A hitchhiker's guide to poset ranking

When ranking objects (like chemicals, geographical sites, river sections, etc.) by multicriteria analysis, it is in most cases controversial and difficult to find a common scale among the criteria of concern. Therefore, ideally, one should not resort to such artificial additional constraints. The theory of partially ordered sets (or posets for short) provides a solid formal framework for the ranking of objects without assigning a common scale and/or weights to the criteria, and therefore constitutes a valuable alternative to traditional approaches. In this paper, we aim to give a comprehensive literature review on the topic. First we formalize the problem of ranking objects according to some predefined criteria. In this theoretical framework, we focus on several algorithms and illustrate them on a toy example. To conclude, a more realistic real-world application shows the power of some of the algorithms considered in this paper.     

A new method for the study of G-quadruplex ligands

A new method for the study of G-quadruplex ligands was developed, in which the interaction of G-quadruplexes with ligands can be judged by the naked eye, eliminating the need for any expensive machines.     

Natural products and their derivatives as G-quadruplex binding ligands

G-quadruplexes comprise a class of secondary structures that are formed in guanine-rich sequences in eukaryotic genomes and play a crucial role in the regulation of many biological events. G-quadruplexes have become targets for anticancer drugs with high selectivity vs. duplex DNA and low cytotoxicity against normal cells. Natural products and their derivatives display polymorphism, structural complexity, and potent activity. It is, therefore, reasonable to seek ligands targeting G-quadruplexes from natural products. Recently, many successful examples have been reported, showing ligands with excellent anticancer activities. In this review, we summarized the development of research on natural products and derivatives that target G-quadruplex structures in an effort to guide future studies.     

Tetramethylpyridiniumporphyrazines--a new class of G-quadruplex inducing and stabilising ligands

3,4-Tetramethylpyridiniumporphyrazines bind strongly and selectively to human telomeric G-quadruplex DNA, inducing the formation of an antiparallel quadruplex in a process that mimics molecular chaperones.     

Structural basis for telomeric G-quadruplex targeting by naphthalene diimide ligands

The folding of the single-stranded 3' end of the human telomere into G-quadruplex arrangements inhibits the overhang from hybridizing with the RNA template of telomerase and halts telomere maintenance in cancer cells. The ability to thermally stabilize human telomeric DNA as a four-stranded G-quadruplex structure by developing selective small molecule compounds is a therapeutic path to regulating telomerase activity and thereby selectively inhibit cancer cell growth. The development of compounds with the necessary selectivity and affinity to target parallel-stranded G-quadruplex structures has proved particularly challenging to date, relying heavily upon limited structural data. We report here on a structure-based approach to the design of quadruplex-binding ligands to enhance affinity and selectivity for human telomeric DNA. Crystal structures have been determined of complexes between a 22-mer intramolecular human telomeric quadruplex and two potent tetra-substituted naphthalene diimide compounds, functionalized with positively charged N-methyl-piperazine side-chains. These compounds promote parallel-stranded quadruplex topology, binding exclusively to the 3' surface of each quadruplex. There are significant differences between the complexes in terms of ligand mobility and in the interactions with quadruplex grooves. One of the two ligands is markedly less mobile in the crystal complex and is more quadruplex-stabilizing, forming multiple electrostatic/hydrogen bond contacts with quadruplex phosphate groups. The data presented here provides a structural rationale for the biophysical (effects on quadruplex thermal stabilization) and biological data (inhibition of proliferation in cancer cell lines and evidence of in vivo antitumor activity) on compounds in this series and, thus, for the concept of telomere targeting with DNA quadruplex-binding small molecules.     

Synthesis of bis-indole carboxamides as G-quadruplex stabilizing and inducing ligands

The design and synthesis of a series of bis‐indole carboxamides with varying amine containing side chains as G‐quadruplex DNA stabilising small molecules are reported. Their interactions with quadruplexes have been evaluated by means of Förster resonance energy transfer (FRET) melting analysis, UV/Vis spectroscopy, circular dichroism spectroscopy and molecular modelling studies. FRET analysis indicates that these ligands exhibit significant selectivity for quadruplex over duplex DNA, and the position of the carboxamide side chains is of paramount importance in G‐quadruplex stabilisation. UV/Vis titration studies reveal that bis‐indole ligands bind tightly to quadruplexes and show a three‐ to fivefold preference for c‐kit2 over h‐telo quadruplex DNA. CD studies revealed that bis‐indole carboxamide with a central pyridine ring induces the formation of a single, antiparallel, conformation of the h‐telo quadruplex in the presence and absence of added salt. The chirality of h‐telo quadruplex was transferred to the achiral ligand (induced CD) and the formation of a preferred atropisomer was observed.     

Contribution of telomere G-quadruplex stabilization to the inhibition of telomerase-mediated telomere extension by chemical ligands

Inhibition of telomerase activity through stabilizing telomere G-quadruplex with small chemical ligands is emerging as a novel strategy for cancer therapy. For the large number of ligands that have been reported to inhibit telomerase activity, it is difficult to validate the contribution of G-quadruplex stabilization to the overall inhibition. Using a modified telomere repeat amplification protocol (TRAP) method to differentiate the telomere G-quadruplex independent effect from dependent ones, we analyzed several ligands that have high affinity and/or selectivity to telomere G-quadruplex. Our results show that these ligands effectively inhibited telomerase activity in the absence of telomere G-quadruplex. The expected G-quadruplex-dependent inhibition was only obvious for the cationic ligands at low K(+) concentration, but it dramatically decreased at physiological concentration of K(+). These observations demonstrate that the ligands are much more than G-quadruplex stabilizers with a strong G-quadruplex-irrelevant off-target effect. They inhibit telomerase via multiple pathways in which stabilization of telomere G-quadruplex may only make a minor or neglectable contribution under physiologically relevant conditions depending on the stability of telomere G-quadruplex under ligand-free conditions.     

Stabilization of G-quadruplex DNA by highly selective ligands via click chemistry

A series of G-quadruplex stabilizing compounds have been prepared via click chemistry employing the Cu(I)-catalyzed Huisgen reaction. These compounds were shown to bind tightly to G-quadruplex DNA even in the presence of competing high concentrations of duplex DNA. Furthermore, a modified TRAP assay has shown that some of these compounds also inhibit telomerase at low micromolar concentration.     

Oxazole-based peptide macrocycles: a new class of G-quadruplex binding ligands

Herein we report on the synthesis and DNA binding properties of a new class of water soluble oxazole-based peptide macrocycles that bind selectively to quadruplex DNA, with no detectable binding to duplex DNA. We have recently identified one quadruplex in the proto-oncogene c-kit that is suspected to act as a regulatory element for the expression of the c-kit gene. Here we provide the first example of a ligand binding to and stabilizing the c-kit quadruplex. Moreover, we show that these macrocycles show a preference for the c-kit quadruplex as compared to the human telomeric quadruplex.     

Discovery of G-quadruplex stabilizing ligands through direct ELISA of a one-bead-one-compound library

We describe the identification of small-molecule G-quadruplex ligands using a direct ELISA screen of a one-bead-one-compound library of unnatural polyamides displayed on a branched linker with a biotin tag. This general purpose parallel screen for small molecule-oligonucleotide interactions was validated by surface plasmon resonance and ELISA of resynthesized compounds. Linear polyamides displayed similar rankings in their affinity for quadruplex as their branched counterparts. Quadruplex affinity as judged by these surface based techniques was a useful predictor of the ability of the ligands to stabilize the quadruplex to thermal unfolding in solution.     

Water soluble extended naphthalene diimides as pH fluorescent sensors and G-quadruplex ligands

Extended naphthalene diimides (NDIs) fused to 1,4-dihydropyrazine-2,3-dione, containing two solubilizing moieties, have been synthesized. Fluorescence spectra of the new NDIs were remarkably affected by pH, as the second deprotonation of the dihydropyrazinedione moiety (pK(a) 6.9) switched off the emission. Binding to a G-quadruplex folded oligonucleotide and stoichiometry were evaluated by FRET melting assay and CD analysis. G-quadruplex binding was strongly enhanced shifting from pH 7.4 to pH 6.0 as a consequence of the dihydropyrazinedione moiety protonation. Cytotoxicity studies using two human telomerase-positive cell lines (HT29 and A549) revealed that the best G-quadruplex ligand was very active against the colon cell line, with an EC(50) of 300 nM.     

A fragment based click chemistry approach towards hybrid G-quadruplex ligands: design,synthesis and biophysical evaluation

A library of hybrid oxazole–triazole based compounds containing contiguously linked aromatic units were synthesised as G-quadruplex binding ligands. The design of these ligands was based upon combining features of our first generation of G-quadruplex bis-triazole ligands and the natural product telomestatin. The syntheses and biophysical studies of these ligands are described.     

Cationic corrole derivatives: a new family of G-quadruplex inducing and stabilizing ligands

Water-soluble cationic corrole derivatives were designed and synthesized, and the first observation of their interactions with the telomeric G-quadruplex was made.     

Unraveling the relationship between structure and stabilization of triarylpyridines as G-quadruplex binding ligands

A series of novel 2,4,6-triarylpyridines have been synthesized and their interactions with intramolecular G-quadruplexes have been measured by F?rster Resonance Energy Transfer (FRET) melting and Fluorescent Intercalator Displacement (FID) assays. A few of these compounds exhibit stabilization of G4-DNA that is comparable to other benchmark G4-DNA ligands with fair to excellent G4-DNA vs. duplex selectivity and significant cytotoxicity towards HeLa cells. The nature of the 4-aryl substituents along with side chain length governs the G4-DNA stabilization ability of the compounds. In addition, we demonstrate that there is a strong correlation between the ability of the compounds to stabilize the same G4-DNA sequence in K(+) and Na(+) conditions and a strong correlation between the ability of the compounds to stabilize different G4-DNA sequences in K(+) or Na(+) buffer.     

Click chemistry assembly of G-quadruplex ligands incorporating a diarylurea scaffold and triazole linkers

A series of diarylurea ligands were designed to interact selectively with G-quadruplexes and were synthesised using copper(I) catalysed 'click' chemistry to incorporate the 1,4-substituted 1,2,3-triazole ring into the core of the ligands; the optimal ligands demonstrate a high degree of selective telomeric G-quadruplex stabilisation and are not cytotoxic in several cancer cell lines.