A metal-based inhibitor of NEDD8-activating enzyme.

A cyclometallated rhodium(III) complex [Rh(ppy)(2)(dppz)](+) (1) (where ppy=2-phenylpyridine and dppz=dipyrido[3,2-a:2',3'-c]phenazine dipyridophenazine) has been prepared and identified as an inhibitor of NEDD8-activating enzyme (NAE). The complex inhibited NAE activity in cell-free and cell-based assays, and suppressed the CRL-regulated substrate degradation and NF-κB activation in human cancer cells with potency comparable to known NAE inhibitor MLN4924. Molecular modeling analysis suggested that the overall binding mode of 1 within the binding pocket of the APPBP1/UBA3 heterodimer resembled that for MLN4924.

Structure-based design of flavone derivatives as c-myc oncogene down-regulators.

Based on molecular docking analysis of complexes between flavone and the c-myc G-quadruplex, we designed and screened 30 flavone derivatives containing various side chains that could potentially form interactions with the G-quadruplex grooves. As a proof-of-concept, the highest-scoring flavone derivatives containing cationic pyridinium side chains were synthesized and their interactions with the c-myc G-quadruplex were examined using a PCR-stop assay. The stabilizing effects of the flavone derivatives were found to be selective towards the c-myc G-quadruplex over other biologically relevant G-quadruplex structures, such as the human telomeric sequence (HTS).

Label-free detection of sub-nanomolar lead(II) ions in aqueous solution using a metal-based luminescent switch-on probe.

A label-free oligonucleotide-based luminescent switch-on assay has been developed for the selective detection of sub-nanomolar Pb(2+) ions in aqueous solution and real water samples. An iridium(III) complex was employed as a G-quadruplex specific luminescent probe and a guanine rich DNA (PS2.M, 5'-GTG(3)TAG(3)CG(3)T(2)G(2)-3') was employed as recognition unit for Pb(2+) ions.

Discovery of a natural product-like c-myc G-quadruplex DNA groove-binder by molecular docking.

The natural product-like carbamide (1) has been identified as a stabilizer of the c-myc G-quadruplex through high-throughput virtual screening. NMR and molecular modeling experiments revealed a groove-binding mode for 1. The biological activity of 1 against the c-myc G-quadruplex was confirmed by its ability to inhibit Taq polymerase-mediated DNA extension and c-myc expression in vitro, demonstrating that 1 is able to control c-myc gene expression at the transcriptional level presumably through the stabilization of the c-myc promoter G-quadruplex.

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.

Discovery of a natural product inhibitor targeting protein neddylation by structure-based virtual screening.

NEDD8-activating enzyme (NAE) controls the specific degradation of proteins regulated by cullin-RING ubiquitin E3 ligase, and has been considered as an attractive molecular target for the development of anti-cancer drugs. We report herein the identification of the dipeptide-conjugated deoxyvasicinone derivative (1) as an inhibitor of NAE by virtual screening of over 90,000 compounds from the ZINC database of natural products. Molecular modelling results suggested that 1 may be a non-covalent competitive inhibitor of NAE by blocking the ATP-binding domain.

Label-free sensing of pH and silver nanoparticles using an "OR" logic gate.

Many natural phenomena are associated with the presence of two or more separate variables. We report here an "OR" DNA logic gate based on a luminescent platinum(II) switch-on probe for silver nanoparticles and pH, both of which may be considered putative indicators of pollution. The modulation of metal complex/double-stranded DNA complex phosphorescence by Ag(+) and H(+) was used to construct a simple, rapid and label-free method for the label-free detection of pH and nanomolar Ag(+) ions and nanoparticles in aqueous solutions with high selectivity.

Antitumor agents 294. Novel E-ring-modified camptothecin-4β-anilino-4'-O-demethyl-epipodophyllotoxin conjugates as DNA topoisomerase I inhibitors and cytotoxic agents.

Two conjugates (1 and 2) of camptothecin (CPT) and 4β-anilino-4'-O-demethylepipodophyllotoxin were previously shown to exert antitumor activity through inhibition of topoisomerase I (topo I). In this current study, two novel conjugates (1E and 2E) with an open E-ring in the CPT moiety were first synthesized and evaluated for biological activity in comparison with their intact E-ring congeners. This novel class of CPT-derivatives exhibits its antitumor effect against CPT-sensitive and -resistant cells, in part, by inhibiting topo I-linked DNA (TLD) religation.

A highly selective G-quadruplex-based luminescent switch-on probe for the detection of gene deletion.

A G-quadruplex-based switch-on luminescence assay has been developed for the detection of gene deletion using a cyclometallated iridium(III) complex as a G-quadruplex-selective probe. Upon hybridization with the target DNA, the two split G-quadruplex-forming sequences assemble into a split G-quadruplex, which greatly enhances the luminescence emission of the iridium(III) probe. The assay is simple and highly selective.

Current advancements in Aβ luminescent probes and inhibitors of Aβ aggregation.

Alzheimer's disease (AD) is a neurodegenerative disorder that severely jeopardizes the health of aging populations all over the world. According to the amyloid cascade hypothesis, the pathological progression of AD is associated with the formation of amyloid plaques in the brain, resulting from the aggregation of amyloid-β (Aβ) peptides. Over the past few years, vast efforts have been dedicated to the development of amyloid probes and inhibitors for the diagnosis and effective treatment of AD.

DNA-binding small molecules as inhibitors of transcription factors.

Accumulating evidence implicating the role of aberrant transcription factor signaling in the pathogenesis of various human diseases such as cancer and inflammation has stimulated the development of small molecule ligands capable of targeting transcription factor activity and modulating gene expression. The use of DNA-binding small molecules to selectively inhibit transcription factor-DNA interactions represents one possible approach toward this goal. In this review, we summarize the development of DNA-binding small molecule inhibitors of transcription factors from 2004 to 2011, and their binding mode and therapeutic potential will be discussed.

In silico screening of quadruplex-binding ligands.

Recent advances in computational processing power and molecular docking algorithms have facilitated the development of computer-aided methods for the rapid and efficient discovery of G-quadruplex-interacting molecules. In this article, we provide an introductory framework for the methodology of in silico screening for the identification of novel DNA G-quadruplex ligands from chemical libraries. We discuss aspects of model construction, database selection and molecular docking techniques, and highlight representative examples from this field.

Luminescent G-quadruplex probes.

G-quadruplexes have found increasing potential in applications such as molecular therapeutics, diagnostics, and sensing. As a consequence, small molecules capable of selectively detecting G-quadruplexes have received significant attention in recent literature. Our review here addresses representative advances in the development of luminescent G-quadruplex probes and highlights their potential applications in sensing and imaging.

A label-free G-quadruplex-based switch-on fluorescence assay for the selective detection of ATP.

A G-quadruplex-based, label-free, switch-on fluorescence detection method has been developed for the selective detection of ATP in aqueous solution using crystal violet as a G-quadruplex-selective probe. The assay is highly simple and rapid, and does not require the use of fluorescent labeling.

Inhibition of TNF-α stimulated nuclear factor-kappa B (NF-κB) activation by cyclometalated platinum(II) complexes.

Cyclometalated platinum(II) complexes [Pt(II)(C^N^N)(C≡NR)](+) (HC^N^N = 6-phenyl-2,2'-bipyridyl) display significant inhibition towards TNF-α stimulated NF-κB-dependent gene transcription at concentrations down to the micromolar range.

Luminescent detection of DNA-binding proteins.

Transcription factors play a central role in cell development, differentiation and growth in biological systems due to their ability to regulate gene expression by binding to specific DNA sequences within the nucleus. The dysregulation of transcription factor signaling has been implicated in the pathogenesis of a number of cancers, developmental disorders, inflammation and autoimmunity. There is thus a high demand for convenient high-throughput methodologies able to detect sequence-specific DNA-binding proteins and monitor their DNA-binding activities.

20(S)-Protopanaxadiol, a metabolite of ginsenosides, induced cell apoptosis through endoplasmic reticulum stress in human hepatocarcinoma HepG2 cells.

20(S)-Protopanaxadiol (PPD), a metabolite of ginsenosides, has been demonstrated to possess cytotoxic effects on several cancer cell lines. The molecular mechanism is, however, not well understood. In this study, we have shown that PPD inhibits cell growth and induces apoptosis in human hepatocarcinoma HepG2 cells.

Crystal violet as a fluorescent switch-on probe for i-motif: label-free DNA-based logic gate.

The first application of crystal violet as a selective fluorescent switch-on probe for i-motif DNA has been reported. This interaction has been exploited to develop a label-free DNA-based "OR" logic gate for potassium and hydrogen ions.

Molecular modeling of drug-DNA interactions: virtual screening to structure-based design.

Virtual ligand screening (VLS) and structure-based design are strategies that have been routinely used for the development of pharmaceuticals, particularly those targeting enzymes and other protein targets. In recent years, an increased understanding of the role played by nucleic acids in biological systems made DNA an alternative candidate for the development of new drugs. This review highlights some successful applications of molecular modeling in virtual ligand screening and structure-based design of organic and inorganic molecules that target non-canonical nucleic acid structures such as G-quadruplex and triplex DNA.

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.

Oligonucleotide-based luminescent detection of metal ions.

Metal ions are prevalent in biological systems and are critically involved in essential life processes. However, excess concentrations of metals can pose a serious danger to living organisms. Oligonucleotides represent a versatile sensing platform for the detection of various molecular entities including metal ions.

A natural product-like inhibitor of NEDD8-activating enzyme.

The natural product-like 6,6″-biapigenin has been identified as only the second inhibitor of NEDD8-activating enzyme using virtual screening. This compound was active in enzyme and cell-based assays, with potency in the micromolar range.