Unraveling the relationship between structure and stabilization of triarylpyridines as G-quadruplex binding ligands

• Published in: Organic & biomolecular chemistry 2011-01, Vol.9 (17), p.6154-6162
• Main Authors: Smith, N M, Labrunie, Gaëlle, Corry, Ben, Tran, Phong Lan Thao, Norret, Marck, Djavaheri-Mergny, Mojgan, Raston, Colin L, Mergny, Jean-Louis
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Binding Sites; Biochemistry, Molecular Biology; Cell Survival - drug effects; DNA - chemistry; DNA - metabolism; Fluorescence Resonance Energy Transfer; G-Quadruplexes; HeLa Cells; Humans; Life Sciences; Ligands; Neoplasms - drug therapy; Pyridines - chemistry; Pyridines - pharmacology
• ISSN: 1477-0520; 1477-0539
• DOI: 10.1039/c1ob05560g

A series of novel 2,4,6-triarylpyridines have been synthesized and their interactions with intramolecular G-quadruplexes have been measured by Förster Resonance Energy Transfer (FRET) melting and Fluorescent Intercalator Displacement (FID) assays. A few of these compounds exhibit stabilization of G4-DNA that is comparable to other benchmark G4-DNA ligands with fair to excellent G4-DNA vs. duplex selectivity and significant cytotoxicity towards HeLa cells. The nature of the 4-aryl substituents along with side chain length governs the G4-DNA stabilization ability of the compounds. In addition, we demonstrate that there is a strong correlation between the ability of the compounds to stabilize the same G4-DNA sequence in K(+) and Na(+) conditions and a strong correlation between the ability of the compounds to stabilize different G4-DNA sequences in K(+) or Na(+) buffer.