Chun-Yuen Wong

A Metal-Based Inhibitor of Tumor Necrosis Factor-α†

Staying in the pocket: A cyclometalated iridium(III) biquinoline complex targets the protein-protein interface (see picture; C yellow, N blue, Ir dark green) of the tumor necrosis factor-α (TNF-α) trimer. Molecular-modeling studies confirm the nature of this interaction. Both enantiomers of the iridium complex display comparable in vitro potency to the strongest small-molecule inhibitor of TNF-α.

Insight into the electrochemical activation of carbon-based cathodes for hydrogen evolution reaction

Recently, carbon nanomaterials with outstanding electrocatalytic performance for the hydrogen evolution reaction (HER) after electrochemical activation have been reported; however, the exact activation mechanism is still under extensive debate. In this study, to better understand the activation, graphite rods and carbon nanohorns, two typical carbon materials in different scales, were electrochemically activated and their catalytic performances in HER were systematically studied, which showed that the HER performance was greatly affected by the counter electrode employed for the activation. An efficient activation was achieved when a platinum wire was used as the counter electrode; simultaneously, Pt transfer from the anode to the cathode was also observed. These results suggest that the improved HER performance was mainly caused by the Pt transfer, rather than the activation of the carbon materials themselves. More importantly, our study implied that the Pt dissolution, although widely ignored, should be taken into consideration during electrochemical tests when Pt metal is utilized as the counter electrode.

Structure-based optimization of FDA-approved drug methylene blue as a c-myc G-quadruplex DNA stabilizer

G-quadruplexes are non-canonical DNA secondary structures putatively present in the promoter regions of oncogenes in the human genome. The targeting of promoter G-quadruplex structures to repress oncogene transcription represents a potential anticancer strategy. Here, we have used high-throughput virtual screening to identify FDA-approved drug methylene blue (MB) as a promising scaffold for binding the c-myc oncogene G-quadruplex DNA. Based on molecular docking analysis of MB to the c-myc G-quadruplex, we designed and screened 50 MB derivatives containing side chains that could interact with the G-quadruplex grooves. As a proof-of-concept, the highest-scoring compounds were synthesized and the interactions with the c-myc G-quadruplex were investigated using the FID assay. The results showed that the methylene blue derivatives 6a-c were able to bind to the c-myc G-quadruplex with greater binding affinity compared to the known G-quadruplex binding ligand, crystal violet. The activity of the most potent compound identified from the FID assay, 6b, as an inhibitor for polymerase-drive DNA extension was examined using a PCR-stop assay and compared against that of the parent compound methylene blue. The results of the PCR-stop assay showed that the addition of the side chain improved the activity of the derivatives as an inhibitor compared to the parent compound. The MB derivative 6b was shown to be highly selective towards c-myc G-quadruplex over double-stranded DNA and other biologically relevant G-quadruplexes using UV-visible spectroscopy and mass spectrometry, respectively. The MB derivative 6b could induce or stabilize c-myc G-quadruplex formation in both cell-free and cellular biological models, and displayed higher cytoxicity against human hepatocarcinoma cells compared to the parent compound, MB.

Rational Design of Inverted Nanopencil Arrays for Cost-effective, Broadband and Omnidirectional Light Harvesting

Due to the unique optical properties, three-dimensional arrays of silicon nanostructures have attracted increasing attention as the efficient photon harvesters for various technological applications. In this work, instead of dry etching, we have utilized our newly developed wet anisotropic etching to fabricate silicon nanostructured arrays with different well-controlled geometrical morphologies, ranging from nanopillars, nanorods, and inverted nanopencils to nanocones, followed by systematic investigations of their photon-capturing properties combining experiments and simulations. It is revealed that optical properties of these nanoarrays are predominantly dictated by their geometrical factors including the structural pitch, material filling ratio, and aspect ratio. Surprisingly, along with the proper geometrical design, the inverted nanopencil arrays can couple incident photons into optical modes in the pencil base efficiently in order to achieve excellent broadband and omnidirectional light-harvesting performances even with the substrate thickness down to 10 μm, which are comparable to the costly and technically difficult to achieve nanocone counterparts. Notably, the fabricated nanopencils with both 800 and 380 nm base diameters can suppress the optical reflection well below 5% over a broad wavelength of 400-1000 nm and a wide angle of incidence between 0 and 60°. All these findings not only offer additional insight into the light-trapping mechanism in these complex 3D nanophotonic structures but also provide efficient broadband and omnidirectional photon harvesters for next-generation cost-effective ultrathin nanostructured photovoltaics.

Surfactant-assisted chemical vapour deposition of high-performance small-diameter GaSb nanowires

Although various device structures based on GaSb nanowires have been realized, further performance enhancement suffers from uncontrolled radial growth during the nanowire synthesis, resulting in non-uniform and tapered nanowires with diameters larger than few tens of nanometres. Here we report the use of sulfur surfactant in chemical vapour deposition to achieve very thin and uniform GaSb nanowires with diameters down to 20 nm. In contrast to surfactant effects typically employed in the liquid phase and thin-film technologies, the sulfur atoms contribute to form stable S-Sb bonds on the as-grown nanowire surface, effectively stabilizing sidewalls and minimizing unintentional radial nanowire growth. When configured into transistors, these devices exhibit impressive electrical properties with the peak hole mobility of ~200 cm(2 )V(-1 )s(-1), better than any mobility value reported for a GaSb nanowire device to date. These factors indicate the effectiveness of this surfactant-assisted growth for high-performance small-diameter GaSb nanowires.

Visualization of Zn2+ ions in live zebrafish using a luminescent iridium(III) chemosensor

A novel luminescent cyclometalated iridium(III) complex-based chemosensor (1) bearing a zinc-specific receptor, tris(2-pyridylmethyl)amine, and the 3-phenyl-1H-pyrazole ligand has been designed and synthesized. Upon the addition of Zn(2+) ions to a solution of iridium(III) complex 1, a pronounced luminescence color change from blue to green can be observed, which may be attributed to the suppression of photoinduced electron transfer upon complexation of complex 1 with Zn(2+) ions. The interaction of iridium(III) complex 1 with Zn(2+) ions was investigated by UV-vis absorption titration, emission titration, and (1)H NMR titration. Furthermore, the iridium(III) complex 1 exhibited good selectivity for Zn(2+) over 13 other common metal ions, including K(+), Ag(+), Na(+), Ni(2+), Fe(3+), Hg(2+), Cd(2+), Mg(2+), Ca(2+), Cu(2+), Mn(2+), Co(2+), and Pb(2+) ions. The practical application of the iridium(III) complex 1 in visualizing intracellular Zn(2+) distribution in live zebrafish was also demonstrated.

Structure‐Based Repurposing of FDA‐Approved Drugs as TNF‐α Inhibitors

High-throughput screening (HTS) of chemical libraries has established itself as a cornerstone of pharmaceutical research. However, notable drawbacks to HTS-based approaches include low hit rates for many targets, as well as significant levels of false positives and false negatives. Furthermore, many drug leads identified through HTS are later found to suffer from poor bioavailability and/or high toxicity, leading to expensive failures during late-stage clinical development. This problem has been partially addressed through the development of biased chemical libraries favoring drug-like or natural productlike structures. It has been estimated that the average drug requires 15 years and 800 million US dollars to bring to the market. This cost can be dramatically reduced by reoptimizing existing drugs for their secondary effects, a technique known as “drug repurposing”. Approved drugs tend to have established pharmacokinetic and pharmacodynamic profiles, and their safety in human subjects will have already been extensively tested as part of the approval process. Therefore, the collection of marketed drugs can also be considered as a validated library of privileged structures. In order to repurpose existing drugs, the secondary or “off-target” effects of the compound must first be identified. Virtual screening has emerged as a powerful tool for predicting drug–biomolecule interactions, complementing traditional HTS techniques. By identifying candidate structures in silico, the numbers of compounds to be tested in vitro can be greatly reduced. The combination of virtual screening and repurposing potentially represents a very efficient method for the identification of drug leads with favorable absorption, delivery, metabolism and excretion (ADME) profiles. For example, Abagyan and co-workers used a virtual screening approach to discover nonsteroidal antagonists of the human androgen receptor from a database of marketed drugs. Tumor necrosis factor-a (TNF-a) is an important human cytokine that mediates a variety of immune functions including inflammation, infection and anticancer responses. However, abnormalities in TNF-a signaling have been linked to increased incidences of autoinflammatory diseases, such as rheumatoid arthritis, psoriatic arthritis, and Crohn’s disease. Anti-TNF-a biologics currently on the market for the treatment of inflammatory diseases, such as the synthetic antibodies etanercept, infliximab, and adalimumab, can elicit serious autoimmune antiantibody responses. However, despite considerable incentives, few small molecules directly targeting TNF-a have been reported. Using structure-based high-throughput virtual screening, we recently reported the discovery of the third and fourth examples of small molecules that are able to directly inhibit TNF-a, as well as small-molecule ligands for other biologically relevant targets such as the c-myc G-quadruplex and NEDD8-activating enzyme. Inspired by these successes, we set out to apply our structure-based, high-throughput virtual screening methods to identify small-molecule inhibitors of TNF-a from a library of marketed drugs. Over 3 000 compounds in a database of US Food and Drug Administration (FDA)-approved drugs were screened in silico in order to identify existing drugs that could potentially be repurposed as effective TNF-a inhibitors. We used the X-ray co-crystal structure of the TNF-a dimer bound by a previously reported small-molecule inhibitor SPD304 (3 ; PDB: 2AZ5) as the molecular model for our investigations. Using the iterated conditional modes (ICM) method [ICM-Pro 3.6-1d molecular docking software (Molsoft)] , the continuously flexible ligands were docked to a grid representation of the receptor and assigned a score reflecting the quality of the complex. Seven high-scoring compounds from the virtual screening results were chosen and tested in a preliminary enzyme-linked immunosorbent assay (ELISA) to assess their ability to inhibit the binding of TNF-a to its cognate receptor. The FDA-approved drugs darifenacin (1) and ezetimibe (2) emerged as the top candidates.

Developing controllable anisotropic wet etching to achieve silicon nanorods, nanopencils and nanocones for efficient photon trapping

Controllable hierarchy of highly regular, single-crystalline nanorod, nanopencil and nanocone arrays with tunable geometry and etch anisotropy has been achieved over large areas (>1.5 cm × 1.5 cm) by using an [AgNO3 + HF + HNO3/H2O2] etching system. The etching mechanism has been elucidated to originate from the site-selective deposition of Ag nanoclusters. Different etch anisotropies and aspect ratios can be accomplished by modulating the relative concentration in the [AgNO3 + HF + HNO3/H2O2] etching system. Minimized optical reflectance is also demonstrated with the fabricated nano-arrays. Overall, this work highlights the technological potency of utilizing a simple wet-chemistry-only fabrication scheme, instead of reactive dry etching, to attain three-dimensional Si nanostructures with different geometrical morphologies for applications requiring large-scale, low-cost and efficient photon trapping (e.g. photovoltaics).

Crystalline GaSb Nanowires Synthesized on Amorphous Substrates: From the Formation Mechanism to p-Channel Transistor Applications

In recent years, because of the narrow direct bandgap and outstanding carrier mobility, GaSb nanowires (NWs) have been extensively explored for various electronics and optoelectronics. Importantly, these p-channel nanowires can be potentially integrated with n-type InSb, InAs, or InGaAs NW devices via different NW transfer techniques to facilitate the III-V CMOS technology. However, until now, there have been very few works focusing on the electronic transport properties of GaSb NWs. Here, we successfully demonstrate the synthesis of crystalline, stoichiometric, and dense GaSb NWs on amorphous substrates, instead of the commonly used III-V crystalline substrates, InAs, or GaAs NW stems as others reported. The obtained NWs are found to grow via the VLS mechanism with a narrow distribution of diameter (220 ± 50 nm) uniformly along the entire NW length (>10 μm) with minimal tapering and surface coating. Notably, when configured into FETs, the NWs exhibit respectable electrical characteristics with the peak hole mobility of ~30 cm(2) V(-1) s(-1) and free hole concentration of ~9.7 × 10(17) cm(-3). All these have illustrated the promising potency of such NWs directly grown on amorphous substrates for various technological applications, as compared with the conventional MOCVD-grown GaSb NWs.

Phosphorescent Imaging of Living Cells Using a Cyclometalated Iridium(III) Complex

A cell permeable cyclometalated iridium(III) complex has been developed as a phosphorescent probe for cell imaging. The iridium(III) solvato complex [Ir(phq)2(H2O]2)] preferentially stains the cytoplasm of both live and dead cells with a bright luminescence.