Inhibition of the p53/hDM2 protein-protein interaction by cyclometallated iridium(III) compounds.

Inactivation of the p53 transcription factor by mutation or other mechanisms is a frequent event in tumorigenesis. One of the major endogenous negative regulators of p53 in humans is hDM2, a ubiquitin E3 ligase that binds to p53 causing proteasomal p53 degradation. In this work, a library of organometallic iridium(III) compounds were synthesized and evaluated for their ability to disrupt the p53/hDM2 protein-protein interaction. The novel cyclometallated iridium(III) compound 1 [Ir(eppy)2(dcphen)](PF6) (where eppy = 2-(4-ethylphenyl)pyridine and dcphen = 4, 7-dichloro-1, 10-phenanthroline) blocked the interaction of p53/hDM2 in human amelanotic melanoma cells. Finally, 1 exhibited anti-proliferative activity and induced apoptosis in cancer cell lines consistent with inhibition of the p53/hDM2 interaction. Compound 1 represents the first reported organometallic p53/hDM2 protein-protein interaction inhibitor.

Development of a luminescent G-quadruplex-selective iridium(III) complex for the label-free detection of adenosine.

A panel of six luminescent iridium(III) complexes were synthesized and evaluated for their ability to act as G-quadruplex-selective probes. The novel iridium(III) complex 1 was found to be highly selective for G-quadruplex DNA, and was employed for the construction of a label-free G-quadruplex-based adenosine detection assay in aqueous solution. Two different detection strategies were investigated for adenosine detection, and the results showed that initial addition of adenosine to the adenosine aptamer gave superior results. The assay exhibited a linear response for adenosine in the concentration range of 5 to 120 µM (R(2) = 0.992), and the limit of detection for adenosine was 5 µM. Moreover, this assay was highly selective for adenosine over other nucleosides, and exhibited potential use for biological sample analysis.

A G-pentaplex-based assay for Cs(+) ions in aqueous solution using a luminescent Ir(III) complex.

A series of 5 randomly designed in-house cyclometalated Ir(III) complexes were examined for their application in G-pentaplex probes and the "proof-of-principle" concept in G-pentaplex-based Cs(+) ions detection. The G-pentaplex-forming sequence (DNA1, 5'-T(iG)4T-3', where iG=isoguanine) is present in single strand DNA form ab initio, however, the addition of Cs(+) ions lead to formation of the intermolecular G-pentaplex structure which is identified by the novel Ir(III) complex 1 afterward and produce an enhanced luminescence signal for Cs(+) ions monitoring. To the best of our knowledge, this is the first G-pentaplex probe and also the first G-pentaplex-based label-free detection platform for Cs(+) ions reported in the literature. The monitoring of spiked Cs(+) ions in natural water samples demonstrates the potential application and technical sound of this "proof-of-principle" concept sensing platform.

Development of an Aptamer-Based Sensing Platform for Metal Ions, Proteins, and Small Molecules through Terminal Deoxynucleotidyl Transferase Induced G-Quadruplex Formation.

We report a label-free, structure-independent luminescent-sensing platform for metal ions, proteins, and small molecules utilizing an Ir(III) complex, terminal deoxynucleotidyl transferase (TdT), and a structure-folding aptamer. A novel G-quadruplex-selective Ir(III) complex was identified to detect the nascent G-quadruplex motifs with an enhanced luminescence response. Unlike most label-free DNA-based assays reported in the literature, this sensing platform does not require a specific secondary structure of aptamer, thus greatly simplifying DNA design. The detection platform was demonstrated by the detection of K(+) ions, thrombin, and cocaine as representative examples of metal ions, proteins, and small molecules.

Luminescence switch-on assay of interferon-gamma using a G-quadruplex-selective iridium(III) complex.

In this study, we synthesized a series of 9 luminescent iridium(III) complexes and studied their ability to function as luminescent probes for G-quadruplex DNA. The iridium(III) complex 8 [Ir(pbtz)2(dtbpy)]PF6 (where pbtz = 2-phenylbenzo[d]thiazole; dtbpy = 4,4'-di-tert-butyl-2,2'-bipyridine) showed high selectivity for G-quadruplex DNA over single-stranded and double-stranded DNA, and was subsequently utilized for the development of a label-free oligonucleotide-based assay for interferon-gamma (IFN-γ), an important biomarker for a range of immune and infectious diseases, in aqueous solution. We further demonstrated that this assay could monitor IFN-γ levels even in the presence of cellular debris. This assay represents the first G-quadruplex-based assay for IFN-γ detection described in the literature.

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.

An Iridium(III) Complex Inhibits JMJD2 Activities and Acts as a Potential Epigenetic Modulator.

A novel iridium(III) complex was synthesized and evaluated for its ability to target JMJD2 enzymatic activity. The iridium(III) complex 1 can inhibit JMJD2 activity and was selective for JMJD2 activity over JARID, JMJD3, and HDAC activities. Moreover, 1 suppressed the trimethylation of the p21 promoter on H3K9me3 and interrupted the JMJD2D-H3K9me3 interactions in human cells, suggesting that it could act as an epigenetic modulator. To our knowledge, 1 represents the first metal-based JMJD2 inhibitor reported in the literature.

Dual Inhibition And Monitoring Of Beta-amyloid Fibrillation By A Luminescent Iridium(III) Complex.

In this study, we report the synthesis and application of the novel cyclometallated luminescent Ir(III) complex 1 bearing the C^C^C ligand as a probe and inhibitor of Aß fibrillation. We envisage that this kinetically-inert Ir(III) complex may be potentially developed as a dual-purpose probe and inhibitor of Aß aggregation for Alzheimer's disease diagnosis and treatment.

Label-free luminescent detection of LMP1 gene deletion using an intermolecular G-quadruplex-based switch-on probe.

We have synthesized a series of luminescent iridium(III) complexes and investigated their ability to act as luminescent split G-quadruplex probes. After screening, the iridium(III) complex 1 [Ir(2-phenylquinoline)2(3,4,7,8-tetramethyl-1,10-phenanthroline)]PF6 was validated as a highly-selective G-quadruplex probe and was utilized to construct a label-free intermolecular G-quadruplex-based assay for the selective and sensitive detection of LMP1 gene deletion. This "mix-and-detect" assay is simple and selective, and could detect down to 10 nM of the target gene in aqueous solution with a linear range from 10 to 500 nM. We also investigated the performance of our split G-quadruplex-based sensing platform for LMP1 gene deletion in the presence of cellular debris, demonstrating the robustness of this sensing system in biological samples. Comparative assays were also performed using either organic dyes or labeled oligonucleotides as signal-transducing agents.

A metal-based tumour necrosis factor-alpha converting enzyme inhibitor.

We report herein a novel iridium(III) complex 1 as an antitumour necrosis factor agent and the first metal-based inhibitor of TACE enzymatic activity. Complex 1 inhibited TNF-α secretion and p38 phosphorylation in human monocytic THP-1 cells.

Label-free luminescence switch-on detection of hepatitis C virus NS3 helicase activity using a G-quadruplex-selective probe.

A series of luminescent Ir(iii) complexes were synthesised and evaluated for their ability to act as luminescent G-quadruplex-selective probes. The Ir(iii) complex 9, [Ir(phq)2(phen)]PF6 (where phq = 2-phenylquinoline; phen = 1,10-phenanthroline), exhibited high luminescence in the presence of G-quadruplex DNA compared to dsDNA and ssDNA, and was employed to construct a label-free G-quadruplex-based assay for hepatitis C virus NS3 helicase activity in aqueous solution. Moreover, the application of the assay for screening potential helicase inhibitors was demonstrated. To our knowledge, this is the first G-quadruplex-based assay for helicase activity.

A G-triplex luminescent switch-on probe for the detection of mung bean nuclease activity.

A cyclometallated Ir(iii) complex was synthesised and evaluated for the ability to act as a luminescent G-triplex probe. The iridium(iii) complex 1 [Ir(phq)2(2,9-dmphen)]PF6 (where phq = 2-phenylquinoline; 2,9-dmphen = 2,9-dimethyl-1,10-phenanthroline) exhibited high luminescence for G-triplex DNA over dsDNA and ssDNA, and was employed to construct a label-free G-triplex-based assay for mung bean nuclease activity in aqueous solution. This method was highly sensitive and selective for MB nuclease activity over other DNA-modifying enzymes.

Synthesis and cytotoxic evaluation of acylated brefeldin a derivatives as potential anticancer agents.

Brefeldin A has attracted considerable attention because of its potential function in cancer prevention. However, its therapeutic use is limited by its poor bioavailability. The modifications on brefeldin A were difficult because of its low stability and selectivity toward two hydroxyl groups within the same molecule. In this study, we report the selective acylation of brefeldin A under mild conditions and the preparation of a series of monoacylated and diacylated brefeldin A derivatives. Their cytotoxicity, antitumor activity against TE-1 cell, and molecular properties of adsorption, distribution, metabolism, and elimination were evaluated. Brefeldin A 7-O-benzoate, brefeldin A 4,7-O-dibenzoate, and brefeldin A 7-O-biotin carboxylate showed the most potent cytotoxic activity, with GI50 values of 0.39, 0.46, and 0.50 µm, respectively. Molecular docking of these analogs revealed that the derivatives were well tolerated at the interface between ARF1 and its guanine nucleotide exchange factor ARNO. Our results may serve as a basis for the development of novel potential anticancer agents from brefeldin A derivatives.

[Intelligence evaluation of 22 patients with congenital velopharyngeal incompetence].

OBJECTIVE: To study the intelligence of 22 patients with CVPI. METHODS: We examined the IQ of 22 patients with CVPI by Wechsler Primary Preschool Scale of Intelligence (WPSSI) and Wechsler Intelligence Scale for Children-Revised (WISC-R). RESULTS: The IQ of patients with CVPI was 44-109. The mean value and SD were 67.46+/-19.29. Patients with normal IQ accounted for 45.5%. 54.5% of patients with CVPI had mental retardation (MR), most of which were mild. CONCLUSION: More than half of the patients with CVPI showed MR. It's necessary to evaluate the intelligence in patients with CVPI, and give treatment as early as possible.