Preprint Article Version 1 This version is not peer-reviewed

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

Version 1 : Received: 5 July 2018 / Approved: 6 July 2018 / Online: 6 July 2018 (08:28:22 CEST)

A peer-reviewed article of this Preprint also exists.

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. 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.

Journal reference: Molecules 2018, 23, 2162
DOI: 10.3390/molecules23092162

Abstract

Acyclic olygoheteroaryl-based compounds represent a valuable class of ligands for nucleic acid recognition. In this regard, acyclic 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 polyheteroaryl oxadiazole/pyridine-ligands targeting DNA G-quadruplexes. In order 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). Interesting, 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.

Subject Areas

G-quadruplex; oxadiazole/pyridine polyheteroaryls; G4-ligands; FRET-melting; G4-FID; circular dichroism

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