Wanhe Wang

Identification of an Iridium(III)-Based Inhibitor of Tumor Necrosis Factor-α

The novel iridium(III) complex 1 was verified as a potent inhibitor of the TNF-α-TNFR protein-protein interaction in vitro and in cellulo. The iridium(III) center plays a critical role in organizing the structure of the bioactive metal complex, as the isolated ligands were found to be completely inactive. Both iridium enantiomers inhibited TNF-α-induced NF-κB activity and TNF-α-TNFR binding. 1 represents a promising scaffold for the further development of more potent organometallic TNF-α inhibitors.

A luminescent cocaine detection platform using a split G-quadruplex-selective iridium(III) complex and a three-way DNA junction architecture

In this study, a series of 10 in-house cyclometalated iridium(III) complexes bearing different auxiliary ligands were tested for their selectivity toward split G-quadruplex in order to construct a label-free switch-on cocaine detection platform employing a three-way junction architecture and a G-quadruplex motif as a signal output unit. Through two rounds of screening, we discovered that the iridium(III) complex 7 exhibited excellent selectivity toward the intermolecular G-quadruplex motif. A detection limit as low as 30 nM for cocaine can be achieved by this sensing approach with a linear relationship between luminescence intensity and cocaine concentration established from 30 to 300 nM. Furthermore, this sensing approach could detect cocaine in diluted oral fluid. We hope that our simple, signal-on, label-free oligonucleotide-based sensing method for cocaine using a three-way DNA junction architecture could act as a useful platform in bioanalytical research.

An Ir(III) complex chemosensor for the detection of thiols

Abstract In this study, we report the use of a cyclometalated luminescent iridium(III) complex for the visualization of thiols. The detection of glutathione (GSH) by complex 1 is achieved through the reduction of its phendione N^N donor, which influences the metal-to-ligand charge-transfer (MLCT) of the complex. Complex 1 produced a maximum threefold luminescence enhancement at 587 nm in response to GSH. The linear detection range of 1 for GSH is between 0.2 and 2 M equivalents of GSH, with a detection limit of 1.67 μM. Complex 1 also displays good selectivity for thiols over other amino acids.

A G-quadruplex-selective luminescent probe with an anchor tail for the switch-on detection of thymine DNA glycosylase activity

Thymine DNA glycosylase (TDG) performs essential functions in maintaining genetic integrity and epigenetic regulation, which also plays an essential role in DNA demethylation. In this work, the novel iridium(III) complex 1 with an anchor tail was synthesized and employed to construct a G-quadruplex-based assay for detecting TDG activity in aqueous solution by using the mismatched base excising property of TDG with T4 DNA ligase and phi29 DNA polymerase, in concert with the rolling circle amplification (RCA) strategy. The assay achieved a detection limit of 0.048UmL(-)(1) (0.012ngmL(-1)), and showed high selectivity towards TDG even in the presence of other proteins and enzymes. Additionally, the assay could function in diluted cellular debris.

A Rhodium(III) Complex as an Inhibitor of Neural Precursor Cell Expressed, Developmentally Down-Regulated 8-Activating Enzyme with in Vivo Activity against Inflammatory Bowel Disease

We report herein the identification of the rhodium(III) complex [Rh(phq)2(MOPIP)]+ (1) as a potent and selective ATP-competitive neural precursor cell expressed, developmentally down-regulated 8 (NEDD8)-activating enzyme (NAE) inhibitor. Structure-activity relationship analysis indicated that the overall organometallic design of complex 1 was important for anti-inflammatory activity. Complex 1 showed promising anti-inflammatory activity in vivo for the potential treatment of inflammatory bowel disease.

A luminescent G-quadruplex-selective iridium(III) complex for the label-free detection of lysozyme

A novel Ir(iii) complex 1 displays high selectivity for the G-quadruplex, and was used to establish a label-free G-quadruplex-based detection platform for lysozyme in buffer. In this study, we employed a special feature of most G-quadruplex probes that they do not respond towards the TBA G-quadruplex. A duplex DNA with a TBA G-quadruplex tail was designed for the detection of lysozyme. The presence of lysozyme will induce duplex dissociation and release the hybridized c-kit87 G-quadruplex, which would be recognized by the Ir(iii) complex to generate a strong luminescence response. Common duplex DNA designs lacking a TBA G-quadruplex tail typically contain long complementary DNA regions that may be too stable to be dissociated, thus decreasing sensitivity. We anticipate that the presence of a TBA tail in the DNA duplex may destabilize the duplex structure, allowing the aptamer to be more easily dissociated and bind to the lysozyme, thereby increasing the sensitivity of the lysozyme detection platform. To our knowledge, this is the first example of the use of the TBA G-quadruplex to improve sensitivity through fine-tuning duplex stability. We believe that this approach may be further employed in sensing platforms for other targets. This assay exhibited a linear response for lysozyme within the concentration range of 2-50 nM (R2 = 0.9904), and the limit of detection for lysozyme was 2 nM. Moreover, this platform exhibited a potential use for biological sample analysis.

The application of a G-quadruplex based assay with an iridium(III) complex to arsenic ion detection and its utilization in a microfluidic chip

In this work, the iridium(iii) complex 1 was synthesized and employed in constructing an assay which is based on a G-quadruplex for detecting arsenic ions in aqueous solution. The assay achieved a detection limit of 7.6 nM (ca. 0.57 μg L-1) and showed high selectivity towards arsenic ions over other metal ions. Additionally, the assay could function in natural water and a simple microfluidic chip was used to investigate the potential of this platform for real-time detection.

Anticancer osmium complex inhibitors of the HIF-1α and p300 protein-protein interaction

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.

First Synthesis of an Oridonin‐Conjugated Iridium(III) Complex for the Intracellular Tracking of NF‐κB in Living Cells

NF-κB is a critical transcription factor that plays an important role in mediating inflammation, the immune response, and cell proliferation. The activation of NF-κB leads to an enhancement of proinflammatory mediator expression, which is implicated in the pathogenesis of a variety of diseases. Therefore, methods that allow the intracellular tracking of NF-κB are particularly attractive because they can provide information regarding the pathways or stimulation responses that are involved in the activation of NF-κB. In this work, we report a novel platform to track intracellular NF-κB by employing the conjugated iridium(III) complex 1, which was synthesized through the unique combination of a luminescent iridium(III) moiety with the natural product oridonin. Experiments conducted with p50 knockdown cells revealed that complex 1 could detect the p50 subunit of NF-κB in cellulo. Furthermore, complex 1 tracked NF-κB translocation induced by tumor necrosis factor-α (TNF-α) as a model stimulus, without affecting the translocation process itself. To the best of our knowledge, complex 1 is the first metal-based compound that has been reported to be capable of monitoring intracellular NF-κB in living cells.

Inhibition of the p53/hDM2 protein-protein interaction by cyclometallated iridium(III) compounds

Inactivation of the p53 transcription factor by mutation or other mechanisms is a frequent event in tumorigenesis. One of the major endogenous negative regulators of p53 in humans is hDM2, a ubiquitin E3 ligase that binds to p53 causing proteasomal p53 degradation. In this work, a library of organometallic iridium(III) compounds were synthesized and evaluated for their ability to disrupt the p53/hDM2 protein-protein interaction. The novel cyclometallated iridium(III) compound 1 [Ir(eppy)2(dcphen)](PF6) (where eppy = 2-(4-ethylphenyl)pyridine and dcphen = 4, 7-dichloro-1, 10-phenanthroline) blocked the interaction of p53/hDM2 in human amelanotic melanoma cells. Finally, 1 exhibited anti-proliferative activity and induced apoptosis in cancer cell lines consistent with inhibition of the p53/hDM2 interaction. Compound 1 represents the first reported organometallic p53/hDM2 protein-protein interaction inhibitor.