Small-molecule quadruplex-targeted drug discovery

Ohnmacht, Stephan A.; Neidle, Stephen

doi:10.1016/j.bmcl.2014.04.029

Cited by 170 publications

(135 citation statements)

References 193 publications

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“…This has opened a new drug intervention field in anticancer therapy. Several different classes of ligands that target G4 DNA have been developed (Granzhan et al, 2010; Monchaud et al, 2010; Ohnmacht and Neidle, 2014). A number of these have been identified by our research group and most of them were discovered in order to target the grooves of the G4 structures (Cosconati et al, 2009, 2010, 2012; Pagano et al, 2010; Petraccone et al, 2011; Di Leva et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Bis-indole derivatives with antitumor activity turn out to be specific ligands of human telomeric G-quadruplex

et al. 2014

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Bis-indolinone derivatives having either 2,6-disubstituted pyridine core (1a and 1b) or 1,10-disubstituted phenanthroline core (2a and 2b), already known to have antitumor activity, have been tested as potential G-quadruplex binders. Compounds 2a and 2b are able to selectively stabilize G-quadruplex over duplex DNA, and also to discriminate among different G-quadruplex structures, having a particular affinity for the parallel form of the human telomeric G-quadruplex. Both compounds are also able to induce telomeric DNA damage that may explain the activity of these compounds.

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Section: Introductionmentioning

confidence: 99%

Bis-indole derivatives with antitumor activity turn out to be specific ligands of human telomeric G-quadruplex

et al. 2014

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“…The similar binding mode of porphyrin has been well documented (Wei, Han, Jia, Zhou, & Li, 2008), in which the π-π contact between G-tetrad platform and porphyrin macrocycle is crucial in maintaining the end-stacking stabilization. The other quadruplex binders, which are validated by X-ray crystallographic and NMR data, have also highlighted the planarity as an essential feature for effective binding (Ohnmacht & Neidle, 2014). Figure ns shows occupancy percentage of 73.3%, with an average distance of 2.937 Å, which indicates its strong stabilization.…”

Section: Ligand Interaction With Parallel Quadruplexmentioning

confidence: 83%

Molecular docking and dynamics simulations on the interaction of cationic porphyrin–anthraquinone hybrids with DNA G-quadruplexes

Arba

Kartasasmita

Tjahjono

2015

Journal of Biomolecular Structure and Dynamics

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A series of cationic porphyrin-anthraquinone hybrids bearing either pyridine, imidazole, or pyrazole rings at the meso-positions have been investigated for their interaction with DNA G-quadruplexes by employing molecular docking and molecular dynamics simulations. Three types of DNA G-quadruplexes were utilized, which comprise parallel, antiparallel, and mixed hybrid topologies. The porphyrin hybrids have a preference to bind with parallel and mixed hybrid structures compared to the antiparallel structure. This preference arises from the end stacking of porphyrin moiety following G-stem and loop binding of anthraquinone tail, which is not found in the antiparallel due to the presence of diagonal and lateral loops that crowd the G-quartet. The binding to the antiparallel, instead, occurred with poorer affinity through both the loop and wide groove. All sites of porphyrin binding were confirmed by 6 ns molecular dynamics simulation, as well as by the negative value of the total binding free energies that were calculated using the MMPBSA method. Free energy analysis shows that the favorable contribution came from the electrostatic term, which supposedly originated from the interaction of either cationic pyridinium, pyrazole, or imidazole groups and the anionic phosphate backbone, and also from the van der Waals energy, which primarily contributed through end stacking interaction.

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“…Consequently, stabilization of GQ structures by small‐molecule ligands has emerged as a novel approach to cancer therapeutics 7. In this context, several small‐molecule ligands that bind and stabilize GQs are being rigorously evaluated as chemotherapeutic candidates, and have been used as tools to understand the biological role of GQ‐forming sequences 8, 9…”

Section: Introductionmentioning

confidence: 99%

Probing Human Telomeric DNA and RNA Topology and Ligand Binding in a Cellular Model by Using Responsive Fluorescent Nucleoside Probes

et al. 2017

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The development of biophysical systems that enable an understanding of the structure and ligand‐binding properties of G‐quadruplex (GQ)‐forming nucleic acid sequences in cells or models that mimic the cellular environment would be highly beneficial in advancing GQ‐directed therapeutic strategies. Herein, the establishment of a biophysical platform to investigate the structure and recognition properties of human telomeric (H‐Telo) DNA and RNA repeats in a cell‐like confined environment by using conformation‐sensitive fluorescent nucleoside probes and a widely used cellular model, bis(2‐ethylhexyl) sodium sulfosuccinate reverse micelles (RMs), is described. The 2′‐deoxy and ribonucleoside probes, composed of a 5‐benzofuran uracil base analogue, faithfully report the aqueous micellar core through changes in their fluorescence properties. The nucleoside probes incorporated into different loops of H‐Telo DNA and RNA oligonucleotide repeats are minimally perturbing and photophysically signal the formation of respective GQ structures in both aqueous buffer and RMs. Furthermore, these sensors enable a direct comparison of the binding affinity of a ligand to H‐Telo DNA and RNA GQ structures in the bulk and confined environment of RMs. These results demonstrate that this combination of a GQ nucleoside probe and easy‐to‐handle RMs could provide new opportunities to study and devise screening‐compatible assays in a cell‐like environment to discover GQ binders of clinical potential.

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Small-molecule quadruplex-targeted drug discovery

Cited by 170 publications

References 193 publications

Bis-indole derivatives with antitumor activity turn out to be specific ligands of human telomeric G-quadruplex

Bis-indole derivatives with antitumor activity turn out to be specific ligands of human telomeric G-quadruplex

Molecular docking and dynamics simulations on the interaction of cationic porphyrin–anthraquinone hybrids with DNA G-quadruplexes

Probing Human Telomeric DNA and RNA Topology and Ligand Binding in a Cellular Model by Using Responsive Fluorescent Nucleoside Probes

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