Photo-cross-linking probes for trapping G-quadruplex DNA

Area of Science:

• Medicinal Chemistry
• Chemical Biology
• Molecular Biology

Background:

• G-quadruplexes (G4) are non-canonical DNA structures implicated in various biological processes.
• Targeting G4 structures with small molecules is a promising therapeutic strategy.
• Photoactivatable ligands offer precise spatial and temporal control for G4 modification.

Purpose of the Study:

• To synthesize and characterize novel photoactivatable G-quadruplex ligands.
• To evaluate the selectivity and efficacy of these ligands against G4 structures.
• To explore their utility as research tools in cellular environments.

Main Methods:

• Development of a synthetic pathway for photoactivatable G-quadruplex ligands.
• Assessment of ligand selectivity using G-quadruplex and duplex DNA.
• Selective alkylation studies on human telomeric and c-myc G-quadruplexes.
• In-cell photoactivation and analysis of G4 binding.

Main Results:

• Six novel photoactivatable G-quadruplex ligands were synthesized.
• The ligands retained high selectivity for G-quadruplex over duplex DNA.
• Selective alkylation of specific G-quadruplexes (telomeric and c-myc) was achieved.
• Ligands demonstrated photoactivity in cells, enabling irreversible G4 binding.

Conclusions:

• The developed ligands are potent and selective G-quadruplex binders.
• Photoactivation allows for targeted modification of G-quadruplex structures.
• These compounds serve as valuable tools for studying G-quadruplex biology in situ.