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

Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry
Filippo DoriaMauro Freccero

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 ...Continue Reading

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Citations

Feb 11, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Loukiani Savva, Savvas N Georgiades
Nov 22, 2020·International Journal of Molecular Sciences·Alessandra BenassiValentina Pirota
May 20, 2020·Bioorganic Chemistry·Domenica MusumeciGiovanni N Roviello

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Methods Mentioned

BETA
FRET
circular dichroism
PCR
Assay

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