C.H. Leung

Cyclometalated gold(III) complexes with N-heterocyclic carbene ligands as topoisomerase I poisons

A panel of stable [Au(R-C--N--C)(N-heterocyclic carbene)](+) complexes displays prominent in vitro anticancer properties; [Au(C--N--C)(IMe)]CF(3)SO(3) (1, IMe = 1,3-dimethylimidazol-2-ylidene) significantly poisons topoisomerase I in vitro and suppresses tumor growth in nude mice model.

Stable Anticancer Gold(III)–Porphyrin Complexes: Effects of Porphyrin Structure

In the design of physiologically stable anticancer gold(III) complexes, we have employed strongly chelating porphyrinato ligands to stabilize a gold(III) ion [Chem. Commun. 2003, 1718; Coord. Chem. Rev. 2009, 253, 1682]. In this work, a family of gold(III) tetraarylporphyrins with porphyrinato ligands containing different peripheral substituents on the meso-aryl rings were prepared, and these complexes were used to study the structure-bioactivity relationship. The cytotoxic IC(50) values of [Au(Por)](+) (Por=porphyrinato ligand), which range from 0.033 to >100 microM, correlate with their lipophilicity and cellular uptake. Some of them induce apoptosis and display preferential cytotoxicity toward cancer cells than to normal noncancerous cells. A new gold(III)-porphyrin with saccharide conjugation [Au(4-glucosyl-TPP)]Cl (2a; H(2)(4-glucosyl-TPP)=meso-tetrakis(4-beta-D-glucosylphenyl)porphyrin) exhibits significant cytostatic activity to cancer cells (IC(50)=1.2-9.0 microM) without causing cell death and is much less toxic to lung fibroblast cells (IC(50)>100 microM). The gold(III)-porphyrin complexes induce S-phase cell-cycle arrest of cancer cells as indicated by flow cytometric analysis, suggesting that the anticancer activity may be, in part, due to termination of DNA replication. The gold(III)-porphyrin complexes can bind to DNA in vitro with binding constants in the range of 4.9 x 10(5) to 4.1 x 10(6) dm(3) mol(-1) as determined by absorption titration. Complexes 2a and [Au(TMPyP)]Cl(5) (4a; [H(2)TMPyP](4+)=meso-tetrakis(N-methylpyridinium-4-yl)porphyrin) interact with DNA in a manner similar to the DNA intercalator ethidium bromide as revealed by gel mobility shift assays and viscosity measurements. Both of them also inhibited the topoisomerase I induced relaxation of supercoiled DNA. Complex 4a, a gold(III) derivative of the known G-quadruplex-interactive porphyrin [H(2)TMPyP](4+), can similarly inhibit the amplification of a DNA substrate containing G-quadruplex structures in a polymerase chain reaction stop assay. In contrast to these reported complexes, complex 2a and the parental gold(III)-porphyrin 1a do not display a significant inhibitory effect (<10%) on telomerase. Based on the results of protein expression analysis and computational docking experiments, the anti-apoptotic bcl-2 protein is a potential target for those gold(III)-porphyrin complexes with apoptosis-inducing properties. Complex 2a also displays prominent anti-angiogenic properties in vitro. Taken together, the enhanced stabilization of the gold(III) ion and the ease of structural modification render porphyrins an attractive ligand system in the development of physiologically stable gold(III) complexes with anticancer and anti-angiogenic activities.

Structure‐Based Discovery of Natural‐Product‐like TNF‐α Inhibitors

Small but effective: two natural-product-like inhibitors of tumor necrosis factor α (TNF-α; represented in green in the picture) have been identified using structure-based virtual screening. These compounds represent only the third and fourth examples of direct targeting of TNF-α by a small molecule, and display potency comparable to that of the strongest TNF-α inhibitor reported to date.

A selective G-quadruplex-based luminescent switch-on probe for the detection of nanomolar silver(I) ions in aqueous solution.

A G-quadruplex-based luminescent platinum(II) switch-on probe has been developed for the selective detection of nanomolar Ag(+) ions in aqueous solution.

A selective oligonucleotide-based luminescent switch-on probe for the detection of nanomolar mercury(II) ion in aqueous solution

An oligonucleotide-based luminescent platinum(II) switch-on probe has been developed for selective detection of nanomolar Hg(2+) ions.

Identification of natural product Fonsecin B as a stabilizing ligand of c-myc G-quadruplex DNA by high-throughput virtual screening

Fonsecin B has been identified as stabilizing ligand of c-myc G-quadruplex DNA using high-throughput virtual screening of a natural product database, and inhibited Taq polymerase-mediated DNA extension in vitro through stabilization of the G-quadruplex secondary structure.

Butyrate mediates nucleotide‐binding and oligomerisation domain (NOD) 2‐dependent mucosal immune responses against peptidoglycan

The interaction between digestive tract microbiological flora and food has an important influence on human health. Butyrate is produced during the fermentation of dietary fibres by intestinal bacteria and plays an important role in the regulation of mucosal immunity. In this report, we studied the impact of butyrate on the defence mechanism against the bacterial membrane component peptidoglycan (PGN). Butyrate was found to enhance PGN‐mediated IL‐8 and GRO‐α production. The expression of these chemokines required the activation of NF‐κB and was dependent on the concentrations of butyrate and PGN. Butyrate was found to up‐regulate nucleotide‐binding and oligomerisation domain (NOD) 2, but not NOD1 or TLR2. NOD2 up‐regulation was mediated by an increase in histone acetylation in the Nod2 promoter region, leading to enhanced PGN‐induced IL‐8 and GRO‐α secretion. Knockdown of NOD2 and TLR2 by siRNA significantly reduced PGN‐mediated chemokine production, suggesting that both NOD2 and TLR2 are required for maximal response. Our findings provide a better understanding of the mechanism by which butyrate regulates mucosal immunity for normal intestinal function. Based on the results of this study, we infer that dietary fibres can impact inflammatory bowel diseases.

Cyclometalated platinum(II) complexes as topoisomerase IIα poisons.

A platinum(II)-based major groove binder [Pt(II)(C^N)(C≡NR)(2)](+) (HC^N = 2-phenylpyridine (phpy), R = 2-naphthyl) was identified as a potent human topoisomerase IIα poison. It stabilizes the covalent TopoIIα-DNA cleavage complex and induces cancer cell death with potency significantly higher than the widely clinically used TopoIIα poison Vp-16.

Correlation between carrier mobility of pentacene thin-film transistor and surface passivation of its gate dielectric

The carrier mobility of pentacene thin-film transistor is studied by passivating the surface of its SiO2 gate dielectric in NH3 at different temperatures, namely, 900, 1000, 1100, and 1150 °C. Measurements demonstrate that the higher the annealing temperature, the higher the carrier mobility of the OTFT is. The device annealed at 1150 °C has a field-effect mobility of 0.74 cm2/V s, which is 35% higher than that of the device annealed at 900 °C. Energy-dispersive x-ray analysis, scanning-electron microscopy, and atomic-force microscopy show that the higher carrier mobility should be due to more nitrogen incorporated at the gate-dielectric surface which results in more passivated dielectric surface and larger pentacene grains for carrier transport.

High-performance organic thin-film transistor by using LaNbO as gate dielectric

Pentacene organic thin-film transistors (OTFTs) using LaxNb(1−x)Oy as gate dielectric with different La contents (x = 0.347, 0.648) have been fabricated and compared with those using Nb oxide or La oxide. The OTFT with La0.648Nb0.352Oy as gate dielectric can achieve a high carrier mobility of 1.14 cm2V−1s−1 (about 1000 times and 2 times those of the devices using Nb oxide and La oxide, respectively), and has negligible hysteresis of −0.130 V, small sub-threshold swing of 0.280 V/dec, and low threshold voltage of −1.35 V. AFM and XPS reveal that La can suppress the formation of oxygen vacancies in Nb oxide while Nb can alleviate the hygroscopicity of La oxide, which results in a more passivated and smoother dielectric surface, leading to larger pentacene grains grown and thus higher carrier mobility. The OTFT with Nb oxide has an anticlockwise hysteresis but the device with La oxide shows an opposite direction. This can be explained in terms of donor-like traps due to oxygen vacancies and acceptor-like tra...