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A Fragment-Based Approach for the Development of G-Quadruplex Ligands: Role of the Amidoxime Moiety
Article

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

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. https://doi.org/10.3390/molecules23092162

AMA Style

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(9):2162. https://doi.org/10.3390/molecules23092162

Chicago/Turabian Style

Doria, Filippo, Valentina Pirota, Michele Petenzi, Marie-Paule Teulade-Fichou, Daniela Verga, and Mauro Freccero. 2018. "Oxadiazole/Pyridine-Based Ligands: A Structural Tuning for Enhancing G-Quadruplex Binding" Molecules 23, no. 9: 2162. https://doi.org/10.3390/molecules23092162

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