ABSTRACT
A panel of iridium(iii) porphyrin complexes containing axial N-heterocyclic carbene (NHC) ligand(s) were synthesized and characterized. X-ray crystal structures of the bis-NHC complexes [IrIII(ttp)(IMe)2]+ (2a), [IrIII(oep)(BIMe)2]+ (2d), [IrIII(oep)(I i Pr)2]+ (2e) and [IrIII(F20tpp)(IMe)2]+ (2f) display ruffled porphyrin rings with mesocarbon displacements of 0.483-0.594 Å and long Ir-CNHC bonds of 2.100-2.152 Å. Variable-temperature 1H NMR analysis of 2a reveals that the macrocycle porphyrin ring inversion takes place in solution with an activation barrier of 40 ± 1 kJ mol-1. The UV-vis absorption spectra of IrIII(por)-NHC complexes display split Soret bands. TD-DFT calculations and resonance Raman experiments show that the higher-energy Soret band is derived from the 1MLCT dπ(Ir) â π*(por) transition. The near-infrared phosphorescence of IrIII(por)-NHC complexes from the porphyrin-based 3(π, π*) state features broad emission bands at 701-754 nm with low emission quantum yields and short lifetimes (Φ em < 0.01; τ < 4 µs). [IrIII(por)(IMe)2]+ complexes (por = ttp and oep) are efficient photosensitizers for 1O2 generation (Φ so = 0.64 and 0.88) and are catalytically active in the light-induced aerobic oxidation of secondary amines and arylboronic acid. The bis-NHC complexes exhibit potent dark cytotoxicity towards a panel of cancer cells with IC50 values at submicromolar levels. The cytotoxicity of these complexes could be further enhanced upon light irradiation with IC50 values as low as nanomolar levels in association with the light-induced generation of reactive oxygen species (ROS). Bioimaging of [IrIII(oep)(IMe)2]+ (2c) treated cells indicates that this Ir complex mainly targets the endoplasmic reticulum. [IrIII(oep)(IMe)2]+ catalyzes the photoinduced generation of singlet oxygen and triggers protein oxidation, cell cycle arrest, apoptosis and the inhibition of angiogenesis. It also causes pronounced photoinduced inhibition of tumor growth in a mouse model of human cancer.
ABSTRACT
Dehydroeffusol (DHE) is a phenanthrene isolated from the Chinese medicinal plant Juncus effusus. Biological evaluation of DHE reveals in vitro and in vivo anticancer effects. We performed a shotgun proteomic analysis using liquid chromatography-tandem mass spectrometry to investigate the changes in the protein profiles in cancer cells upon DHE treatment. DHE affected cancer-associated signaling pathways, including NF-κB, ß-catenin, and endoplasmic reticulum stress. Through quantitative pathway and key node analysis of the proteomics data, activating transcription factor 2 (ATF-2) and c-Jun kinase (JNK) were found to be the key components in DHE's modulated biological pathways. Based on the pathway analysis as well as chemical similarity to estradiol, DHE is proposed to be a phytoestrogen. The proteomic, bioinformatic, and chemoinformatic analyses were further verified with individual cell-based experiments. Our study demonstrates a workflow for identifying the mechanisms of action of DHE through shotgun proteomic analysis.
Subject(s)
Antineoplastic Agents/pharmacology , Phenanthrenes/pharmacology , Phytochemicals/pharmacology , Activating Transcription Factor 2/metabolism , JNK Mitogen-Activated Protein Kinases/metabolism , Neoplasms/pathology , Phytoestrogens , Poaceae/chemistry , Proteomics/methods , Signal Transduction/drug effectsABSTRACT
Two classes of cationic palladium(II) acetylide complexes containing pincer-type ligands, 2,2':6',2''-terpyridine (terpy) and 2,6-bis(1-butylimidazol-2-ylidenyl)pyridine (C^N^C), were prepared and structurally characterized. Replacing terpy with the strongly σ-donating C^N^C ligand with two N-heterocyclic carbene (NHC) units results in the PdII acetylide complexes displaying phosphorescence at room temperature and stronger intermolecular interactions in the solid state. X-ray crystal structures of [Pd(terpy)(C≡CPh)]PF6 (1) and [Pd(C^N^C)(C≡CPh)]PF6 (7) reveal that the complex cations are arranged in a one-dimensional stacking structure with pair-like PdII â â â PdII contacts of 3.349â Å for 1 and 3.292â Å for 7. Density functional theory (DFT) and time-dependent density functional theory (TD-DFT) calculations were used to examine the electronic properties. Comparative studies of the [Pt(L)(C≡CPh)]+ analogs by 1 Hâ NMR spectroscopy shed insight on the intermolecular interactions of these PdII acetylide complexes. The strong Pd-Ccarbene bonds render 7 and its derivative sufficiently stable for investigation of photo-cytotoxicity under cellular conditions.
Subject(s)
Coordination Complexes/pharmacology , Palladium/pharmacology , Photosensitizing Agents/pharmacology , Pyridines/pharmacology , Quantum Theory , Apoptosis/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Coordination Complexes/chemical synthesis , Coordination Complexes/chemistry , Crystallography, X-Ray , Dose-Response Relationship, Drug , Humans , Ligands , Models, Molecular , Molecular Structure , Palladium/chemistry , Photochemical Processes , Photosensitizing Agents/chemical synthesis , Photosensitizing Agents/chemistry , Pyridines/chemistry , Structure-Activity RelationshipABSTRACT
A macrocyclic ruthenium(III) complex [RuIII (N2 O2 )Cl2 ]Cl (Ru-1) is reported as an inhibitor of angiogenesis and an anti-tumor compound. The complex is relatively non-cytotoxic towards endothelial and cancer cell lines inâ vitro, but specifically inhibited the processes of angiogenic endothelial cell tube formation and cancer cell invasion. Moreover, compared with known anti-cancer ruthenium complexes, Ru-1 is distinct in that it suppressed the expression of vascular endothelial growth factor receptor-2 (VEGFR2), and the associated downstream signaling that is crucial to tumor angiogenesis. In addition, inâ vivo studies showed that Ru-1 inhibited angiogenesis in a zebrafish model and suppressed tumor growth in nude mice bearing cancer xenografts.
Subject(s)
Angiogenesis Inhibitors/pharmacology , Antineoplastic Agents/pharmacology , Coordination Complexes/pharmacology , Macrocyclic Compounds/pharmacology , Neovascularization, Pathologic/drug therapy , Ruthenium/pharmacology , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Angiogenesis Inhibitors/chemistry , Animals , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Coordination Complexes/chemistry , Dose-Response Relationship, Drug , Down-Regulation/drug effects , Drug Screening Assays, Antitumor , Female , Human Umbilical Vein Endothelial Cells/drug effects , Humans , Macrocyclic Compounds/chemistry , Mammary Neoplasms, Experimental/drug therapy , Mammary Neoplasms, Experimental/pathology , Mice , Mice, Nude , Neovascularization, Pathologic/pathology , Ruthenium/chemistry , Structure-Activity Relationship , Vascular Endothelial Growth Factor Receptor-2/metabolism , ZebrafishABSTRACT
The inhibition of amyloid ß (Aß) peptide production is a key approach in the development of therapeutics for the treatment of Alzheimer's disease (AD). We have identified that timosaponins consisting of sarsasapogenin (SSG) as the aglycone can effectively lower the production of Aß peptides and stimulate neurite outgrowth in neuronal cell cultures. Structure-activity relationship studies revealed that the cis-fused AB ring, 3ß-configuration, spiroketal F-ring and 25S-configuration of SSG are the essential structural features responsible for the Aß-lowering effects and neurite-stimulatory activity. New synthetic derivatives that retain the SSG scaffold also exhibited an Aß lowering effect. Treatment of cells with timosaponins led to modulation of amyloid precursor protein (APP) processing through the suppression of ß-cleavage and preferential lowering of the production of the 42-amino acid Aß species (Aß42) without affecting another γ-secretase substrate. The SSG and "SSG-aglyconed" timosaponins also penetrated brain tissue and lowered brain Aß42 levels in mice. Our studies demonstrate that timosaponins represent a unique class of steroidal saponins that may be useful for the development of AD therapeutics.
ABSTRACT
In recent years a blossoming interest in the synthesis, photophysics and application of phosphorescent Pt(ii) complexes, particularly on their uses in bioimaging, photocatalysis and phosphorescent organic light-emitting diodes (OLEDs), has been witnessed. The superior performance of phosphorescent Pt(ii) complexes in these applications is linked to their diverse spectroscopic and photophysical properties, which can be systematically modulated by appropriate choices of auxiliary ligands. Meanwhile, an important criterion for the practical application of phosphorescent metal complexes is their stability which is crucial for biological utilization and industrial OLED applications. Taking both the luminescence properties and stability into consideration, chelating ligands having rigid scaffolds and with strong σ-donor atoms are advantageous for the construction of highly robust phosphorescent Pt(ii) complexes. The square-planar coordination geometry endows Pt(ii) complexes with the intriguing spectroscopic and photophysical properties associated with their intermolecular interactions in both the ground and excited states. In this article, we discuss the design and synthesis of phosphorescent Pt(ii) complexes with elaboration on the effects of ligands on the structure and luminescence properties. Based on their photophysical and emission properties, we intend to shed light on the great promise of highly robust phosphorescent Pt(ii) emitters in an array of applications from molecular materials to biosensors.
ABSTRACT
Luminescent pincer-type Pt(II) â complexes supported by C-deprotonated π-extended tridentate RC^N^NR' ligands and pentafluorophenylacetylide ligands show emission quantum yields up to almost unity. Femtosecond time-resolved fluorescence measurements and time-dependent DFT calculations together reveal the dependence of excited-state structural distortions of [Pt(RC^N^NR')(CC-C6 F5 )] on the positional isomers of the tridentate ligand. Ptâ complexes [Pt(R-C^N^NR')(CC-Ar)] are efficient photocatalysts for visible-light-induced reductive CC bond formation. The [Pt(R-C^N^NR')(CC-C6 F5 )] complexes perform strongly as phosphorescent dopants for green- and red-emitting organic light-emitting diodes (OLEDs) with external quantum efficiency values over 22.1 %. These complexes are also applied in two-photon cellular imaging when incorporated into mesoporous silica nanoparticles (MSNs).
ABSTRACT
Two cytotoxic iron(II) complexes [Fe(L)(CH3 CN)n ](ClO4 )2 (L=qpy for Fe-1 a, Py5 -OH for Fe-2 a) were synthesized. Both complexes are stable against spontaneous demetalation and oxidation in buffer solutions. Cyclic voltammetry measurements revealed the higher stability of Fe-2 a (+0.82â V vs Fc) against Fe(II) to Fe(III) oxidation than Fe-1 a (+0.57â V vs Fc). These two complexes display potent cytotoxicity at micromolar level against a panel of cancer cell lines (Fe-1 a=0.8-3.1â µM; Fe-2 a=0.6-3.4â µM), and induce apoptosis that involves caspase activation. Transcriptomic and Connectivity Map analyses revealed that the changes of gene expression induced by Fe-1 a and Fe-2 a are similar to that induced by ciclopirox, an antifungal compound whose mode of action involves formation of intracellular cytotoxic iron chelates. Both Fe-1 a and Fe-2 a caused cellular nuclear DNA damage, as revealed by Comet assay and H2 AX immunofluorescence experiments. The cytotoxicity is associated with production of reactive oxygen species (for Fe-1 a), cell cycle regulation, and stress kinase pathways. The relative contributions of these to the overall cytotoxic mechanism is significantly affected by the structure of penta-N-donor ligand.
Subject(s)
DNA Damage/genetics , Iron/chemistry , Apoptosis , Cell Culture Techniques , Gene Expression Profiling , HeLa Cells , Humans , Ligands , Reactive Oxygen Species , TranscriptomeABSTRACT
Construction of delivery systems for anticancer gold complexes to decrease their toxicity while maintaining efficacy is a key strategy to optimize and develop anticancer gold medicines. Herein, we describe cancer-targeted mesoporous silica nanoparticles (MSN) for delivery of a gold(III) porphyrin complex (Au-1 a@MSN(R)) to enhance its anticancer efficacy and selectivity between cancer and normal cells. Encapsulation of Au-1 a within mesoporous silica nanoparticles amplifies its inhibitory effects on thioredoxin reductase (TrxR), resulting in a loss of redox balance and overproduction of reactive oxygen species (ROS). Elevated cellular oxidative stress activates diversified downstream ROS-mediated signaling pathways, leading to enhanced apoptosis-inducing efficacy.