir complex as the photosensitizer and triethylamine as the sacrificial reductant, representing the first example of photocatalytic Cu complex-based water reduction catalysts.
ABSTRACT
[Ru(bpy)2(py-SO3)](+) (3, bpy = 2,2'-bipyridine, py-SO3 = pyridine-2-sulfonate) was recently found to undergo py-SO3 ligand dissociation and py-SO3Ë radical generation under hypoxic conditions upon irradiation (Chem. Commun., 2015, 51, 428). To explore the substituent effect on the Ru-O homolysis by which the py-SO3Ë radical may be produced, [Ru(4,4'-(R)2-bpy)(py-SO3)](+), where R = OCH3 (1), CH3 (2), COOCH3 (4), were synthesized and their photochemical properties were investigated. The py-SO3Ë radical generation efficiencies followed the order of 4 > 3 > 2 > 1, and the radical generation efficiencies are wavelength dependent. As a result, 3 and 4 may lead to DNA covalent binding and DNA cleavage upon 355 nm irradiation, but merely DNA covalent binding upon 470 nm irradiation. In contrast, 1 and 2 can serve as DNA photo-binding agents only due to their less efficient Ru-O homolysis. The Ru-O homolysis via the (3)σ(Ru-O)π*(R-bpy) state is proposed to rationalize the substituent effect and the wavelength dependence, which is supported by TD-DFT calculations. This work gave insights into the mechanism of the Ru-O homolysis and provided guidelines for developing new [Ru(bpy)2(py-SO3)](+)-type complexes with higher Ru-O homolysis efficiency. Such complexes have dual activities of photoactivated chemotherapy (PACT) and photodynamic therapy (PDT) under hypoxic conditions and are therefore promising as a new class of antitumor drugs.
Subject(s)
2,2'-Dipyridyl/chemistry , Antineoplastic Agents/chemistry , Coordination Complexes/chemistry , Photosensitizing Agents/chemistry , Ruthenium/chemistry , Sulfonic Acids/chemistry , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Coordination Complexes/chemical synthesis , Coordination Complexes/pharmacology , DNA/chemistry , DNA Cleavage/drug effects , Drug Discovery , Energy Transfer , Free Radicals/chemistry , Light , Molecular Structure , Photolysis , Photosensitizing Agents/chemical synthesis , Photosensitizing Agents/pharmacologyABSTRACT
A series of cobaloxime complexes, [Co(iii)(dmgH)2(py-m-X)Cl] (dmgH = dimethylglyoxime, py-m-X = meta-substituted pyridine, X = COOH (2), COOCH3 (3), CH2CH2COOH (6), and CH2CH2COOCH3 (7)), and [Co(iii)(dmgH)2(py-p-X)Cl], (py-p-X = para-substituted pyridine, X = COOH (4) and COOCH3 (5)), were synthesized and their photocatalytic H2 production activities were compared in an artificial photosynthesis system containing a xanthene dye Eosin Y as the photosensitizer (PS) and triethanolamine (TEOA) as the sacrificial reductant (SR) in CH3CN/H2O (1 : 1, pH = 7.5). Irrespective of substitution by an electron-donating or electron withdrawing group, the photocatalytic H2 production activities of 2-7 are all higher than that of [Co(iii)(dmgH)2(py)Cl] (1). Importantly, meta-substitution is more efficient than para-substitution, and COOH is more efficient than COOCH3, in enhancing the photocatalytic activities. 6 showed the highest activity among the examined complexes. The -CH2CH2- chain linking COOH and pyridine might play a role in the promising performance of 6, which makes the proton relay via interaction between COOH and dmgH possible. This work may open new avenues for developing more efficient cobaloxime-based H2 evolution catalysts (HERs).
ABSTRACT
BODIPY (boron dipyrromethene) derivatives and Ru(ii) complexes are two types of functional compounds that have found wide applications in the fields of biology and medicine. We herein synthesized two new Ru(ii) arene complexes based on an iodized BODIPY-containing pyridine (py-I-BODIPY) ligand, [(p-cym)Ru(bpy)(py-I-BODIPY)](2+) (2) and [(p-cym)Ru(2-pydaT)(py-I-BODIPY)](2+) (3), where p-cym = para-cymene, bpy = 2,2'-bipyridine, and 2-pydaT = 2,4-diamino-6-(2-pyridyl)-1,3,5-triazine. The photophysical, photochemical and photobiological properties of 2 and 3 were compared with that of [(p-cym)Ru(bpy)(py-BODIPY)](2+) (1). While 1 undergoes efficient monodentate ligand dissociation upon visible light irradiation and therefore may photobind DNA as a potential photoactivated chemotherapy (PACT) agent, 2 and 3 can generate (1)O2 effectively and thus may serve as photosensitizers in photodynamic therapy (PDT). In electrophoresis experiments, 2 and 3 are even able to retard the mobility of plasmid DNA in the dark at high concentrations. More importantly, the cytotoxicities of 2 and 3 against human ovarian adenocarcinoma SKOV3 cells are enhanced about ten times under irradiation, leading to cytotoxicities more than one order of magnitude higher than that of cisplatin, demonstrating an efficient hybridization of the iodized BODIPY chromophore and the Ru(ii) arene complex.
Subject(s)
Boron Compounds , Coordination Complexes , Photosensitizing Agents , Ruthenium , Boron Compounds/chemistry , Boron Compounds/pharmacology , Boron Compounds/radiation effects , Cell Line, Tumor , Cell Survival/drug effects , Cell Survival/radiation effects , Coordination Complexes/chemistry , Coordination Complexes/pharmacology , Coordination Complexes/radiation effects , DNA/drug effects , DNA/metabolism , DNA/radiation effects , DNA Cleavage , Humans , Ligands , Light , Photochemotherapy , Photosensitizing Agents/chemistry , Photosensitizing Agents/pharmacology , Photosensitizing Agents/radiation effects , Plasmids , Ruthenium/chemistry , Ruthenium/pharmacology , Ruthenium/radiation effectsABSTRACT
A novel azopyridine-based Ru(II) complex [Ru(bpy)2(L1)2](2+) (bpy = 2,2'-bipyridine, L1 = 4,4'-azopyridine) was designed and synthesized as a potential glutathione (GSH)-responsive photoactivated chemotherapy (PACT) agent, the DNA covalent binding capability of which can only be activated after GSH reduction and visible light irradiation.
Subject(s)
2,2'-Dipyridyl/chemistry , Coordination Complexes/chemistry , DNA/chemistry , Glutathione/chemistry , Ruthenium/chemistry , Light , Oxidation-Reduction , Quantum TheoryABSTRACT
A piperazine-modified Crystal Violet was found to be able to selectively inactivate Gram-negative bacteria upon visible light irradiation but left Gram-positive bacteria less damaged, which can serve as a blueprint for the development of novel narrow-spectrum agents to replenish the current arsenal of photodynamic antimicrobial chemotherapy (PACT).
Subject(s)
Anti-Bacterial Agents/pharmacology , Gentian Violet/pharmacology , Gram-Negative Bacteria/drug effects , Gram-Negative Bacteria/radiation effects , Photochemotherapy , Piperazines/chemistry , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/radiation effects , Cations/chemistry , Cations/pharmacology , Cations/radiation effects , Dose-Response Relationship, Drug , Gentian Violet/chemistry , Gentian Violet/radiation effects , Gram-Negative Bacteria/cytology , Gram-Positive Bacteria/cytology , Gram-Positive Bacteria/drug effects , Gram-Positive Bacteria/radiation effects , Light , Microbial Sensitivity Tests , Molecular Structure , Photochemical Processes , Piperazine , Structure-Activity RelationshipABSTRACT
A series of six Ru(arene) complexes, [(η(6)-p-cymene)Ru(dpb)(py-R)](2+) (1-6, dpb = 2,3-bis(2-pyridyl)benzoquinoxaline, py-R = 4-substituted pyridine, R = N(CH3)2, NH2, OCH3, H, COOCH3 and NO2), were synthesized and their photochemical and photobiological properties were compared in detail. The electron push/pull character of the R groups has a significant impact on both ligand photodissociation and (1)O2 generation of the complexes. The photoinduced DNA covalent binding capabilities increase from 1 to 6 under both aerobic and anaerobic conditions, and DNA photocleavage occurs simultaneously in aerobic environments. 4 has the most potent phototoxicity against human lung carcinoma A549 cells among the examined complexes. The substituent effect may be ascribed to the influences of the R groups on the energy levels of (3)MC and (3)MLCT states as well as the energy gaps between (3)MC, (3)MLCT and dpb-based (3)IL states. Similar chemical modification on bidentate and arene ligands or other sites of the pyridine ligand may lead to more efficient agents with PDT and/or PACT activities.
Subject(s)
Coordination Complexes/chemistry , DNA/chemistry , Ruthenium/chemistry , Cell Line, Tumor , Cell Survival/drug effects , Cell Survival/radiation effects , Coordination Complexes/chemical synthesis , Coordination Complexes/toxicity , Cymenes , Humans , Ligands , Light , Magnetic Resonance Spectroscopy , Monoterpenes/chemistry , Photolysis/drug effects , Photolysis/radiation effects , Pyridines/chemistry , Quinoxalines/chemistry , Superoxides/chemistry , Superoxides/metabolismABSTRACT
[Ru(bpy)2(py-SO3)](+) (bpy = 2,2'-bipyridine and py-SO3 = pyridine-2-sulfonate) was found to undergo py-SO3 dissociation upon visible light irradiation (≥470 nm) via Ru-O homolysis, producing reactive free radical species, and is thus able to not only photobind but also photocleave DNA in hypoxic conditions.
Subject(s)
2,2'-Dipyridyl/analogs & derivatives , DNA Cleavage/drug effects , DNA/chemistry , Organometallic Compounds/chemistry , Organometallic Compounds/pharmacology , Photolysis/drug effects , 2,2'-Dipyridyl/chemistry , 2,2'-Dipyridyl/pharmacology , Anaerobiosis , Free Radicals/chemistry , Light , Sulfonic Acids/chemistry , Sulfonic Acids/pharmacologyABSTRACT
Three new triarylmethane dyes (TAMs), MPCV, DPCV, and AEV, were synthesized and their photodynamic inactivation abilities against E. coli and human pulmonary carcinoma A549 cells were compared to two commercial TAMs, CV and EV. The enhanced hydrophilicity of MPCV and AEV decreases their cellular uptake to A549 cells dramatically. However, their binding affinity toward E. coli cells are comparable to that of CV and EV by virtue of the improved electrostatic attraction with highly negatively charged E. coli outer membranes. MPCV and AEV were also found to generate hydroxyl radicals more efficiently upon irradiation than CV and EV. Consequently, MPCV and AEV exhibited markedly improved photodynamic inactivation of E. coli cells but remarkably diminished photodynamic inactivation of A549 cells than CV and EV. The photodynamic inactivation ability of DPCV was much lower than that of CV due to its high propensity for bleaching in neutral aqueous solution. Our work demonstrates that the introduction of protonatable groups in a proper manner into the structures of TAMs may lead to selective binding and photodynamic inactivation toward bacterial cells over mammalian cells. This strategy may be extended to other types of photodynamic antimicrobial chemotherapy (PACT) agents to improve their clinical potential.
Subject(s)
Methane/chemistry , Photosensitizing Agents/chemistry , Photosensitizing Agents/pharmacology , Anti-Infective Agents/adverse effects , Anti-Infective Agents/chemistry , Anti-Infective Agents/pharmacology , Cell Line , Escherichia coli/drug effects , Humans , Microbial Sensitivity Tests , Photosensitizing Agents/adverse effectsABSTRACT
Transition metal complexes with dual functions of DNA photobinding via coordination and DNA photocleavage via(1)O2 may present potent antitumor activities with high selectivity and a wide anticancer spectrum. We herein report such a complex, [(η(6)-p-cymene)Ru(dpb)(py)](2+) (dpb = 2,3-bis(2-pyridyl)benzoquinoxaline, py = pyridine, 1). The highly delocalized nature of dpb provides 1 with long wavelength-absorbing properties and a long-lived excited state, facilitating (1)O2 generation. Additionally, the bulky nature of dpb leads to a distorted coordination geometry, and allow the (3)MC (metal-centered) state to be more accessible. From this, dissociation of py and dpb may occur, followed by the coordination of the resultant Ru fragment to nucleic bases if DNA is present. The dissociation of dpb can turn on fluorescence of its own, enabling real-time imaging of the photoactivation process. The fascinating properties of 1 and the underlying mechanisms that occur may provide guidelines for developing more efficient metallodrugs with dual potential for photodynamic therapy (PDT) and photoactivated chemotherapy (PACT).
Subject(s)
Antineoplastic Agents/pharmacology , Coordination Complexes/pharmacology , DNA/metabolism , Lung Neoplasms/drug therapy , Photochemotherapy/methods , Photosensitizing Agents/pharmacology , Ruthenium/pharmacology , Antineoplastic Agents/chemistry , Cell Line, Tumor , Coordination Complexes/chemistry , Cymenes , Humans , Models, Molecular , Monoterpenes/chemistry , Monoterpenes/pharmacology , Photosensitizing Agents/chemistry , Pyridines/chemistry , Pyridines/pharmacology , Quinoxalines/chemistry , Quinoxalines/pharmacology , Ruthenium/chemistryABSTRACT
The dissociation of one pyridine of a pentadentate ligand (N4Py) from the Co centre was found to be responsible for the formation of a Co(III) hydride species, an indispensable intermediate for photocatalytic proton reduction.