A Model of Smart G-Quadruplex Ligand

Haudecoeur, Romain; Stefan, Loïc; Denat, Franck; Monchaud, David

doi:10.1021/ja310056y

Cited by 82 publications

(82 citation statements)

References 39 publications

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“…Indeed, G‐quadruplex formation has been shown to hinder telomerase activity, but in addition it is implicated in the regulation of gene expression and quadruplex structures have thus become a potential target in oncology . A range of small molecules has been shown to strongly bind and stabilise such G‐quadruplex structures, thereby rendering these compounds potential anticancer drugs . Recent findings, such as the fact that parallel quadruplexes can still act as a substrate for telomerase, suggest, however, that indirect telomerase inhibition is not necessarily the dominant contribution in anticancer activity of quadruplex‐binding ligands.…”

Section: Introductionmentioning

confidence: 99%

A Water‐Soluble Tetraazaperopyrene Dye as Strong G‐Quadruplex DNA Binder

Hahn

Buurma

Gade

2016

Chemistry A European J

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The interactions of the water‐soluble tetraazaperopyrene dye 1 with ct‐DNA, duplex‐[(dAdT)12 ⋅(dAdT)12], duplex‐[(dGdC)12 ⋅(dGdC)12] as well as with two G‐quadruplex‐forming sequences, namely the human telomeric 22AG and the promotor sequence c‐myc, were investigated by means of UV/visible and fluorescence spectroscopy, isothermal titration calorimetry (ITC) and molecular docking studies. Dye 1 exhibits a high affinity for G‐quadruplex structures over duplex DNA structures. Furthermore, the ligand shows promising G‐quadruplex discrimination, with an affinity towards c‐myc of 2×107 m −1 (i.e., K d=50 nm), which is higher than for 22AG (4×106 m −1). The ITC data reveal that compound 1 interacts with c‐myc in a stoichiometric ratio of 1:1 but also indicate the presence of two identical lower affinity secondary binding sites per quadruplex. In 22AG, there are two high affinity binding sites per quadruplex, that is, one on each side, with a further four weaker binding sites. For both quadruplex structures, the high affinity interactions between compound 1 and the quadruplex‐forming nucleic acid structures are weakly endothermic. Molecular docking studies suggest an end‐stacking binding mode for compound 1 interacting with quadruplex structures, and a higher affinity for the parallel conformation of c‐myc than for the mixed‐hybrid conformation of 22AG. In addition, docking studies also suggest that the reduced affinity for duplex DNA structures is due to the non‐viability of an intercalative binding mode.

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Section: Introductionmentioning

confidence: 99%

A Water‐Soluble Tetraazaperopyrene Dye as Strong G‐Quadruplex DNA Binder

Hahn

Buurma

Gade

2016

Chemistry A European J

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“…A ligand was designed as a template-assembled synthetic G-quartet (TASQ), which can form an external G-quartet stacking onto the end of G-quadruplex with its positive appendages hooked by the negative phosphates of G-quadruplex. 20 Furthermore, a pentacationic manganese(III) porphyrin complex was invented to show a binding affinity 4 orders of magnitude higher than that of duplex DNA. 21 In fact, experiments suggested that certain ligands do more than stabilize G-quadruplexes.…”

Section: Introductionmentioning

confidence: 99%

All-Atomic Simulations on Human Telomeric G-Quadruplex DNA Binding with Thioflavin T

Luo

2015

J. Phys. Chem. B

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Ligand-stabilized human telomeric G-quadruplex DNA is believed to be an anticancer agent, as it can impede the continuous elongation of telomeres by telomerase in cancer cells. In this study, five well-established human telomeric G-quadruplex DNA models were probed on their binding behaviors with thioflavin T (ThT) via both conventional molecular dynamics (MD) and well-tempered metadynamics (WT-MetaD) simulations. Novel dynamics and characteristic binding patterns were disclosed by the MD simulations. It was observed that the K(+) promoted parallel and hybridized human telomeric G-quadruplex conformations pose higher binding affinities to ThT than the Na(+) and K(+) promoted basket conformations. It is the end, sandwich, and base stacking driven by π-π interactions that are identified as the major binding mechanisms. As the most energy favorable binding mode, the sandwich stacking observed in (3 + 1) hybridized form 1 G-quadruplex conformation is triggered by reversible conformational change of the G-quadruplex. To further examine the free energy landscapes, WT-MetaD simulations were utilized on G-quadruplex-ThT systems. It is found that all of the major binding modes predicted by the MD simulations are confirmed by the WT-MetaD simulations. The results in this work not only accord with existing experimental findings, but also reinforce our understanding on the dynamics of G-quadruplexes and aid future drug developments for G-quadruplex stabilization ligands.

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“…This structure has attracted significant attention due to its proposed role in telomere maintenance and consequently its potential as a target for the development of new anticancer therapies 1, 2, 3, 4. Therefore, a large number of small molecules have been developed over the past two decades with the aim of selectively binding and stabilizing G‐quadruplex DNA 5, 6, 7, 8, 9. Although the structures of single G‐quadruplexes containing four repeats of the 5′‐TTAGGG sequence have been studied in detail,10, 11, 12, 13, 14, 15 less is known about the higher‐order structures formed by longer telomeric sequences 16, 17, 18, 19.…”

Section: Introductionmentioning

confidence: 99%

“…Though a large number of small molecules have been previously developed as single G‐quadruplex DNA binders,5, 6, 7, 8, 9 comparatively very few have been studied (or indeed specifically designed) as binders for multimeric G‐quadruplex structures 24, 25, 26, 27, 28, 29, 30, 31, 32. This includes a chiral cyclic helicene proposed to bind in the cleft between two human telomeric G‐quadruplexes linked by a TTA spacer 25.…”

Section: Introductionmentioning

confidence: 99%

Dinickel–Salphen Complexes as Binders of Human Telomeric Dimeric G‐Quadruplexes

Zhou

Liao

et al. 2017

Chemistry A European J

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Three new polyether‐tethered dinickel–salphen complexes (2 a–c) have been synthesized and fully characterized by NMR spectroscopy, mass spectrometry, and elemental analyses. The binding affinity and selectivity of these complexes and of the parent mono‐nickel complex (1) towards dimeric quadruplex DNA have been determined by UV/Vis titrations, fluorescence spectroscopy, CD spectroscopy, and electrophoresis. These studies have shown that the dinickel–salphen complex with the longest polyether linker (2 c) has higher binding affinity and selectivity towards dimeric quadruplexes (over monomeric quadruplexes) than the dinickel–salphen complexes with the shorter polyether linkers (2 a and 2 b). Complex 2 c also has higher selectivity towards human telomeric dimeric quadruplexes with one TTA linker than the monometallic complex 1. Based on the spectroscopic data, a possible binding mode between complex 2 c and the dimeric G‐quadruplex DNA under study is proposed.

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A Model of Smart G-Quadruplex Ligand

Cited by 82 publications

References 39 publications

A Water‐Soluble Tetraazaperopyrene Dye as Strong G‐Quadruplex DNA Binder

A Water‐Soluble Tetraazaperopyrene Dye as Strong G‐Quadruplex DNA Binder

All-Atomic Simulations on Human Telomeric G-Quadruplex DNA Binding with Thioflavin T

Dinickel–Salphen Complexes as Binders of Human Telomeric Dimeric G‐Quadruplexes

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