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

• Published in: Molecules (Basel, Switzerland) Switzerland), 2018-08, Vol.23 (9), p.2162
• Main Authors: Doria, Filippo, Pirota, Valentina, Petenzi, Michele, Teulade-Fichou, Marie-Paule, Verga, Daniela, Freccero, Mauro
• Format: Article
• Language: English
• Subjects: Appendages; Aromatic compounds; Binders; Binding; Chemical Sciences; Circular Dichroism; Coordination chemistry; Deoxyribonucleic acid; DNA; Drug Design; Drug Stability; Flexibility; Fluorescence Resonance Energy Transfer; FRET-melting; G-quadruplex; G-Quadruplexes; G4-FID; G4-ligands; Genomes; Ligands; Medicinal Chemistry; Molecular Structure; Oligomerization; oxadiazole/pyridine polyheteroaryls; Oxadiazoles; Oxadiazoles - chemical synthesis; Oxadiazoles - chemistry; Oxadiazoles - pharmacology; Oxazole; Pyridines; Pyridines - chemical synthesis; Pyridines - chemistry; Pyridines - pharmacology; Regulatory sequences; Selectivity; Sludge; Therapeutic applications
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules23092162

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.