Kwok-Yin Wong

G‐Quadruplexes: Targets in Anticancer Drug Design

G‐quadruplexes are special secondary structures adopted in some guanine‐rich DNA sequences. As guanine‐rich sequences are present in important regions of the eukaryotic genome, such as telomeres and the regulatory regions of many genes, such structures may play important roles in the regulation of biological events in the body. G‐quadruplexes have become valid targets for new anticancer drugs in the past few decades. Many leading compounds that target these structures have been reported, and a few of them have entered preclinical or clinical trials. Nonetheless, the selectivity of this kind of antitumor compound has yet to be improved in order to suppress the side effects caused by nonselective binding. As drug design targets, the topology and structural characteristics of quadruplexes, their possible biological roles, and the modes and sites of small‐ligand binding to these structures should be understood clearly. Herein we provide a summary of published research that has set out to address the above problem to provide useful information on the design of small ligands that target G‐quadruplexes. This review also covers research methodologies that have been developed to study the binding of ligands to G‐quadruplexes.

A Highly Selective Luminescent Switch‐On Probe for Histidine/Histidine‐Rich Proteins and Its Application in Protein Staining

The luminescence sensing of histidine and histidine-rich proteins plays a pivotal role in biochemistry and molecular biology, in particular when both temporal and spatial resolution are required. An abnormal level of histidine-rich proteins is an indicator for many diseases, such as advanced liver cirrhosis, AIDS, renal disease, asthma, pulmonary disorders, thrombotic disorders, f] and malaria. Some analyses of histidine and histidine-rich proteins have been developed in conjunction with immunoassay and colorimetric detection methods. The most commonly used method for the detection of histidine and histidine-rich proteins in biological samples is chromatography, which is usually performed through the combination of an effective separation technique, such as thin-layer chromatography, gas chromatography, or HPLC, followed by UV/Vis or fluorescence spectroscopy. The use of high-performance capillary electrophoresis with a derivation reagent has also been reported. However, the aforementioned methods are generally tedious, laborious, and, most importantly, expensive for routine detection in a biochemistry laboratory. Although numerous studies have dealt with the detection of histidine or histidine-rich proteins, studies on the use of luminescent probes for this purpose remain sparse. Notable examples include research by Fabbrizzi and co-workers, who developed competitive noncovalent fluorescence turn-on probes for histidine in the form of dizinc(II) or dicopper(II) macrocyclic complexes, which recognize histidine through the formation of an imidazolate bridge between the two dizinc(II) or dicopper(II) centers; however, the resulting noncovalent ensemble may be less stable than a covalently linking sensory system, and the complexity of the synthetic process makes it difficult to implement in a convenient manner. Photoluminescent iridium(III) complexes have emerged as a topical area of interest in inorganic photochemistry and phosphorescent materials for optoelectronic and luminescence signaling applications. Significant changes in the photophysical behavior and emission properties of iridium(III) complexes may be induced by the presence of biomolecules. Luminescent transition-metal complexes for protein staining, such as the luminescent ruthenium complex known as SYPRO Ruby dye, have been reported previously. However, despite its high sensitivity and its broad dynamic range, the use of SYPRORuby dye is limited, as it is sold only as a formulated solution; therefore, it is not possible to optimize the dye for a particular electrophoresis protocol and protein. In this context, the luminescent cyclometalated iridium(III) solvent complex [Ir(ppy)2(solv)2] + (1; ppy= 2phenylpyridine, solv=H2O or CH3CN) has received particular attention for the following reasons: 1) [Ir(ppy)2(OH2)2] , which contains weakly bound solvent ligands, may bind covalently to amino acids/proteins through a ligand substitution reaction with the OH2 ligand; 2) an intriguing solvent/ media dependence of the emission properties of [Ir(ppy)2(OH2)2] + has been observed; 3) [Ir(ppy)2(OH2)2] + can be synthesized conveniently and rapidly; 4) the use of organic solvents is not required for the optimal sensing of amino acids/proteins with [Ir(ppy)2(OH2)2] , and the iridium complex is readily soluble and stable in aqueous staining solutions. In this study, [Ir(ppy)3] (2) was also prepared for comparative studies, as its binding with proteins was expected to be largely hydrophobic in nature. Herein, we describe the luminescent switch-on probe [Ir(ppy)2(solv)2] + (1) for histidine/histidinerich proteins and demonstrate its utility in protein staining. The Ir complexes 1-CF3SO3 and 2 (Figure 1a) were prepared according to a previously reported method. The structure of 1-ClO4 was established by X-ray crystallography and is depicted in Figure 1b, and the crystal-packing diagrams are given in the Supporting Information. The metal–ligand bonding parameters for 1-ClO4 are comparable to those reported previously for cyclometalated iridium(III) complexes. The complex 1-CF3SO3 (50 mm) is weakly emissive in phosphate buffered saline (PBS). In the presence of histidine (His), 1-CF3SO3 exhibits an intense emission at lmax= 505 nm, the intensity of which reaches saturation level at [His]/[Ir] 4 (Figure 2a). A plot of I/I0 versus [His]/[1-CF3SO3] (I and I0 are emission intensities with and without His) shows an up-to180-fold intensity enhancement at ratios [His]/[1-CF3SO3] 4:1. The luminescence response of 1-CF3SO3 to various other [*] Dr. D.-L. Ma, Dr. W.-L. Wong, W.-H. Chung, F.-Y. Chan, P.-K. So, Dr. T.-S. Lai, Z.-Y. Zhou, Prof. Y.-C. Leung, Prof. K.-Y. Wong Department of Applied Biology and Chemical Technology, Central Laboratory of the Institute of Molecular Technology for Drug Discovery and Synthesis, The Hong Kong Polytechnic University Hung Hom, Kowloon, Hong Kong (China) Fax: (+1)852-2364-9932 E-mail: bcedmond@polyu.edu.hk bckywong@inet.polyu.edu.hk

Significant enhancement in photocatalytic reduction of water to hydrogen by Au/Cu2ZnSnS4 nanostructure

Enhanced photocatalytic activities by Au core Novel Au/Cu2 ZnSnS4 core/shell nanoparticles (NPs) are synthesized for the first time via wet chemistry approach. The insertion of Au core into CZTS NPs dramatically enhances light absorption due to surface plasmon resonance effect, especially in the Vis-NIR region. Au/CZTS core/shell NPs show much higher photocatalytic activities for hydrogen evolution compared with other CZTS nanostructures.

5-N-Methylated Quindoline Derivatives as Telomeric G-Quadruplex Stabilizing Ligands: Effects of 5-N Positive Charge on Quadruplex Binding Affinity and Cell Proliferation

A series of 5-N-methyl quindoline (cryptolepine) derivatives (2a- x) as telomeric quadruplex ligands was synthesized and evaluated. The designed ligands possess a positive charge at the 5- N position of the aromatic quindoline scaffold. The quadruplex binding of these compounds was evaluated by circular dichroism (CD) spectroscopy, fluorescence resonance energy transfer (FRET) melting assay, polymerase chain reaction (PCR) stop assay, nuclear magnetic resonance (NMR), and molecular modeling studies. Introduction of a positive charge not only significantly improved the binding ability but also induced the selectivity toward antiparallel quadruplex, whereas the nonmethylated derivatives tended to stabilize hybrid-type quadruplexes. NMR and molecular modeling studies revealed that the ligands stacked on the external G-quartets and the positively charged 5- N atom could contribute to the stabilizing ability. Long-term exposure of human cancer cells to 2r showed a remarkable cessation in population growth and cellular senescence phenotype and accompanied by a shortening of the telomere length.

Isaindigotone Derivatives: A New Class of Highly Selective Ligands for Telomeric G-Quadruplex DNA

Four isaindigotone derivatives (5a,b and 6a,b) designed as telomeric G-quadruplex ligands have been synthesized and characterized. The unfused aromatic rings in these compounds allow a flexible and adaptive conformation in G-quadruplex recognition. The interaction of human telomeric G-quadruplex DNA with these designed ligands was explored by means of FRET melting, fluorescence titration, CD spectroscopy, continuous variation, and molecular modeling studies. Our results showed that the adaptive scaffold might not only allow the ligands to well occupy the G-quartet but also perfectly bind to the grooves of the G-quadruplex. The synergetic effect of the multiple binding modes might be responsible for the improved binding ability and high selectivity of these ligands toward G-quadruplex over duplex DNA. Long-term exposure of HL60 and CA46 cancer cells to compound 5a showed a remarkable decrease in population growth, cellular senescence phenotype, and shortening of the telomere length, which is consistent with the behavior of an effective telomeric G-quadruplex ligand and telomerase inhibitor.

Palladium–(S,pR)‐FerroNPS‐Catalyzed Asymmetric Allylic Etherification: Electronic Effect of Nonconjugated Substituents on Benzylic Alcohols on Enantioselectivity

The development of efficient methods for enantioselective synthesis remains at the center of modern-day organic chemistry, as such methods have many important applications, from the total synthesis of natural products to the preparation of analogues of lead compounds in the pharmaceutical industry. The ability to prepare compounds by a carbon–heteroatom bond-forming process from a common intermediate is of great significance to the drug-discovery process. In particular, the stereoselective construction of an ether linkage adjacent to a stereogenic carbon center is important for the synthesis of many biologically active targets. However, this process requires further development. For example, the conventional formation of a C O bond by a direct SN2-type O alkylation (Williamson ether synthesis) is sometimes impractical synthetically owing to the strong basicity of the alkoxide anion, which may be incompatible with other functional groups present in the system. It would clearly be advantageous to construct C O bonds in a catalytic manner under mild conditions rather than through traditional organic synthesis. Enantioselective transitionmetal-catalyzed allylic substitution has become one of the most powerful tools for the generation of carbon–carbon and carbon–heteroatom bonds with various nucleophiles. The development of the synthesis of chiral compounds containing carbon–carbon or carbon–nitrogen bonds from racemic allylic electrophiles has been documented well [Eq. (1)]. In contrast, the enantioselective allylic substitution of unactivated allylic acetates with relatively hard oxygen nucleophiles has only been studied sporadically. Enantioselective iridium-catalyzed allylic substitution reactions with a broad range of phenols (relatively soft nucleophiles) have been reported. They generally proceed with good selectivity with monodentate phosphoramidite ligands. Asymmetric palladium-catalyzed C O bond formation between phenols and various allylic substrates to give ethers has also been studied. In a separate study, Kim and Lee demonstrated that the palladium-catalyzed etherification of allylic acetates with aliphatic alcohols afforded achiral ethers by using zinc alkoxides generated from diethyl zinc and an alcohol. Haight et al. reported an asymmetric variant of the protocol described by Kim and Lee. However, the more reactive allylic carbonate and harsher conditions (reflux in THF) were required, and the observed enantioselectivities were rather poor. Spurred by these findings, we undertook the challenge to develop an efficient etherification process that can proceed under mild reaction conditions with good stereoselectivity. Herein, we report a general palladiumcatalyzed asymmetric allylic substitution of racemic 1,3diphenyl-2-propenyl acetate with aliphatic alcohols in the presence of newly developed fine-tunable phosphinamidite– thioether ligands with a ferrocene motif (Scheme 1) to generate chiral ethers in high yields with excellent enantioselectivities. We recently developed a convenient synthesis of the versatile Ugi amine in optically pure form with a view to using it as a building block for the development of novel and highly modular chiral ligands. The chiral intermediate aminothioether 2 of FerroNPS was synthesized by diastereoselective ortho lithiation of the Ugi amine by treatment with sBuLi in Et2O followed by quenching with the appropriate

The effect of weak Brönsted acids on the electrocatalytic reduction of carbon dioxide by a rhenium tricarbonyl bipyridyl complex

Abstract The effect of four weak Bronsted acids, 2,2,2-trifluoroethanol, phenol, methanol and water on the electrocatalytic reduction of CO 2 by [Re(bpy)(CO) 3 (py)] 2+ (bpy=2,2′-bipyridine, py=pyridine) in acetonitrile was investigated. The addition of weak Bronsted acids enhances the rate of the catalytic process and improves the lifetime of the rhenium catalyst. Under the experimental conditions employed in this study, CO was produced as the only product with faradaic efficiency close to 100%. Kinetic analysis indicated that the reaction order in acid is 2. The Bronsted acids probably stabilise the rhenium–carbon dioxide intermediate through protonation and facilitate the cleavage of one of the C–O bonds to yield CO. The efficiency of the acid increases with its acidity. Thus, trifluoroethanol and phenol are more effective in enhancing the rate of catalysis than methanol and water. Even though the acid strength of water and methanol are very similar, water is much less effective in enhancing the rate of CO 2 reduction. This can be attributed to the relatively strong ligating property of water, which would compete with CO 2 for the binding site on rhenium.

Optical characteristics of a ruthenium(II) complex immobilized in a silicone rubber film for oxygen measurement

The optical characteristics of tris(4,7-diphenyl-1,10-phenanthroline)ruthenium(II) perchlorate immobilized in a silicone rubber film were studied for its application to the measurement of oxygen. The luminescence intensity and the degree of quenching of the ruthenium complex by oxygen were shown to be affected by the concentration of the complex in the silicone rubber film. The optimum concentration was found to be about 0.2 mmol dm–3. At this concentration, the silicone rubber film containing the immobilized ruthenium complex emits the highest luminescence intensity and is able to undergo a high degree of quenching of the luminescence by oxygen. The quenching curves for 20 samples containing various concentrations of the ruthenium complex were correlated with high accuracy by using a modified form of the Stern–Volmer equation. The film preparation procedure and the solvent used were found to be critical for performance. The effect of the film thickness on the luminescence intensity and the dynamic response was also studied.

Benzothiazole-substituted benzofuroquinolinium dye: a selective switch-on fluorescent probe for G-quadruplex

A new switch-on fluorescent probe containing the natural product cryptolepine analogue benzofuroquinolinium moiety (binding scaffold) and a benzothiazole moiety (signalling unit) shows a remarkable fluorescence enhancement selective for the G-quadruplex nucleic acid structure. Binding studies revealed that the highly selective response of the fluorescent probe arises from end-stack binding to G-quadruplex.

Effects of electrode surface pretreatments on the electrochemistry of a macrocyclic dioxoruthenium(VI) complex

Abstract The reductive electrochemistry of trans -[Ru VI (TMC)(O) 2 ] 2+ (TMC = 1,4,8,11-tetramethyl-1,4,8,11-tetraazacyclotetradecane) follows different courses in aprotic and aqueous media. In acetonitrile, a one-electron reduction to trans -[Ru V (TMC)(O) 2 ] + occurs. In aqueous acid trans -[Ru IV (TMC)O(OH 2 )] 2+ is formed in a single, two-electron, two-proton step. [Ru V (TMC)(O) 2 ] + disproportionates to [Ru VI (TMC)(O) 2 ] 2+ and [Ru IV (TMC)O(OH 2 )] 2+ in the presence of acid. The oxidation of [Ru IV (TMC)O(OH 2 )] 2+ in aqueous acid is facile at pyrolytic graphite and oxidatively “activated” glassy carbon electrodes but hindered at unactivated glassy carbon, platinum and gold electrodes. Slow proton transfer is identified as the origin of the slow oxidation and oxygen-containing groups on “activated” electrodes are suggested as the catalysts for this step.