An Acyclic Oligoheteroaryle That Discriminates Strongly between Diverse G‐Quadruplex Topologies

Hamon, Florian; Largy, Eric; Guédin-Beaurepaire, Aurore; Rouchon-Dagois, Myriam; Sidibe, Assitan; Monchaud, David; Mergny, Jean‐Louis; Riou, Jean‐François; Nguyen, Chi-Hung; Teulade-Fichou, Marie-Paule

doi:10.1002/anie.201103422

Cited by 99 publications

(128 citation statements)

References 45 publications

(12 reference statements)

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“…This lack of selectivity among G-quadruplexes is in line with a previous study in which selectivity against duplexes was established but not discrimination of a G-quadruplex conformation [25a]. The TOxaPy ligand is reported to stabilise the Na þ fold of the human telomeric sequence but not the K þ one [9]. When tested in the above conditions, no significant stabilisation was observed for any of the sequences (Figure SI-2) but the reported stabilisation of 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 F21T in Na þ could be reproduced ( Figure SI-3).…”

Section: Effects Of Ligands On Stability Of G-quadruplexessupporting

confidence: 88%

“…Braco19 [11] and TmPyP4 were purchased from Sigma. 360A, Phen-DC 3 [14], TrisQ [15] and TOxaPy [9] were synthesised and kindly provided by Teulade-Fichou and colleagues as previously described. Pyridostatin [16] was purchased from Chemietek.…”

Section: Reagentsmentioning

confidence: 99%

“…Gquadruplex ligands that recognised and stabilised only certain types of G-quadruplexes have been reported. For example, the TOxaPY ligand stabilises the fold of the human telomeric sequence observed in Na þ but not that observed in K þ [9]. The identification of ligands able to discriminate one G-quadruplex topology from another would require further development of G-quadruplex-targeting drugs.…”

Section: Introduction Q2mentioning

confidence: 99%

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Assessment of selectivity of G-quadruplex ligands via an optimised FRET melting assay

2015

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Section: Effects Of Ligands On Stability Of G-quadruplexessupporting

confidence: 88%

Section: Reagentsmentioning

confidence: 99%

Section: Introduction Q2mentioning

confidence: 99%

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Assessment of selectivity of G-quadruplex ligands via an optimised FRET melting assay

2015

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“…20−22 Evidently, successful anticancer ligands used in such interventions should exhibit an exquisite specificity for G-quadruplexes over duplexes and ability to discriminate one G-quadruplex over the other. 23,24 In attempting to find such ligands, understanding the driving forces that determine the stability and folding pathways of G-quadruplex structures and their dependence on the solution conditions (temperature, cation type) and the type of the ligand undoubtedly plays a crucial role. 12,25−27 Despite tremendous progress in understanding of Gquadruplexes made over the last years, there are still many unanswered questions concerning their biological role, formation, structure, and physicochemical properties.…”

Section: ■ Introductionmentioning

confidence: 99%

Energetic Basis of Human Telomeric DNA Folding into G-Quadruplex Structures

et al. 2012

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Recent theoretical studies performed on the folding/unfolding mechanism of the model telomeric human DNA, 5'-AGGGTTAGGGTTAGGGTTAGGG-3' (Tel22), have indicated that in the presence of K(+) ions Tel22 folds into two hybrid G-quadruplex structures characterized by one double and two reversal TTA loops arranged in a different way. They predicted a new unfolding pathway from the initial mixture of hybrid G-quadruplexes via the corresponding intermediate triplex structures into the final, fully unfolded state. Significantly, no experimental evidence supporting the suggested pathway has been reported. In the current work, we performed a comprehensive global thermodynamic analysis of calorimetric (DSC, ITC) and spectroscopic (CD) data obtained on monitoring the folding/unfolding of Tel22 induced by changes of temperature and K(+) concentration. We show that unfolding of Tel22 may be described as a monomolecular equilibrium three-state process that involves thermodynamically distinguishable folded (F), intermediate (I), and unfolded (U) state. Considering that calorimetric methods cannot distinguish between energetically similar G-quadruplex or triplex conformations predicted by the theoretical model one can conclude that our results represent the first experimental support of the suggested unfolding/folding mechanism of Tel22. This conclusion is confirmed by the fact that the estimated number of K(+) ions released upon each unfolding step in our thermodynamic model agrees well with the corresponding values predicted by the theoretical model and that the observed changes in enthalpy, entropy, and heat capacity accompanying the F → I and I → U transitions can be reasonably explained only if the intermediate state I is considered to be a triplex structural conformation.

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“…promoting -stacking through a size-controlled planar aromatic surface and electrostatics interaction with various possibilities like protonable chains or charged metal center. However these simple rules know exceptions like Telomestatin and its derived compounds (HXDV [4] and TOxaPy [5]). Screening of large chemical libraries appears to be a complementary approach to rational design in order to discover new scaffolds able to distinguish additional features.…”

Section: Introductionmentioning

confidence: 99%

Screening of a Chemical Library by HT-G4-FID for Discovery of Selective G-quadruplex Binders

Largy¹,

Saettel²,

Hamon³

et al. 2012

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Due to the lack of structural guidelines about G-quadruplex ligands, rational design cannot be the only approach to discover potent G4-ligands. As a complementary approach, screening of chemical library may provide interesting scaffolds known as hits provided that specific tools are available. In this work, the Institut Curie-CNRS chemical library was firstly screened by chemoinformatics methods. Similarity estimations by comparison with reference compounds (Phen-DC3, 360A, MMQ12) provided a set of molecules, which were then evaluated by high-throughput G4-FID (HT-G4-FID) against various G-quadruplex DNA. A full investigation of the most interesting molecules, using the HT-G4-FID assay and molecular modeling, supplied an interesting structure-activity relationship confirming the efficiency of this general approach. Overall, we demonstrated that HT-G4-FID coupled with screening of chemical libraries is a powerful tool to identify new G4-DNA binding scaffolds.

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An Acyclic Oligoheteroaryle That Discriminates Strongly between Diverse G‐Quadruplex Topologies

Cited by 99 publications

References 45 publications

Assessment of selectivity of G-quadruplex ligands via an optimised FRET melting assay

Assessment of selectivity of G-quadruplex ligands via an optimised FRET melting assay

Energetic Basis of Human Telomeric DNA Folding into G-Quadruplex Structures

Screening of a Chemical Library by HT-G4-FID for Discovery of Selective G-quadruplex Binders

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