Xanthene and xanthone derivatives as G-quadruplex stabilizing ligands

Area of Science:

• Medicinal Chemistry
• Biochemistry
• Molecular Biology

Background:

• G-quadruplexes are non-canonical DNA structures implicated in various biological processes, including cancer.
• Developing selective small molecules to target G-quadruplexes is a key strategy in anticancer drug discovery.
• Previous research focused on anthraquinone and acridine scaffolds for G-quadruplex ligand development.

Purpose of the Study:

• To design and synthesize novel xanthone and xanthene derivatives as G-quadruplex ligands.
• To evaluate the binding affinity and selectivity of these compounds for G-quadruplex DNA versus duplex DNA.
• To identify lead compounds with enhanced G-quadruplex targeting capabilities.

Main Methods:

• Chemical synthesis of xanthone, xanthene, and dimeric bridged derivatives.
• Electrospray Ionization (ESI) mass spectrometry for compound characterization.
• Förster Resonance Energy Transfer (FRET) assays to assess G-quadruplex binding.
• Molecular modeling simulations to complement experimental findings.

Main Results:

• All synthesized compounds demonstrated good binding to G-quadruplex DNA at telomeres and oncogene promoters.
• A dimeric compound and a three-side chain xanthone derivative emerged as the most potent ligands.
• These lead compounds exhibited high selectivity for G-quadruplex structures over duplex DNA.
• Experimental data were consistent with molecular modeling predictions.

Conclusions:

• Xanthone and xanthene scaffolds are effective for developing selective G-quadruplex ligands.
• The dimeric and three-side chain xanthone derivatives represent promising candidates for further investigation.
• These ligands show potential for therapeutic applications targeting G-quadruplex DNA in diseases like cancer.