Abstract
The binding affinities of three carbazole derivatives to the intramolecular G-quadruplex (GQ) DNA formed by the sequence 5′-AGGGAGGGCGCTGGGAGGAGGG-3′, derived from the c-KIT 1 oncogene region, were investigated. All carbazole cationic ligands that differed in the substituents on the nitrogen atom were able to stabilize G-quadruplex, as demonstrated using UV-Vis, fluorescence and CD spectroscopic techniques as well as molecular modeling. The spectrophotometric titration results showed spectral features characteristic of these ligands-bathochromic shifts and initial hypochromicity followed by hyperchromicity at higher GQ concentrations. All free carbazole ligands exhibited modest fluorescent properties, but after binding to the DNA the fluorescence intensity increased significantly. The binding affinities of carbazole ligands to the c-KIT 1 DNA were comparable showing values in the order of 105 M−1. Molecular modeling highlights the differences in interactions between each particular ligand and studied G-quadruplex, which potentially influenced binding strength. Obtained results relevant that all three investigated ligands have stabilization properties on studied G-quadruplex.
Highlights
Human genomic DNA contains guanine-rich sequences which can form stable four-stranded structures called G-quadruplexes (GQs) [1]
We have been interested in carbazole ligands interacting with G-quadruplexes formed by oligonucleotides with sequences corresponding to promoter regions of oncogenes [71]
Three carbazole compounds were investigated as c-KIT 1 G-quadruplex targeting probes
Summary
Human genomic DNA contains guanine-rich sequences which can form stable four-stranded structures called G-quadruplexes (GQs) [1]. These tetraplex structures are formed from co-planar arrangements of four guanines that are linked by Hoogsteen-type hydrogen bonds. The structures of G-quadruplex are important in human telomeres [5], and promoter regions of oncogenes. Due to putative existence of G-quadruplexes in the promoter regions of oncogene such as c-MYC [6,7,8,9], bcl-2 [10,11], RET [12,13], VEGF [14], hTERT [15], or c-KIT [16,17,18], G-quadruplexes have received even more attention after the publication of reports on existence of G-quadruplex structures in human cells [19,20,21]. The structures of c-KIT G-quadruplex DNA have been determined using the NMR and X-ray crystallography (PDB id: 2O3M [22], 2KQG, 2KQH [23], 2KYP [24], 3QXR [25])
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