Neomycin-capped aromatic platforms: quadruplex DNA recognition and telomerase inhibition

Area of Science:

• Medicinal Chemistry
• Biochemistry
• Molecular Biology

Background:

• G-quadruplex (G4) DNA structures are crucial in telomere maintenance and oncogene regulation.
• Developing selective G4 binders is a key strategy for targeted cancer therapies.
• Aminoglycoside-based macrocycles offer a unique scaffold for G4 DNA interaction.

Purpose of the Study:

• To synthesize and characterize novel aminoglycoside-capped macrocyclic compounds.
• To evaluate their binding affinity and selectivity for G4 DNA structures.
• To assess their potential as telomerase inhibitors.

Main Methods:

• Intramolecular bis-tethering of neomycin on aromatic platforms (phenanthroline, acridine, quinacridine).
• Nuclear Magnetic Resonance (NMR) and computational studies for structural analysis.
• Förster Resonance Energy Transfer (FRET)-melting and FRET competition assays for DNA binding.
• Telomeric Repeat Amplification Protocol (TRAP) assay for telomerase inhibition.

Main Results:

• Synthesized macrocyclic compounds exhibit high flexibility without conformational restriction of the neomycin moiety.
• Compounds show moderate to high affinity for the G4-conformation of human telomeric repeats, dependent on aromatic moiety size.
• Demonstrated poor binding to duplex DNA and preference for intramolecular G4 structures over tetramolecular parallel G4 DNA.
• Quinacridine-based macrocycle identified as a potent and selective telomerase inhibitor with submicromolar IC(50) (200 nM).

Conclusions:

• Aminoglycoside-capped macrocycles are effective G4 DNA binders with selectivity for specific G4 topologies.
• The quinacridine derivative represents a promising lead compound for telomerase-targeted cancer therapy.
• Structural flexibility and aromatic moiety size are key determinants of G4 DNA binding affinity.