Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

"One Ring to Bind Them All"-Part II: Identification of Promising G-Quadruplex Ligands by Screening of Cyclophane-Type Macrocycles.

ABSTRACT: A collection of 26 polyammonium cyclophane-type macrocycles with a large structural diversity has been screened for G-quadruplex recognition. A two-step selection procedure based on the FRET-melting assay was carried out enabling identification of macrocycles of high affinity (DeltaT(1/2) up to 30 degrees C) and high selectivity for the human telomeric G-quadruplex. The four selected hits possess sophisticated architectures, more particularly the presence of a pendant side-arm as well as the existence of a particular topological arrangement appear to be strong determinants of quadruplex binding. These compounds are thus likely to create multiple contacts with the target that may be at the origin of their high selectivity, thereby suggesting that this class of macrocycles offers unique advantages for targeting G-quadruplex-DNA.

SUBMITTER: Granzhan A

PROVIDER: S-EPMC2915812 | biostudies-other | 2010

REPOSITORIES: biostudies-other

ACCESS DATA

Json Xml

Publications

"One Ring to Bind Them All"-Part II: Identification of Promising G-Quadruplex Ligands by Screening of Cyclophane-Type Macrocycles.

Granzhan Anton A Monchaud David D Saettel Nicolas N Guédin Aurore A Mergny Jean-Louis JL Teulade-Fichou Marie-Paule MP

Journal of nucleic acids 20100509

A collection of 26 polyammonium cyclophane-type macrocycles with a large structural diversity has been screened for G-quadruplex recognition. A two-step selection procedure based on the FRET-melting assay was carried out enabling identification of macrocycles of high affinity (DeltaT(1/2) up to 30 degrees C) and high selectivity for the human telomeric G-quadruplex. The four selected hits possess sophisticated architectures, more particularly the presence of a pendant side-arm as well as the exi ...[more]

PMID: 20725622

Similar Datasets

"One ring to bind them all"-part I: the efficiency of the macrocyclic scaffold for g-quadruplex DNA recognition.

Project description:Macrocyclic scaffolds are particularly attractive for designing selective G-quadruplex ligands essentially because, on one hand, they show a poor affinity for the "standard" B-DNA conformation and, on the other hand, they fit nicely with the external G-quartets of quadruplexes. Stimulated by the pioneering studies on the cationic porphyrin TMPyP4 and the natural product telomestatin, follow-up studies have developed, rapidly leading to a large diversity of macrocyclic structures with remarkable-quadruplex binding properties and biological activities. In this review we summarize the current state of the art in detailing the three main categories of quadruplex-binding macrocycles described so far (telomestatin-like polyheteroarenes, porphyrins and derivatives, polyammonium cyclophanes), and in addressing both synthetic issues and biological aspects.

| S-EPMC2915875 | biostudies-other

How proteins bind macrocycles.

Project description:The potential utility of synthetic macrocycles (MCs) as drugs, particularly against low-druggability targets such as protein-protein interactions, has been widely discussed. There is little information, however, to guide the design of MCs for good target protein-binding activity or bioavailability. To address this knowledge gap, we analyze the binding modes of a representative set of MC-protein complexes. The results, combined with consideration of the physicochemical properties of approved macrocyclic drugs, allow us to propose specific guidelines for the design of synthetic MC libraries with structural and physicochemical features likely to favor strong binding to protein targets as well as good bioavailability. We additionally provide evidence that large, natural product-derived MCs can bind targets that are not druggable by conventional, drug-like compounds, supporting the notion that natural product-inspired synthetic MCs can expand the number of proteins that are druggable by synthetic small molecules.

| S-EPMC4417626 | biostudies-literature

A fluorescence-based helicase assay: application to the screening of G-quadruplex ligands.

Project description:Helicases, enzymes that unwind DNA or RNA structure, are present in the cell nucleus and in the mitochondrion. Although the majority of the helicases unwind DNA or RNA duplexes, some of these proteins are known to resolve unusual structures such as G-quadruplexes (G4) in vitro. G4 may form stable barrier to the progression of molecular motors tracking on DNA. Monitoring G4 unwinding by these enzymes may reveal the mechanisms of the enzymes and provides information about the stability of these structures. In the experiments presented herein, we developed a reliable, inexpensive and rapid fluorescence-based technique to monitor the activity of G4 helicases in real time in a 96-well plate format. This system was used to screen a series of G4 structures and G4 binders for their effect on the Pif1 enzyme, a 5' to 3' DNA helicase. This simple assay should be adaptable to analysis of other helicases and G4 structures.

| S-EPMC4477640 | biostudies-literature

Artificial Macrocycles by Ugi Reaction and Passerini Ring Closure.

Project description:Artificial macrocycles can be convergently synthesized by a sequence of an Ugi multicomponent reaction (MCR) followed by an intramolecular Passerini MCR used to close the macrocycle. Significantly, in this work, the first intramolecular macrocyclization through a Passerini reaction is described. We describe 21 macrocycles of a size of 15-20. The resulting macrocyclic depsipeptides are model compounds for natural products and could find applications in drug discovery.

| S-EPMC6280654 | biostudies-other

Nanorings with copper(ii) and zinc(ii) centers: forcing copper porphyrins to bind axial ligands in heterometallated oligomers.

Project description:The affinity of copper(ii) porphyrins for pyridine ligands is extremely weak, but oligo-pyridine templates can be used to direct the synthesis of Cu-containing cyclic porphyrin oligomers when they also have Zn centers. We report the synthesis of two heterometallated nanorings: a six-porphyrin ring prepared from a Zn/Cu/Zn linear trimer and a ten-porphyrin ring prepared from a Zn/Zn/Cu/Zn/Zn pentamer. Both these macrocycles have copper porphyrins at two specific positions across the diameter of the ring and zinc at other sites. The presence of a paramagnetic metal results in broadening of the 1H NMR spectra and reduces the relaxation time constants (T1 and T2). The changes in T1 provide quantitative information on the distance of each proton from the copper atom. The Zn/Zn/Cu/Zn/Zn linear porphyrin pentamer binds strongly to a penta-pyridyl template, despite the weakness of the Cu-N interaction, because of the chelate cooperativity of the neighboring Zn-N coordination. The stabilities of a family of four linear porphyrin pentamer complexes were determined by UV-vis-NIR titration and analyzed using a chemical double-mutant cycle. The results show that the free energy of interaction of a copper center to axial pyridine ligands is -6.2 kJ mol-1 when the entropy cost of bringing together the two molecules has already been paid by pyridine-zinc interactions. The development of template-directed approaches to the synthesis of nanorings with combinations of different metals at specific positions around the ring opens up many possibilities for controlling the photophysical behavior of these supramolecular systems and for probing their conformations by EPR.

| S-EPMC5355962 | biostudies-literature

Quadruplex Ligands in Cancer Therapy.

Project description:Nucleic acids can adopt alternative secondary conformations including four-stranded structures known as quadruplexes. To date, quadruplexes have been demonstrated to exist both in human chromatin DNA and RNA. In particular, quadruplexes are found in guanine-rich sequences constituting G-quadruplexes, and in cytosine-rich sequences forming i-Motifs as a counterpart. Quadruplexes are associated with key biological processes ranging from transcription and translation of several oncogenes and tumor suppressors to telomeres maintenance and genome instability. In this context, quadruplexes have prompted investigations on their possible role in cancer biology and the evaluation of small-molecule ligands as potential therapeutic agents. This review aims to provide an updated close-up view of the literature on quadruplex ligands in cancer therapy, by grouping together ligands for DNA and RNA G-quadruplexes and DNA i-Motifs.

| S-EPMC8267697 | biostudies-literature

Affinity Chromatography-Based Assays for the Screening of Potential Ligands Selective for G-Quadruplex Structures.

Project description:DNA G-quadruplexes (G4s) are key structures for the development of targeted anticancer therapies. In this context, ligands selectively interacting with G4s can represent valuable anticancer drugs. Aiming at speeding up the identification of G4-targeting synthetic or natural compounds, we developed an affinity chromatography-based assay, named G-quadruplex on Oligo Affinity Support (G4-OAS), by synthesizing G4-forming sequences on commercially available polystyrene OAS. Then, due to unspecific binding of several hydrophobic ligands on nude OAS, we moved to Controlled Pore Glass (CPG). We thus conceived an ad hoc functionalized, universal support on which both the on-support elongation and deprotection of the G4-forming oligonucleotides can be performed, along with the successive affinity chromatography-based assay, renamed as G-quadruplex on Controlled Pore Glass (G4-CPG) assay. Here we describe these assays and their applications to the screening of several libraries of chemically different putative G4 ligands. Finally, ongoing studies and outlook of our G4-CPG assay are reported.

| S-EPMC9127747 | biostudies-literature

Copper(II) Complexes with Mixed Heterocycle Ligands as Promising Antibacterial and Antitumor Species.

Project description:Complexes with mixed ligands [Cu(N-N)2(pmtp)](ClO4)2 ((1) N-N: 2,2'-bipyridine; (2) L: 1,10-phenanthroline and pmpt: 5-phenyl-7-methyl-1,2,4-triazolo[1,5-a]pyrimidine) were synthesized and structurally and biologically characterized. Compound (1) crystallizes into space group Pa and (2) in P-1. Both complexes display an intermediate stereochemistry between the two five-coordinated ones. The biological tests indicated that the two compounds exhibited superoxide scavenging capacity, intercalative DNA properties, and metallonuclease activity. Tests on various cell systems indicated that the two complexes neither interfere with the proliferation of Saccharomyces cerevisiae or BJ healthy skin cells, nor cause hemolysis in the active concentration range. Nevertheless, the compounds showed antibacterial potential, with complex (2) being significantly more active than complex (1) against all tested bacterial strains, both in planktonic and biofilm growth state. Both complexes exhibited a very good activity against B16 melanoma cells, with a higher specificity being displayed by compound (1). Taken together, the results indicate that complexes (1) and (2) have specific biological relevance, with potential for the development of antitumor or antimicrobial drugs.

| S-EPMC7504215 | biostudies-literature

Large ring-forming alkylations provide facile access to composite macrocycles.

Project description:Macrocyclic compounds have potential to enable drug discovery for protein targets with extended, solvent-exposed binding sites. Crystallographic structures of peptides bound at such sites show strong surface complementarity and frequent aromatic side-chain contacts. In an effort to capture these features in stabilized small molecules, we describe a method to convert linear peptides into constrained macrocycles based upon their aromatic content. Designed templates initiate the venerable Friedel-Crafts alkylation to form large rings efficiently at room temperature - routinely within minutes - and unimpeded by polar functional groups. No protecting groups, metals, or air-free techniques are required. Regiochemistry can be tuned electronically to explore diverse macrocycle connectivities. Templates with additional reaction capabilities can further manipulate macrocycle structure. The chemistry lays a foundation to extend studies of how the size, shape and constitution of peptidyl macrocycles correlate with their pharmacological properties.

| S-EPMC5485560 | biostudies-literature

Quadruplex ligands may act as molecular chaperones for tetramolecular quadruplex formation.

Project description:G-quadruplexes are a family of four-stranded DNA structures, stabilized by G-quartets, that form in the presence of monovalent cations. Efforts are currently being made to identify ligands that selectively bind to G-quadruplex motifs as these compounds may interfere with the telomere structure, telomere elongation/replication and proliferation of cancer cells. The kinetics of quadruplex-ligands interactions are poorly understood: it is not clear whether quadruplex ligands lock into the preformed structure (i.e. increase the lifetime of the structure by lowering the dissociation constant, k(off)) or whether ligands actively promote the formation of the complex and act as quadruplex chaperones by increasing the association constant, k(on). We studied the effect of a selective quadruplex ligand, a bisquinolinium pyridine dicarboxamide compound called 360A, to distinguish these two possibilities. We demonstrated that, in addition to binding to and locking into preformed quadruplexes, this molecule acted as a chaperone for tetramolecular complexes by acting on k(on). This observation has implications for in vitro and in vivo applications of quadruplexes and should be taken into account when evaluating the cellular responses to these agents.

| S-EPMC1885647 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data