Peptide-Conjugated Long-Lived Theranostic Imaging for Targeting GRPr in Cancer and Immune Cells.

Gastrin-releasing peptide receptor (GRPr) plays proliferative and inflammatory roles in living systems. Here, we report a highly selective GRPr antagonist (JMV594)-tethered iridium(III) complex for probing GRPr in living cancer cells and immune cells. This probe exhibited desirable photophysical properties and also displayed negligible cytotoxicity, overcoming the inherent toxicity of the iridium(III) complex. Its long emission lifetime enabled its luminescence signal to be readily distinguished from the interfering fluorescence of organic dyes by using a time-resolved technique. This probe selectively visualized living cancer cells via specific binding to GRPr, while it also modulated the function of GRPr on TNF-α secretion in immune cells. To our knowledge, this is the first peptide-conjugated iridium(III) complex developed as a GRPr bioimaging probe and modulator of GRPr activity. This theranostic agent shows great potential at unmasking the diverse roles of GRPr in living systems.

A long-lived peptide-conjugated iridium(iii) complex as a luminescent probe and inhibitor of the cell migration mediator, formyl peptide receptor 2.

Formyl peptide receptors play important biological and therapeutic roles in wound repair and inflammatory diseases. In this work, we present a luminescent iridium(iii) complex (6) conjugated with the peptide agonist WKYMVm as a luminescent formyl peptide receptor 2 (FPR2) imaging probe in living cells. Complex 6 displayed ideal cell imaging characteristics, high photostability and low cytotoxicity. Competition assays with a known FPR2 antagonist, WRW4, and siRNA knockdown experiments both revealed that complex 6 selectively targeted FPR2 in living HUVEC cells. Moreover, complex 6 regulated FPR2 signalling in HUVEC cells as shown using a mechanical scratch assay. Finally, complex 6 reduced epithelial cell migration capacity and inhibited lipoxin A4 (LXA4)-triggered cell migration in HUVEC cells, demonstrating the ability of this complex to inhibit FPR2 in living cells. To our knowledge, this is the first long-lived probe for imaging FPR2 in living cells.

Iridium(iii) complexes as reaction based chemosensors for medical diagnostics.

Transition metal complexes have attracted interest in the fields of cancer therapy, medical and environmental detection, and materials of organic light-emitting diodes (OLED). Recently, iridium(iii) complexes have been explored in a reaction based way for luminescence monitoring and imaging due to their salient photophysical properties, including large Stokes shifts, long-lived luminescence and high luminescent quantum yields. This frontier article will introduce recent developments and applications of iridium(iii) complexes as luminescent probes for ions and biomolecules. Our outlook for this class of complexes is also discussed.

Recent progress and developments of iridium-based compounds as probes for environmental analytes.

Metal complexes based on iridium metal centers have attracted attention as probes due to their tunable biological and chemical characteristics. This review highlights recent examples of iridium-based compounds that have been developed as probes for various environmental analytes. We also discuss the further challenges to be overcome for this class of probes in the future.

Cell imaging of dopamine receptor using agonist labeling iridium(iii) complex.

Dopamine receptor expression is correlated with certain types of cancers, including lung, breast and colon cancers. In this study, we report luminescent iridium(iii) complexes (11-14) as intracellular dopamine receptor (D1R/D2R) cell imaging agents. Complexes 11 and 13, which are conjugated with a dopamine receptor agonist, showed superior cell imaging characteristics, high stability and low cytotoxicity (>100 µM) in A549 lung cancer cells. siRNA knockdown and dopamine competitive assays indicated that complexes 11 and 13 could selectively bind to dopamine receptors (D1R/D2R) in A549 cells. Fluorescence lifetime microscopy demonstrated that complex 13 has a longer luminescence lifetime at the wavelength of 560-650 nm than DAPI and other chromophores in biological fluids. The long luminescence lifetime of complex 13 not only provides an opportunity for efficient dopamine receptor tracking in biological media, but also enables the temporal separation of the probe signal from the intense background signal by fluorescence lifetime microscopy for efficient analysis. Complex 13 also shows high photostability, which could allow it to be employed for long-term cellular imaging. Furthermore, complex 13 could selectively track the internalization process of dopamine receptors (D1R/D2R) in living cells. To the best of our knowledge, complex 13 is the first metal-based compound that has been used to monitor intracellular dopamine receptors in living cells.

Identification of a rhodium(iii) complex as a Wee1 inhibitor against TP53-mutated triple-negative breast cancer cells.

The rhodium(iii) complex 1 was identified as a potent Wee1 inhibitor in vitro and in cellulo. It decreased Wee1 activity and unscheduled mitotic entry, and induced cell damage and death in TP53-mutated triple-negative breast cancer cells. 1 represents a promising scaffold for further development of more potent metal-based Wee1 antagonists.

A long-lifetime iridium(iii) complex for lysosome tracking with high specificity and a large Stokes shift.

Investigating the role of lysosome dysfunction in cancer requires the development of efficient probes for lysosomes. We report herein a cyclometalated iridium(iii) complex (Ir-Ly) as a luminescent probe for visualizing lysosomes in cancer cells. The morpholine and hydroxy moieties within Ir-Ly provide suitable hydrophilicity and responsiveness to pH. Importantly, Ir-Ly exhibits a large Stokes shift, long lifetime and high photostability, which are important advantages for lysosome tracking in living cells.

Development of a Long-Lived Luminescence Probe for Visualizing ß-Galactosidase in Ovarian Carcinoma Cells.

ß-Galactosidase (ß-gal) is an important biomarker for ovarian cancers. In this work, we designed and synthesized a novel iridium(III)-based probe 1 for discriminating ovarian carcinoma cell lines from normal cell lines. The probe could detect ß-gal even in the presence of a highly autofluorescent background. The probe also showed a good linear response to ß-gal between 0 and 30 U/mL, with a detection limit of 0.51 U/mL. Importantly, complex 1 could selectively "light up" ovarian carcinoma cells, while exhibiting negligible luminescence in normal cells. Overall, complex 1 could be potentially used as a useful probe for detecting ß-gal expression in the context of ovarian cancer diagnostics.

Construction of a Nano Biosensor for Cyanide Anion Detection and Its Application in Environmental and Biological Systems.

We have developed a Ag@Au core-shell nanoparticle (NP)/iridium(III) complex-based sensing platform for the sensitive luminescence "turn-on" sensing of cyanide ions, an acutely toxic pollutant. The assay is based on the quenching effect of Ag@Au NPs on the emission of complex 1, but luminescence is restored after the addition of cyanide anions due to their ability to dissolve the Au shell. Our sensing platform exhibited a high sensitivity toward cyanide anions with a detection limit of 0.036 µM, and also showed high selectivity for cyanide over 10-fold excess amounts of other anions. The sensing platform was also successfully applied to monitor cyanide anions in drinking water and in living cells.

Luminescent turn-on detection of Hg(II) via the quenching of an iridium(III) complex by Hg(II)-mediated silver nanoparticles.

A novel luminescent turn-on detection method for Hg(II) was developed. The method was based on the silver nanoparticle (AgNP)-mediated quenching of Ir(III) complex 1. The addition of Hg(II) ions causes the luminescence of complex 1 to be recovered due to the oxidation of AgNPs by Hg(II) ions to form Ag(I) and Ag/Hg amalgam. The luminescence intensity of 1 increased in accord with an increased Hg(II) concentration ranging from 0 nM to 180 nM, with the detection limit of 5 nM. This approach offers an innovative method for the quantification of Hg(II).

A natural product-like JAK2/STAT3 inhibitor induces apoptosis of malignant melanoma cells.

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.

Recent development of transition metal complexes with in vivo antitumor activity.

The often severe side effects displayed by currently used platinum and ruthenium complexes have motivated researchers to design and develop transition metal-based anti-tumor agents with reduced toxicity. Distinct from organic anti-tumor drugs, transition metal complexes possess several properties that render them as promising scaffolds for anti-cancer drug discovery. While a vast number of metal complexes have been synthesized and reported to be promising and potent in vitro anticancer active compounds, fewer have shown efficacy in in vivo models. The demonstration of in vivo potency is an essential step for lead candidates for clinical trials. In this review, we highlight examples of transition metal-based complexes that have shown in vivo anti-tumor activities that have been described in recent years.

Luminescent Strategies for Label-Free G-Quadruplex-Based Enzyme Activity Sensing.

By catalyzing highly specific and tightly controlled chemical reactions, enzymes are essential to maintaining normal cellular physiology. However, aberrant enzymatic activity can be linked to the pathogenesis of various diseases. Therefore, the unusual activity of particular enzymes can represent testable biomarkers for the diagnosis or screening of certain diseases. In recent years, G-quadruplex-based platforms have attracted wide attention for the monitoring of enzymatic activities. In this Personal Account, we discuss our group's works on the development of G-quadruplex-based sensing system for enzyme activities by using mainly iridium(III) complexes as luminescent label-free probes. These studies showcase the versatility of the G-quadruplex for developing assays for a variety of different enzymes.

A reaction-based luminescent switch-on sensor for the detection of OH- ions in simulated wastewater.

A series of luminescent iridium(iii) complexes were synthesized and evaluated for their ability to interact with hydroxide ions in semi-aqueous media at ambient temperature. Upon the addition of OH-, a nucleophilic aromatic substitution reaction takes place at the bromine groups of the N^N ligand of complex 1, resulting in the generation of a yellow-green luminescence. Complex 1 showed a 35-fold enhanced emission at pH 14 when compared to neutral pH, and the detection limit for OH- ions was 4.96 µM. Complex 1 exhibited high sensitivity and selectivity, long-lived luminescence and impressive stability. Additionally, we have demonstrated the practical application of complex 1 to detect OH- ions in simulated wastewater.

A Rhodium(III)-Based Inhibitor of Lysine-Specific Histone Demethylase 1 as an Epigenetic Modulator in Prostate Cancer Cells.

We report herein a novel rhodium(III) complex 1 as a new LSD1 targeting agent and epigenetic modulator. Complex 1 disrupted the interaction of LSD1-H3K4me2 in human prostate carcinoma cells and enhanced the amplification of p21, FOXA2, and BMP2 gene promoters. Complex 1 was selective for LSD1 over other histone demethylases, such as KDM2b, KDM7, and MAO activities, and also showed antiproliferative activity toward human cancer cells. To date, complex 1 is the first metal-based inhibitor of LSD1 activity.

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.

A cyclometalated iridium(III) complex used as a conductor for the electrochemical sensing of IFN-γ.

A novel iridium(III) complex was prepared and used as a conductor for sensitive and enzyme-free electrochemical detection of interferon gamma (IFN-γ). This assay is based on a dual signal amplification mechanism involving positively charged gold nanoparticles ((+)AuNPs) and hybridization chain reaction (HCR). To construct the sensor, nafion (Nf) and (+)AuNPs composite membrane was first immobilized onto the electrode surface. Subsequently, a loop-stem structured capture probe (CP) containing a special IFN-γ interact strand was modified onto the (+)AuNP surface via the formation of Au-S bonds. Upon addition of IFN-γ, the loop-stem structure of CP was opened, and the newly exposed "sticky" region of CP then hybridized with DNA hairpin-1 (H1), which in turn opened its hairpin structure for hybridizing with DNA hairpin-2 (H2). Happen of HCR between H1 and H2 thus generated a polymeric duplex DNA (dsDNA) chain. Meanwhile, the iridium(III) complex could interact with the grooves of the dsDNA polymer, producing a strong current signal that was proportional to IFN-γ concentration. Thus, sensitive detection of IFN-γ could be realized with a detection limit down to 16.3 fM. Moreover, satisfied results were achieved by using this method for the detection of IFN-γ in human serum samples.

Multi-chelation approach towards natural product-like skeletons: one-pot access to a nitrogen-containing tetracyclic framework from AlaAla dipeptide.

Reductive transformation of the dipeptide BocAlaAlaOMe to a complex, internally charge-stabilized, natural product-like skeleton in one synthetic step is discussed. Stepwise replacement of the B-H bonds in borane by B-N or B-O resulted in incorporation of three boron atoms in a tetracyclic framework whereby one is stereogenic!