Towards the Development of Structure-Selective G-Quadruplex-Binding Indolo[3,2-b]quinolines

Area of Science:

• Medicinal Chemistry
• Molecular Biology
• Biophysical Chemistry

Background:

• DNA G-quadruplexes are non-canonical DNA structures implicated in various biological processes.
• Indoloquinoline derivatives are investigated for their potential as ligands targeting specific DNA structures.

Purpose of the Study:

• To investigate the interaction of phenyl-substituted indoloquinolines with DNA G-quadruplexes of varying topologies.
• To evaluate the selectivity of these ligands for parallel-stranded G-quadruplexes over other DNA structures.

Main Methods:

• Spectroscopic techniques (e.g., UV-Vis, fluorescence) were employed to study ligand-DNA interactions.
• Isothermal titration calorimetry (ITC) was used to determine binding affinities and thermodynamic parameters.
• Competition assays with double-helical DNA were performed to assess selectivity.

Main Results:

• N5-Methylated indoloquinoline derivatives ((Me) PIQ) demonstrated high binding affinities for the parallel-stranded MYC G-quadruplex and a (3+1)-hybrid structure.
• These ligands exhibited significant selectivity, effectively discriminating against antiparallel thrombin-binding aptamer (TBA) and human telomeric (HT) G-quadruplexes.
• Dissociation constants for MYC G-quadruplex binding were in the submicromolar range, approximately one order of magnitude lower than for antiparallel quadruplexes.
• Binding to the MYC G-quadruplex was driven by comparable enthalpic and entropic contributions, irrespective of the cation present.

Conclusions:

• Phenyl-substituted indoloquinolines, particularly (Me) PIQ derivatives, are potent and selective ligands for parallel DNA G-quadruplexes.
• The observed selectivity suggests potential applications in targeting specific G-quadruplex structures in biological systems.
• The thermodynamic profile indicates a complex binding mechanism involving both enthalpy and entropy contributions.