Carbazole ligands as c-myc G-quadruplex binders

Area of Science:

• Biochemistry
• Medicinal Chemistry
• Molecular Biology

Background:

• The c-myc oncogene plays a crucial role in cell proliferation and cancer development.
• G-quadruplex structures in DNA, particularly in the c-myc promoter region (Pu22), are potential targets for anticancer drugs.
• Carbazole derivatives are explored for their therapeutic potential due to their diverse biological activities.

Purpose of the Study:

• To investigate the interaction between novel carbazole derivatives and the c-myc G-quadruplex DNA.
• To determine the binding mode and stoichiometry of these ligands with the G-quadruplex Pu22.
• To assess the potential of these carbazole derivatives as G-quadruplex-targeting agents.

Main Methods:

• UV-Vis spectrophotometry to monitor binding events.
• Fluorescence spectroscopy to detect ligand-G-quadruplex interactions and changes in ligand fluorescence.
• Circular Dichroism (CD) spectroscopy to analyze structural changes in G-quadruplex DNA upon ligand binding.
• Molecular modeling to elucidate the binding mechanism and interactions at the atomic level.

Main Results:

• The functionalized carbazole derivatives effectively stabilized the intramolecular G-quadruplex formed by the Pu22 DNA sequence.
• Binding of the ligands to G-quadruplex Pu22 resulted in a significant increase in fluorescence intensity.
• All three ligands exhibited a binding stoichiometry of two ligand molecules per G-quadruplex, indicating comparable binding affinities.
• The binding mode was consistent with end-stacking interactions on the terminal G-tetrads of the G-quadruplex.

Conclusions:

• The studied carbazole derivatives show promising interactions with the c-myc G-quadruplex DNA.
• These findings suggest that functionalized carbazoles can act as effective binders and stabilizers of G-quadruplex structures.
• The observed binding characteristics support their potential development as therapeutic agents targeting G-quadruplexes in cancer therapy.