Tunable G-Quadruplex Ligands: Azobenzene Derivatives for Light-Controlled DNA Modulation

Area of Science:

• Medicinal Chemistry
• Biochemistry
• Molecular Biology

Background:

• Guanine-rich sequences form G-quadruplexes (G4s) during DNA processes.
• G4s are therapeutic targets in cancer due to their role in replication stress.
• Existing G4 ligands have permanent effects; light-switchable systems offer better control.

Purpose of the Study:

• To design and synthesize novel photoactive G4 ligands based on azobenzene.
• To investigate how structural variations (substitution, size, electronics) affect G4 binding and stabilization.
• To explore bidirectional modulation of G4 properties using external stimuli like light.

Main Methods:

• Synthesis of diverse azobenzene-based compounds.
• Orthogonal biophysical methods for G4 interaction analysis.
• Quantum-chemical calculations to understand structure-activity relationships.

Main Results:

• Azobenzene substitution patterns influence G4 binding and stabilization.
• The trans isomer's interaction mode bidirectionally modulates G4 properties.
• Photoactivity allows for tunable on-off control of G4 ligands.

Conclusions:

• Insights into designing photoactive G4 ligands with tunable functionality.
• Potential for precise control of G4 structures in biological applications.
• Azobenzene-based compounds are promising candidates for light-switchable G4-targeting therapies.