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Molecules 2018, 23(9), 2162; https://doi.org/10.3390/molecules23092162

Oxadiazole/Pyridine-Based Ligands: A Structural Tuning for Enhancing G-Quadruplex Binding

1
Dipartimento di Chimica, Università di Pavia, 27100 Pavia, Italy
2
Institut Curie, PSL Research University, CNRS UMR9187, INSERM U1196, F-91405 Orsay, France
3
Paris Sud University, Paris-Saclay University, CNRS UMR9187, INSERM U1196, F-91405 Orsay, France
*
Authors to whom correspondence should be addressed.
Academic Editors: Ramon Eritja, Lajos Kovacs and Daniela Montesarchio
Received: 5 July 2018 / Revised: 16 August 2018 / Accepted: 20 August 2018 / Published: 28 August 2018
(This article belongs to the Collection New Frontiers in Nucleic Acid Chemistry)
Full-Text   |   PDF [2390 KB, uploaded 28 August 2018]   |  

Abstract

Non-macrocyclic heteroaryls represent a valuable class of ligands for nucleic acid recognition. In this regard, non-macrocyclic pyridyl polyoxazoles and polyoxadiazoles were recently identified as selective G-quadruplex stabilizing compounds with high cytotoxicity and promising anticancer activity. Herein, we describe the synthesis of a new family of heteroaryls containing oxadiazole and pyridine moieties targeting DNA G-quadruplexes. To perform a structure–activity analysis identifying determinants of activity and selectivity, we followed a convergent synthetic pathway to modulate the nature and number of the heterocycles (1,3-oxazole vs. 1,2,4-oxadiazole and pyridine vs. benzene). Each ligand was evaluated towards secondary nucleic acid structures, which have been chosen as a prototype to mimic cancer-associated G-quadruplex structures (e.g., the human telomeric sequence, c-myc and c-kit promoters). Interestingly, heptapyridyl-oxadiazole compounds showed preferential binding towards the telomeric sequence (22AG) in competitive conditions vs. duplex DNA. In addition, G4-FID assays suggest a different binding mode from the classical stacking on the external G-quartet. Additionally, CD titrations in the presence of the two most promising compounds for affinity, TOxAzaPy and TOxAzaPhen, display a structural transition of 22AG in K-rich buffer. This investigation suggests that the pyridyl-oxadiazole motif is a promising recognition element for G-quadruplexes, combining seven heteroaryls in a single binding unit. View Full-Text
Keywords: G-quadruplex; oxadiazole/pyridine polyheteroaryls; G4-ligands; FRET-melting; G4-FID; circular dichroism G-quadruplex; oxadiazole/pyridine polyheteroaryls; G4-ligands; FRET-melting; G4-FID; circular dichroism
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Doria, F.; Pirota, V.; Petenzi, M.; Teulade-Fichou, M.-P.; Verga, D.; Freccero, M. Oxadiazole/Pyridine-Based Ligands: A Structural Tuning for Enhancing G-Quadruplex Binding. Molecules 2018, 23, 2162.

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