Zhen-Zhen Dong

An Aldol Reaction-Based Iridium(III) Chemosensor for the Visualization of Proline in Living Cells

A long-lived aldol reaction-based iridium(III) chemosensor [Ir(ppy)2(5-CHOphen)]PF6 (1, where ppy = 2-phenylpyridine and 5-CHOphen = 1,10-phenanthroline-5-carbaldehyde) for proline detection has been synthesized. The iridium(III) complex 1, incorporating an aldehyde group in N^N donor ligand, can take part in aldol reaction with acetone mediated by proline. The transformation of the sp2-hybridized carbonyl group into a sp3-hybridized alcohol group influences the metal-to-ligand charge-transfer (MLCT) state of the iridium(III) complex, resulting in a change in luminescence in response to proline. The interaction of the iridium(III) complex 1 with proline was investigated by 1H NMR, HRMS and emission titration experiments. Upon the addition of proline to a solution of iridium(III) complex 1, a maximum 8-fold luminescence enhancement was observed. The luminescence signal of iridium(III) complex 1 could be recognized in strongly fluorescent media using time-resolved emission spectroscopy (TRES). The detection of proline in living cells was also demonstrated.

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.

A long-lived phosphorescence iridium(III) complex as a switch on-off-on probe for live zebrafish monitoring of endogenous sulfide generation

In this work, we report a novel iridium(III)-based luminescent switch on-off-on probe, for the in vitro and in vivo detection of sulfide ion. The mechanism of this platform is based on the effective charge transfer quenching of the iridium(III) complex 1 by Fe3+, followed by the restoration of luminescence upon the addition of Na2S. The probe, hereinafter referred to as 1-Fe3+, exhibited a linear range of detection for Na2S from 0.01 to 1.5mM, with a detection limit of 2.9μM at signal-to-noise ratio (S/N) of 3. We also demonstrate the utility of 1-Fe3+ for cell-based imaging as well as for the detection of enzymatic sulfide generation in living zebrafish.

A suspending-droplet mode paper-based microfluidic platform for low-cost, rapid, and convenient detection of lead(II) ions in liquid solution

A paper-based microfluidic device based on unconventional principle was developed and used to detect lead ions through a two-step process including heated incubation and subsequent mixing. The device was made by generating a superhydrophobic pattern, which defines channel and reservoir barriers, on a water-impermeable paper substrate, followed by loading and drying the reagents in the defined reservoirs. Different from the conventional paper-based devices that are made of water-permeable paper, the as-prepared device holds water drops in discrete reservoirs, and the water drops will not move unless the device is titled along the direction of the predefined channels. In this way, the liquid samples applied onto the device are handled as individual drops and could be stored, transported, and mixed on demand. Different from the conventional paper-based devices that use capillary force to drive liquid, our new device uses wetting and gravity as driving force. We name this operation principle suspending-droplet mode paper-based device (SD-μPAD). The use of a Teflon contact-printing stamp makes the production of such devices rapid, cost efficient, and mass productive. Utilizing a G-quadruplex-based luminescence switch-on assay, we demonstrated rapid, convenient, highly sensitive, and low cost detection of lead(II) ions in water samples, using a custom made battery-powered portable device, and a smart phone as the detector.

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.

Turn-on Luminescent Probe for Hydrogen Peroxide Sensing and Imaging in Living Cells based on an Iridium(III) Complex–Silver Nanoparticle Platform

A sensitive turn-on luminescent sensor for H2O2 based on the silver nanoparticle (AgNP)-mediated quenching of an luminescent Ir(III) complex (Ir-1) has been designed. In the absence of H2O2, the luminescence intensity of Ir-1 can be quenched by AgNPs via non-radiative energy transfer. However, H2O2 can oxidize AgNPs to soluble Ag+ cations, which restores the luminescence of Ir-1. The sensing platform displayed a sensitive response to H2O2 in the range of 0−17 μM, with a detection limit of 0.3 μM. Importantly, the probe was successfully applied to monitor intracellular H2O2 in living cells, and it also showed high selectivity for H2O2 over other interfering substances.

The Development of G‐Quadruplex‐Based Assays for the Detection of Small Molecules and Toxic Substances

G-Quadruplexes can be induced to form guanine-rich DNA sequences by certain small molecules or metal ions. In concert with an appropriate signal transducer, such as a fluorescent dye or a phosphorescent metal complex, the ligand-recognition event can be transduced into a luminescent response. This focus review aims to highlight recent examples of aptamer-based and metal-mediated G-quadruplex assays for the detection of small molecules and toxic substances in the last three years. We discuss the mechanisms and features of the different assays and present an outlook and a perspective for the future of this field.

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 groups 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.