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Herein we report on the synthesis and DNA recognition properties of a series of three N-phenyl carbazole-based light-up probes initially designed for two-photon absorption. The vinylic derivatives (Cbz-2Py, Cbz-3Py) display strong fluorescence enhancement when bound to various duplex- and quadruplex-forming oligonucleotides whereas the oxazole derivative is not fluorescent in DNA. Determination of...
The potential formation of G-quadruplexes in many regions of the genome makes them an attractive target for drug design. A large number of small molecules synthesized in recent years display an ability to selectively target and stabilize G-quadruplexes. To screen for G4 ligands, we modified a G4-FID (G-quadruplex Fluorescent Intercalator Displacement) assay. This test is based on the displacement...
This focused review article discusses in detail, all available high-resolution small molecule ligand/G-quadruplex structural data derived from crystallographic and NMR based techniques, in an attempt to understand key factors in ligand binding and to highlight the biological importance of these complexes. In contrast to duplex DNA, G-quadruplexes are four-stranded nucleic acid structures folded from...
The thrombin-binding DNA aptamer (TBA) 5′-d(GGTTGGTGTGGTTGG)-3′ forms a G-quadruplex that is necessary for binding to the coagulation factor thrombin. The stability of the G-quadruplex of TBA when bound to thrombin and potassium ion (K + ) were investigated for the wild-type oligonucleotide and for mutants in which thymine residues were substituted by adenine. In the presence of thrombin,...
The growing amount of literature about G-quadruplex DNA clearly demonstrates that such a structure is no longer viewed as just a biophysical strangeness but it is instead being considered as an important target for the treatment of various human disorders such as cancers or venous thrombosis. In this scenario, with the aim of finding brand new molecular scaffolds able to interact with the groove of...
The physiological and pharmacological role of nucleic acids structures folded into the non canonical G-quadruplex conformation have recently emerged. Their activities are targeted at vital cellular processes including telomere maintenance, regulation of transcription and processing of the pre-messenger or telomeric RNA. In addition, severe conditions like cancer, fragile X syndrome, Bloom syndrome,...
G-quadruplex nucleic acids are emerging as therapeutic targets for small molecules referred to as small-molecule G-quadruplex ligands. The porphyrin H 2 -TMPyP4 was early reported to be a suitable motif for G-quadruplex DNA recognition. It probably binds to G-quadruplex nucleic acid through π-π stacking with the external G-quartets. We explored chemical modifications of this porphyrin such...
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...
Triplex-forming oligonucleotides (TFOs) can bind to the major groove of homopurine–homopyrimidine stretches of double-stranded DNA in a sequence-specific manner through Hoogsteen hydrogen bonding to form DNA triplexes. TFOs by themselves or conjugated to reactive molecules can be used to direct sequence-specific DNA damage, which in turn results in the induction of several DNA metabolic activities...
In the presence of specific metal ions, DNA oligonucleotides containing guanine repeat sequences can adopt G-quadruplex structures. In this work, we used a combination of spectroscopic and calorimetric techniques to investigate the conformation and unfolding thermodynamics of the K + -form of five G-quadruplexes with sequences: d(G 2 T 2 G 2 TGTG 2 T 2 ...
A number of small molecules demonstrate selective recognition of G-quadruplexes and are able to stabilize their formation. In this work, we performed the synthesis of two biotin-tagged G4 ligands and analyzed their interactions with DNA by two complementary techniques, FRET and FID. The compound that exhibited the best characteristics (a biotin pyridocarboxamide derivative with high stabilization...
G-quadruplexes (GQ) are formed by the association of guanine-rich stretches of DNA. Certain small molecules can influence kinetics and thermodynamics of this association. Understanding the mechanism of ligand-assisted GQ folding is necessary for the design of more efficient cancer therapeutics. The oligonucleotide d(TAGGG) 2 forms parallel bimolecular GQ in the presence of ≥66 mM K + ...
Human telomeres are comprised of d(TTAGGG) repeats involved in the formation of G-quadruplex DNA structures. Ligands that stabilize these G-quadruplex DNA structures are potential inhibitors of the cancer cell-associated enzyme telomerase. In human cells, telomerase adds multiple copies of the 5′-GGTTAG-3′ motif to the end of the G-strand of the telomere and in the majority of tumor cells it results...
Both G-quadruplexes and natural polyamines are intimately associated with tumor growth and proliferation. The effect of the natural polyamines on telomeric and some oncogenic G-quadruplexes including bcl-2, c-kit, and c-myc G-quadruplexes has been studied by using absorption, fluorescence, CD, and NMR methods. The results exhibited an interesting dual-effect depending on polyamineś concentration....
Selective recognition and alkylation of G-quadruplex oligonucleotides has been achieved by substituted naphathalene diimides (NDIs) conjugated to engineered phenol moieties by alkyl-amido spacers with tunable length and conformational mobility. FRET-melting assays, circular dichroism titrations and gel electrophoresis analysis have been carried out to evaluate both reversible stabilization and alkylation...
Solvent-accessible surface area calculations have been performed on two human telomeric quadruplex structures, the parallel crystal structure and an (3 + 1) anti-parallel structure determined by NMR methods. The differences in net ligand solvent-accessible surface area (Δ SASA ) for four structurally distinct categories of small-molecule ligand have been computed, using docked structures of...
The present study has employed a combination of spectroscopic, calorimetric and computational methods to explore the binding of the three side-chained triazatruxene derivative, termed azatrux, to a human telomeric G-quadruplex sequence, under conditions of molecular crowding. The binding of azatrux to the tetramolecular parallel [d(TGGGGT)] 4 quadruplex in the presence and absence of crowding...
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