Modi Wang

Recent Developments in G-Quadruplex Probes

Accumulating evidence has linked G-quadruplex structures to a number of biological processes in vivo, including DNA replication, transcription, and genomic maintenance. However, the precise function and mechanism of G-quadruplex formation in mammalian cells remains poorly defined. Therefore, the development of small-molecule G-quadruplex probes has attracted significant attention in recent years. This review highlights examples of G-quadruplex probes that have been reported over the last few years, some of which have been employed for cellular imaging or for use in the construction of G-quadruplex-based analytical sensing platforms.

A colorimetric chemosensor for Cu2+ ion detection based on an iridium(III) complex

We report herein the synthesis and application of a series of novel cyclometalated iridium(III) complexes 1−3 bearing a rhodamine-linked NˆN ligand for the detection of Cu2+ ions. Under the optimised conditions, the complexes exhibited high sensitivity and selectivity for Cu2+ ions over a panel of other metal ions, and showed consistent performance in a pH value range of 6 to 8. Furthermore, the potential application of this system for the monitoring of Cu2+ ions in tap water or natural river water samples was demonstrated.

Identification of an Iridium(III)-Based Inhibitor of Tumor Necrosis Factor-α

The novel iridium(III) complex 1 was verified as a potent inhibitor of the TNF-α-TNFR protein-protein interaction in vitro and in cellulo. The iridium(III) center plays a critical role in organizing the structure of the bioactive metal complex, as the isolated ligands were found to be completely inactive. Both iridium enantiomers inhibited TNF-α-induced NF-κB activity and TNF-α-TNFR binding. 1 represents a promising scaffold for the further development of more potent organometallic TNF-α inhibitors.

Label-Free Luminescent Switch-On Probe for Ochratoxin A Detection Using a G-Quadruplex-Selective Iridium(III) Complex

A library of six luminescent Ir(III) complexes were synthesized and studied for their capacity to function as probes for G-quadruplex DNA. The novel Ir(III) complex 1 was discovered to be selective for G-quadruplex structures and was subsequently used for the construction of a label-free G-quadruplex-based ochratoxin A (OTA) sensing platform in aqueous solution. The assay exhibited linearity for OTA in the range of 0 to 60 nM (R2=0.9933), and the limit of detection for OTA was 5 nM. Furthermore, this assay was highly selective for OTA over its structurally related analogues.

Discovery of a natural product-like iNOS inhibitor by molecular docking with potential neuroprotective effects in vivo

In this study, we applied structure-based virtual screening techniques to identify natural product or natural product-like inhibitors of iNOS. The iNOS inhibitory activity of the hit compounds was characterized using cellular assays and an in vivo zebrafish larvae model. The natural product-like compound 1 inhibited NO production in LPS-stimulated Raw264.7 macrophages, without exerting cytotoxic effects on the cells. Significantly, compound 1 was able to reverse MPTP-induced locomotion deficiency and neurotoxicity in an in vivo zebrafish larval model. Hence, compound 1 could be considered as a scaffold for the further development of iNOS inhibitors for potential anti-inflammatory or anti-neurodegenerative applications.

G-quadruplex-based logic gates for HgII and AgI ions employing a luminescent iridium(III) complex and extension of metal-mediated base pairs by polymerase

We report herein the synthesis of a series of cyclometallated iridium(iii) complexes as luminescent G-quadruplex-selective probes, which were used to construct AND, OR and INHIBIT logic gates for the detection of HgII and AgI ions. To our knowledge, this is the first time that the C-AgI-T mismatched base pair has been used for the construction of luminescent assays or logic gates.

A luminescent cocaine detection platform using a split G-quadruplex-selective iridium(III) complex and a three-way DNA junction architecture

In this study, a series of 10 in-house cyclometalated iridium(III) complexes bearing different auxiliary ligands were tested for their selectivity toward split G-quadruplex in order to construct a label-free switch-on cocaine detection platform employing a three-way junction architecture and a G-quadruplex motif as a signal output unit. Through two rounds of screening, we discovered that the iridium(III) complex 7 exhibited excellent selectivity toward the intermolecular G-quadruplex motif. A detection limit as low as 30 nM for cocaine can be achieved by this sensing approach with a linear relationship between luminescence intensity and cocaine concentration established from 30 to 300 nM. Furthermore, this sensing approach could detect cocaine in diluted oral fluid. We hope that our simple, signal-on, label-free oligonucleotide-based sensing method for cocaine using a three-way DNA junction architecture could act as a useful platform in bioanalytical research.

A G-quadruplex-based, label-free, switch-on luminescent detection assay for Ag+ ions based on the exonuclease III-mediated digestion of C–Ag+–C DNA

We report herein the ability of exonuclease III to cleave C-Ag+-C mismatched DNA, which was utilised for the construction of an exonuclease III-assisted, label-free, switch-on luminescent platform for Ag+ ions using a novel G-quadruplex-selective iridium(iii) complex.

A luminescent G-quadruplex-selective iridium(III) complex for the label-free detection of lysozyme

A novel Ir(iii) complex 1 displays high selectivity for the G-quadruplex, and was used to establish a label-free G-quadruplex-based detection platform for lysozyme in buffer. In this study, we employed a special feature of most G-quadruplex probes that they do not respond towards the TBA G-quadruplex. A duplex DNA with a TBA G-quadruplex tail was designed for the detection of lysozyme. The presence of lysozyme will induce duplex dissociation and release the hybridized c-kit87 G-quadruplex, which would be recognized by the Ir(iii) complex to generate a strong luminescence response. Common duplex DNA designs lacking a TBA G-quadruplex tail typically contain long complementary DNA regions that may be too stable to be dissociated, thus decreasing sensitivity. We anticipate that the presence of a TBA tail in the DNA duplex may destabilize the duplex structure, allowing the aptamer to be more easily dissociated and bind to the lysozyme, thereby increasing the sensitivity of the lysozyme detection platform. To our knowledge, this is the first example of the use of the TBA G-quadruplex to improve sensitivity through fine-tuning duplex stability. We believe that this approach may be further employed in sensing platforms for other targets. This assay exhibited a linear response for lysozyme within the concentration range of 2-50 nM (R2 = 0.9904), and the limit of detection for lysozyme was 2 nM. Moreover, this platform exhibited a potential use for biological sample analysis.

Identification of an iridium(III) complex with anti-bacterial and anti-cancer activity

Group 9 transition metal complexes have been widely explored as therapeutic agents due to their unique geometry, their propensity to undergo ligand exchanges with biomolecules and their diverse steric and electronic properties. These metal complexes can offer distinct modes of action in living organisms compared to carbon-based molecules. In this study, we investigated the antimicrobial and anti-proliferative abilities of a series of cyclometallated iridium(III) complexes. The iridium(III) complex 1 inhibited the growth of S. aureus with MIC and MBC values of 3.60 and 7.19 μM, respectively, indicating its potent bactericidal activity. Moreover, complex 1 also exhibited cytotoxicity against a number of cancer cell lines, with particular potency against ovarian, cervical and melanoma cells. This cyclometallated iridium(III) complex is the first example of a substitutionally-inert, Group 9 organometallic compound utilized as a direct and selective inhibitor of S. aureus.