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

Abstract

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.

Triarylpyridine Compounds and Chloroquine Act in Concert to Trigger Lysosomal Membrane Permeabilization and Cell Death in Cancer Cells

“…In addition to the parent compound 20A, three new 20A derivatives were synthesized ( Figure S2a) and then tested for their ability to stabilize G4 structures. These three new 20A derivatives stabilize the human telomeric quadruplex in a concentration-dependent manner ( Figure S2b), as previously reported for 20A [25].…”

Design of Modular G‐quadruplex Ligands

“…With the exception of compounds 14 e and 14 f , modifications in the terminal amino groups (piperazine vs. pyrrolidine) do not significantly affect the Δ T m values. Most triphenylpyridine derivatives 14 – 18 that display high to midrange stabilization of G4 DNA also exhibit significant cytotoxicity toward HeLa cells …”

A FRET-based screening assay for nucleic acid ligands

“…It is a very simple assay for determining the stabilizing effect of compounds on nucleic acid structures [24,25]. Similar procedures have been described to evaluate quadruplex binding compounds [26][27][28][29][30][31][32], triplex ligands [23] and trinucleotide repeat ligands [33]. This paper expands these assays to different nucleic acid secondary structures including: -d-G 3 (T 2 AG 3 ) 3 human telomere DNA quadruplex, -r-(C 3 UA 2 ) 2 C 3 :d-GT 2 AG 3 T 2 AG DNA:RNA duplex based on the short human telomere motif, -d-(GAA) 6 :(TTC) 6 duplex related to Friedreich ataxia and -d-(CTG) 7 hairpin related to myotonic dystrophy type 1.…”