ABSTRACT
The new amphiphilic BODPY-porphyrin conjugate BZnPP and its precursor BZnPH were synthesised, and their linear and two-photon photophysical properties, together with their cellular uptake and photo-cytotoxicity, were studied. This amphiphilic conjugate consists of a hydrophobic BODIPY moiety and a hydrophilic tetra(ethylene glycol) chain bridging a cationic triphenylphosphonium group to an amphiphilic porphyrin ZnP through acetylide linkers at its meso positions. A large two-photon absorption cross-section (σ=1725 GM) and a high singlet oxygen quantum yield (0.52) were recorded. Intense linear- and two-photon-induced red emissions were also observed for both BZnPP and BZnPH. Further in vitro studies showed that BZnPP exhibited very efficient cellular uptake and strong photocytotoxic but weak dark cytotoxic properties towards human breast carcinoma MCF-7 cells. In summary, the two-photon-induced emission and the potent photo-cytotoxicity of BZnPP make it an efficacious dual-purpose tumour-imaging and photodynamic therapeutic agent in the tissue-transparent spectral windows.
Subject(s)
Boron Compounds/chemistry , Photosensitizing Agents/chemistry , Porphyrins/chemistry , Cell Survival/drug effects , Humans , MCF-7 Cells , Microscopy, Confocal , Neoplasms/drug therapy , Photochemotherapy , Photons , Photosensitizing Agents/therapeutic use , Photosensitizing Agents/toxicity , Quantum Theory , Singlet Oxygen/chemistry , Singlet Oxygen/metabolismABSTRACT
Six water-soluble free-base porphyrin-Ru(II) conjugates, 1-3, and Zn(II) porphyrin-Ru(II) conjugates, 4-6, with different linkers between the hydrophobic porphyrin moiety and the hydrophilic Ru(II)-polypyridyl complex, have been synthesized. The linear and two-photon-induced photophysical properties of these conjugates were measured and evaluated for their potential application as dual in vitro imaging and photodynamic therapeutic (PDT) agents. Conjugates 1-3, with their high luminescence and singlet oxygen quantum yields, were selected for further study of their cellular uptake, subcellular localization, and cytotoxic and photocytotoxic (under linear and two-photon excitation) properties using HeLa cells. Conjugate 2, with its hydrophobic phenylethynyl linker, was shown to be highly promising for further development as a bifunctional probe for two-photon (NIR) induced PDT and in vitro imaging. Cellular uptake and subcellular localization properties were shown to be crucial to its PDT efficacy.
Subject(s)
Intracellular Space/metabolism , Metalloporphyrins/metabolism , Metalloporphyrins/pharmacology , Ruthenium/chemistry , Absorption , Antineoplastic Agents/chemistry , Antineoplastic Agents/metabolism , Antineoplastic Agents/pharmacology , Biological Transport , HeLa Cells , Humans , Hydrogen-Ion Concentration , Hydrophobic and Hydrophilic Interactions , Metalloporphyrins/chemistry , Molecular Imaging , Photosensitizing Agents/chemistry , Photosensitizing Agents/metabolism , Photosensitizing Agents/pharmacology , Water/chemistryABSTRACT
Two axially ligated rhodamine-Si(IV)-phthalocyanine (Rh-SiPc) conjugates, bearing one and two rhodamine B, were synthesized and their linear and two-photon photophysical, subcellular localization and photocytotoxic properties were studied. These Rh-SiPc conjugates exhibited an almost exclusive mitochondrial localizing property in human nasopharyngeal carcinoma (HK-1) cells and human cervical carcinoma (HeLa) cells. Strong photocytotoxic but low dark cytotoxic properties were also observed for the two Rh-SiPc conjugates toward the HK-1 cells. Using nuclei staining method and flow cytometric DNA content analysis, apoptotic cell death was induced by these conjugates upon photoactivation. This observation is consistent with their mitochondrial localization property. The observed properties of these conjugates qualify them as promising PDT agents.
Subject(s)
Indoles/chemistry , Mitochondria/drug effects , Photochemotherapy/methods , Rhodamines/chemistry , Silicon Compounds/chemistry , Silicon Compounds/pharmacology , Apoptosis/drug effects , Carcinoma , Cell Line, Tumor , HeLa Cells/drug effects , Humans , Isoindoles , Magnetic Resonance Spectroscopy , Mitochondria/metabolism , Molecular Structure , Nasopharyngeal Carcinoma , Nasopharyngeal Neoplasms/drug therapy , Photosensitizing Agents/chemistry , Photosensitizing Agents/pharmacology , Silicon Compounds/chemical synthesis , Singlet Oxygen/metabolismABSTRACT
A water-soluble porphyrinato ytterbium complex linked with rhodamine B (Yb-2) showed mitochondria-specific subcellular localization and strong two-photon-induced NIR emissions (λ(em) = 650 nm, porphyrinate ligand π â π* transition; λ(em) = 1060 nm, Yb(III) (5)F(5/2) â (5)F(7/2) transitions; σ(2) = 375 GM in DMSO) with an impressive Yb(III) NIR emission quantum yield (1% at λ(ex) = 340 nm; 2.5% at λ(ex) = 430 nm) in aqueous solution.
Subject(s)
Mitochondria/chemistry , Spectroscopy, Near-Infrared , Water/chemistry , Ytterbium/chemistry , SolubilityABSTRACT
A series of cationic lanthanide porphyrinate complexes of the general formula [(Por)Ln(H(2)O)(3)](+) (Ln(3+)=Yb(3+) and Er(3+)) were synthesized in moderate yields through the interaction of meso-pyridyl-substituted porphyrin free bases (H(2)Por) with [Ln{N(SiMe(3))(2)}(3)]·x[LiCl(thf)(3)], and the corresponding neutral derivatives [(Por)Ln(L(OMe))] (L(OMe)(-)=[(η(5)-C(5)H(5))Co{P(=O)(OMe)(2)}(3)](-)) were also prepared from [(Por)Ln(H(2)O)(3)](+) by the addition of the tripodal anion, L(OMe)(-), an effective encapsulating agent for lanthanide ions. Furthermore, the water-soluble lanthanide(III) porphyrinate complexes--including [(cis-DMPyDPP)Yb(H(2)O)(3)]Cl(3) (cis-DMPyDPP=5,10-bis(N-methylpyridinium-4'-y1)-15,20-di(phenyl)porphyrin), [(trans-DMPyDPP)Yb(H(2)O)(3)]Cl(3) (trans-DMPyDPP=5,15-bis(N-methylpyridinium-4'-y1)-10,20-di(phenyl)porphyrin), [(TMPyP)Yb(L(OMe))]I(4), and [(TMPyP)Er(L(OMe))]I(4) (TMPyP=tetrakis(N-methylpyridinium-4-y1)porphyrin)--were obtained by methylation of the corresponding complexes with methyl iodide and unambiguously characterized. The binding interactions and photocleavage activities of the water-soluble lanthanide(III) porphyrinate complexes towards DNA were investigated by UV-visible, fluorescence, and near-infrared luminescence spectroscopy, as well as circular dichroism and gel electrophoresis.
Subject(s)
DNA/chemistry , Ions/chemistry , Lanthanoid Series Elements/chemistry , Oxides/chemistry , Porphyrins/chemistry , Water/chemistry , Crystallography, X-Ray , Luminescence , Molecular Structure , Spectroscopy, Near-Infrared , X-Ray DiffractionABSTRACT
Two Ru(II) polypyridyl-porphyrin and Zn(II) porphyrin conjugates (Ru-L and Ru-Zn-L) have been synthesized and their photophysical properties studied. The two conjugates, which contained a hydrophobic tetraphenylporphyrin L conjugated via an acetylide linker at its ß-position with a hydrophilic Ru(II) polypyridyl complex, showed high singlet oxygen quantum yields (>70%) and substantial two-photon absorption cross-sections (~500 GM). Ru-L gave strong emissions at ~660 and ~733 nm through linear or two-photon excitation. Solvatochromism was observed in the fluorescence spectra of Ru-L and Ru-Zn-L, where in less polar solvents (i.e., toluene and dichloromethane) their fluorescence emissions became slightly blue-shifted with a 3-fold reduction in intensity relative to those observed in polar solvents (i.e., acetonitrile and methanol). Cell-based studies of these complex conjugates were conducted using human nasopharyngeal carcinoma HK-1 and cervical carcinoma HeLa cells on which Ru-L showed rapid cellular uptake, low dark-cytotoxicity, and high photo-cytotoxicity. Furthermore, Ru-L can be excited and emits in the "biological window"in vitro, making it a potential potent new generation photodynamic therapeutic agent capable of singlet oxygen generation and in vitro near-infrared emission.
Subject(s)
Metalloporphyrins/chemistry , Metalloporphyrins/pharmacology , Photosensitizing Agents/chemistry , Photosensitizing Agents/pharmacology , Singlet Oxygen/metabolism , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Cytotoxins/chemistry , Cytotoxins/pharmacokinetics , Cytotoxins/pharmacology , Humans , Luminescence , Metalloporphyrins/pharmacokinetics , Neoplasms/drug therapy , Photochemotherapy , Photosensitizing Agents/pharmacokineticsABSTRACT
Photodynamic therapy (PDT) is an emerging alternative cancer treatment modality that utilizes photo-sensitivity to cause cell death upon photo-irradiation. However, PDT efficiency has been hampered by tumor hypoxia, blue-shifted excitation wavelengths, and the high dark toxicity of photo-sensitizers. We designed and synthesized two novel porphycene-based photosensitizers (TBPoS-OH and TBPoS-2OH) with potent photo-cytotoxicity and a LD50 in the nM range under both normoxic and hypoxic conditions in a variety of cell types after photo-irradiation (λ = 640 ± 15 nm). Further studies showed fast-cellular uptake for TBPoS-OH that localized lysosomes and subsequently induced cell apoptosis via the lysosomal-mitochondrial pathway. Moreover, TBPoS-OH significantly reduced tumor growth in two xenografted mouse models bearing melanoma A375 and B16 cells. Finally, TBPoS-OH exhibited no obvious immunogenicity and toxicity to blood cells and major organs in mice. These data demonstrated that these two porphycene-based photosensitizers, especially TBPoS-OH, could be developed as a potential PDT modality.
Subject(s)
Melanoma/drug therapy , Photosensitizing Agents/therapeutic use , Porphyrins/therapeutic use , Sulfonamides/therapeutic use , Tumor Hypoxia/drug effects , Animals , Apoptosis/drug effects , Crystallography, X-Ray , Humans , Light , Male , Melanoma/metabolism , Melanoma/pathology , Mice , Mice, Inbred BALB C , Models, Molecular , Photochemotherapy , Photosensitizing Agents/chemistry , Porphyrins/chemistry , Sulfonamides/chemistryABSTRACT
Aristolochic acid (AA), derived from the herbal genus Aristolochia and Asarum, has recently been shown to be associated with the development of nephropathy. Upon enzyme activation, AA is metabolized to the aristolactam-nitrenium ion intermediate, which reacts with the exocyclic amino group of the DNA bases via an electrophilic attack at its C7 position, leading to the formation of the corresponding DNA adducts. The AA-DNA adducts are believed to be associated with the nephrotoxic and carcinogenic effects of AA. In this study, liquid chromatography coupled with electrospray ionization mass spectrometry (LC-MS) was used to identify and quantify the AA-DNA adducts isolated from the kidney and liver tissues of the AA-dosed rats. The deoxycytidine adduct of AA (dC-AA) and the deoxyadenosine-AA adduct (dA-AA) were detected and quantified in the tissues of rats with one single oral dose (5mg or 30mg AA/kg body weight). The deoxyguanosine adduct (dG-AA), however, was detected only in the kidney of rats that were dosed at 30mg AA/kg body weight for three consecutive days. The amount of AA-DNA adducts found in the rats correlated well with the dosage.
Subject(s)
Aristolochic Acids/chemistry , Chromatography, Liquid/methods , DNA Adducts/analysis , Kidney/chemistry , Liver/chemistry , Spectrometry, Mass, Electrospray Ionization/methods , Animals , DNA Adducts/chemistry , DNA Adducts/isolation & purification , Male , Molecular Structure , Rats , Rats, Sprague-DawleySubject(s)
Alzheimer Disease/metabolism , Amyloid beta-Peptides/antagonists & inhibitors , Amyloid beta-Peptides/chemistry , Carbazoles/chemistry , Fluorescent Dyes/chemistry , Alzheimer Disease/drug therapy , Animals , Carbazoles/pharmacology , Disease Models, Animal , Humans , Mice , Mice, Transgenic , Molecular StructureABSTRACT
We have synthesized a bifunctional erbium-porphyrin tumor imaging and PDT agent (Er-R3) that is capable of killing bladder cancer cells via its selective binding to the integrin αvß3 isoform overexpressed on the cell membrane.
Subject(s)
Erbium/metabolism , Erbium/therapeutic use , Integrin alphaVbeta3/metabolism , Metalloporphyrins/metabolism , Metalloporphyrins/therapeutic use , Photochemotherapy , Urinary Bladder Neoplasms/diagnostic imaging , Urinary Bladder Neoplasms/drug therapy , Cell Line , Cell Proliferation/drug effects , Erbium/chemistry , Humans , Integrin alphaVbeta3/genetics , Metalloporphyrins/chemistry , Molecular Imaging , Urinary Bladder Neoplasms/pathologyABSTRACT
The hypoxia inducible factor (HIF) pathway has been considered to be an attractive anti-cancer target. One strategy to inhibit HIF activity is through the disruption of the HIF-1α-p300 protein-protein interaction. We report herein the identification of an osmium(II) complex as the first metal-based inhibitor of the HIF-1α-p300 interaction. We evaluated the effect of complex 1 on HIF-1α signaling pathway in vitro and in cellulo by using the dual luciferase reporter assay, co-immunoprecipitation assay, and immunoblot assay. Complex 1 exhibited a dose-dependent inhibition of HRE-driven luciferase activity, with an IC50 value of 1.22 µM. Complex 1 interfered with the HIF-1α-p300 interaction as revealed by a dose-dependent reduction of p300 co-precipitated with HIF-1α as the concentration of complex 1 was increased. Complex 1 repressed the phosphorylation of SRC, AKT and STAT3, and had no discernible effect on the activity of NF-κB. We anticipate that complex 1 could be utilized as a promising scaffold for the further development of more potent HIF-1α inhibitors for anti-cancer treatment.
Subject(s)
Coordination Complexes/chemical synthesis , E1A-Associated p300 Protein/metabolism , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Osmium/chemistry , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Line , Coordination Complexes/chemistry , Coordination Complexes/pharmacology , Dose-Response Relationship, Drug , E1A-Associated p300 Protein/chemistry , HEK293 Cells , Humans , Hypoxia-Inducible Factor 1, alpha Subunit/chemistry , Mice , Molecular Structure , Phosphorylation/drug effects , Protein Binding/drug effects , Signal Transduction/drug effectsABSTRACT
The JAK2/STAT3 signaling pathway plays a critical role in tumorigenesis, and has been suggested as a potential molecular target for anti-melanoma therapeutics. However, few JAK2 inhibitors were being tested for melanoma therapy. In this study, eight amentoflavone analogues were evaluated for their activity against human malignant melanoma cells. The most potent analogue, compound 1, inhibited the phosphorylation of JAK2 and STAT3 in human melanoma cells, but had no discernible effect on total JAK2 and STAT3 levels. A cellular thermal shift assay was performed to identify that JAK2 is engaged by 1 in cell lysates. Moreover, compound 1 showed higher antiproliferative activity against human melanoma A375 cells compared to a panel of cancer and normal cell lines. Compound 1 also activated caspase-3 and cleaved PARP, which are markers of apoptosis, and suppressed the anti-apoptotic Bcl-2 level. Finally, compound 1 induced apoptosis in 80% of treated melanoma cells. To our knowledge, compound 1 is the first amentoflavone-based JAK2 inhibitor to be investigated for use as an anti-melanoma agent.
Subject(s)
Apoptosis/drug effects , Biological Products/pharmacology , Janus Kinase 2/antagonists & inhibitors , Melanoma/pathology , STAT3 Transcription Factor/antagonists & inhibitors , Cell Line, Tumor , HumansABSTRACT
A novel luminescent cyclometalated iridium(III) complex was synthesized and employed as a chemosensor for the detection of Al(3+) ions. Compared with common organic chemosensors, displays a larger Stokes shift and a long lifetime luminescence that allow to detect Al(3+) ions in fluorescent dye spiked strong fluorescence media and potentially be used in strongly autofluorescent biological samples.
ABSTRACT
Targeting STAT5 is an appealing therapeutic strategy for the treatment of hematologic malignancies and inflammation. Here, we present the novel osmium(II) complex 1 as the first metal-based inhibitor of STAT5B dimerization. Complex 1 exhibited superior inhibitory activity against STAT5B DNA binding compared to STAT5A DNA binding. Moreover, 1 repressed STAT5B transcription and blocked STAT5B dimerization via binding to the STAT5B protein, thereby inhibiting STAT5B translocation to the nucleus. Furthermore, 1 was able to selectively inhibit STAT5B phosphorylation without affecting the expression level of STAT5B.
Subject(s)
Osmium Compounds/metabolism , Protein Multimerization/drug effects , STAT5 Transcription Factor/antagonists & inhibitors , STAT5 Transcription Factor/metabolism , Cell Line , DNA/metabolism , Humans , Phosphorylation/drug effects , Protein Binding/drug effects , Protein Processing, Post-Translational/drug effectsABSTRACT
Sequence-specific photo-modification of DNA has been demonstrated, for the first time, in a vanadium(V)-peroxo complex, NH4[VO(O2)2(5,6-Me2phen)] (where 5,6-Me2phen = 5,6-dimethyl-1,10-phenanthroline). Using molecular cloning technique, a consensus sequence motif of 5'-G(A/G)TA(T/C)C was identified associated with the two specific photo-modification sites, 5'-ATC and 5'-TACC found on a plasmid DNA, pBluescript, by a modified Sanger sequencing technique. DNA supercoiling was shown to be a critical prerequisite for this observed sequence-specific photo-modification activity.
Subject(s)
DNA, Superhelical , Organometallic Compounds/chemistry , Peroxides/chemistry , Vanadium Compounds/chemistry , Base Sequence , Cloning, Molecular , Molecular Sequence Data , Photochemistry , PlasmidsABSTRACT
Biological systems have developed an intact network and strategies in response to various environmental pressures such as irradiation, viral invasion and oxidative stress. Therefore, elucidation of the cellular response mechanism toward oxidative stress can contribute to the knowledge of redox regulation. By using a newly developed gadolinium based photodynamic therapy (PDT) agent Gd-N and SILAC quantified proteomic analysis, we observed 485 proteins dysregulated in expression, 106 in phosphorylation and 1050 in oxidation. Interestingly, lysosome was discovered as the main organelle affected by Gd-N induced singlet oxygen, along with the down regulation of a majority of lysosomal acid hydrolases and proton pump complex ATP6V/TCIRG1. Besides, phosphorylation sites with sequence patterns "TP" or "SP" were enriched in dysregulated phosphoproteins. Protein oxidation also shows sequence patterns in target proteins with "M.D" or "KM" taking methionine as the central residue. Oxidized proteins were most enriched in the pathways of Parkinson's disease, an oxidative stress closely related neurodegenerative disease. In conclusion, our study reveals new insights into the cellular mechanism to oxidative stress and may contribute to the discovery of new targets and development of novel PDT agents.
Subject(s)
Gadolinium/therapeutic use , Isotope Labeling/methods , Lysosomes/metabolism , Metalloporphyrins/therapeutic use , Ovarian Neoplasms/drug therapy , Oxidative Stress/drug effects , Photochemotherapy , Proteomics/methods , Blotting, Western , Cell Line, Tumor , Female , Gadolinium/pharmacology , Gene Ontology , Humans , Lysosomes/drug effects , Metalloporphyrins/pharmacology , Models, Biological , Oxidation-Reduction/drug effects , Peptides/metabolism , Phosphorylation/drug effects , Reactive Oxygen Species/metabolismABSTRACT
A water-soluble light-responsive antitumor agent, PtEuL, based on a cisplatin-linked europium-cyclen complex has been synthesized and evaluated for controlled cisplatin release by linear/two-photon excitation in vitro with concomitant turn-on and long-lived europium emission as a responsive traceable signal.
Subject(s)
Antineoplastic Agents/chemistry , Cisplatin/chemistry , Coordination Complexes/chemistry , Drug Monitoring/methods , Europium/chemistry , Luminescent Agents/chemistry , Ultraviolet Rays , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/pharmacology , Antineoplastic Agents/radiation effects , Cell Line, Tumor , Cell Survival/drug effects , Circular Dichroism , Cisplatin/pharmacokinetics , Cisplatin/pharmacology , Cisplatin/radiation effects , Coordination Complexes/radiation effects , Delayed-Action Preparations , Drug Delivery Systems/methods , Drug Liberation , Europium/radiation effects , Humans , Luminescent Agents/radiation effects , Luminescent Measurements/methods , PhotonsABSTRACT
We report herein a novel iridium(III) complex 1 as an antitumour necrosis factor agent and the first metal-based inhibitor of TACE enzymatic activity. Complex 1 inhibited TNF-α secretion and p38 phosphorylation in human monocytic THP-1 cells.
Subject(s)
ADAM Proteins/antagonists & inhibitors , Iridium/chemistry , Organometallic Compounds/chemistry , Organometallic Compounds/pharmacology , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , ADAM17 Protein , Cell Line , Humans , Monocytes/drug effects , Monocytes/metabolism , Phosphorylation/drug effects , Tumor Necrosis Factor-alpha/metabolism , p38 Mitogen-Activated Protein Kinases/metabolismABSTRACT
A novel iridium(III) complex was synthesized and evaluated for its ability to target JMJD2 enzymatic activity. The iridium(III) complex 1 can inhibit JMJD2 activity and was selective for JMJD2 activity over JARID, JMJD3, and HDAC activities. Moreover, 1 suppressed the trimethylation of the p21 promoter on H3K9me3 and interrupted the JMJD2D-H3K9me3 interactions in human cells, suggesting that it could act as an epigenetic modulator. To our knowledge, 1 represents the first metal-based JMJD2 inhibitor reported in the literature.
Subject(s)
Epigenesis, Genetic/drug effects , Iridium/chemistry , Jumonji Domain-Containing Histone Demethylases/antagonists & inhibitors , Jumonji Domain-Containing Histone Demethylases/genetics , Organometallic Compounds/chemistry , Organometallic Compounds/pharmacology , Apoptosis/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Histones/metabolism , Humans , Iron/metabolismABSTRACT
We report herein the synthesis and application of a series of novel cyclometalated iridium(III) complexes 1-3 bearing a rhodamine-linked NËN ligand for the detection of Cu(2+) ions. Under the optimised conditions, the complexes exhibited high sensitivity and selectivity for Cu(2+) ions over a panel of other metal ions, and showed consistent performance in a pH value range of 6 to 8. Furthermore, the potential application of this system for the monitoring of Cu(2+) ions in tap water or natural river water samples was demonstrated.