New Xanthone Derivatives as Potent G-Quadruplex Binders for Developing Anti-Cancer Therapeutics

Area of Science:

• Medicinal Chemistry
• Biochemistry
• Molecular Biology

Background:

• Xanthone scaffolds are crucial in medicinal chemistry but underexplored for G-quadruplex (G4) DNA targeting.
• G4 DNA stabilization is a promising strategy for developing novel anticancer agents.
• Selective G4 DNA recognition over double-stranded DNA (dsDNA) is key for targeted cancer therapy.

Purpose of the Study:

• To synthesize and evaluate xanthone-based derivatives for selective G4 DNA binding and anticancer activity.
• To investigate the binding mode and mechanism of interaction between xanthone derivatives and G4 DNA.
• To explore the potential of these compounds as targeted anticancer agents.

Main Methods:

• Synthesis of functionalized xanthone derivatives.
• Biophysical experiments to assess G4 DNA selectivity (e.g., fluorescence spectroscopy, surface plasmon resonance).
• Computational studies (molecular docking) and competitive ligand binding assays to elucidate binding modes.

Main Results:

• Synthesized xanthone derivatives demonstrated significant selectivity for G4 DNA over dsDNA.
• Biophysical and computational studies confirmed an end-stacking binding mode with G4 DNA.
• Compounds induced conformational changes in flanking nucleotides, enhancing binding pocket formation.
• Selective action against cancer cells indicated potent anticancer efficacy.

Conclusions:

• Xanthone derivatives represent a promising scaffold for developing selective G4 DNA-targeting anticancer agents.
• Structure-based screening approaches are vital for designing molecules with specific recognition of non-canonical DNA structures like G4.
• This research highlights the therapeutic potential of targeting G4 DNA with novel chemical entities.