New (Iso)quinolinyl-pyridine-2,6-dicarboxamide G-Quadruplex Stabilizers. A Structure-Activity Relationship Study

Area of Science:

• Medicinal Chemistry
• Chemical Biology
• Molecular Biology

Background:

• G-quadruplex (G4) structures are crucial in biological processes and are targets for therapeutic intervention.
• Small molecules interacting with G4s have potential as drugs and sensors.
• Understanding structure-activity relationships (SAR) is key for designing effective G4 ligands.

Purpose of the Study:

• To synthesize analogues of a known G4 ligand (360A) and explore SAR.
• To identify structural modifications that enhance G4 stabilization and selectivity.
• To investigate the impact of charge and spatial orientation on G4 binding and function.

Main Methods:

• Synthesis of bis-quinolinium and bis-isoquinolinium G4 ligand analogues.
• Thermal denaturation experiments to assess G4 stabilization.
• Polymerase chain reaction (PCR)-stop assays to evaluate DNA polymerization inhibition.
• Molecular dynamics simulations to study ligand-G4 interactions.

Main Results:

• Non-methylated ligands moderately stabilize G4s, preferring hybrid G4s.
• Methylated ligands with positive charges show increased selectivity for G4s over duplex DNA, favoring parallel structures.
• Ligands with a 1,3-positioning of charged groups are superior G4 stabilizers.
• Ligands exhibit varying abilities to block DNA polymerization and induce G4 conformational changes.
• Molecular simulations reveal that the spatial arrangement of quinoline/isoquinoline rings dictates binding affinity and mode.

Conclusions:

• Specific structural features, including methylation and the relative positioning of aromatic rings and linkers, are critical for G4 ligand efficacy.
• The synthesized analogues demonstrate tunable G4 interaction properties, paving the way for rational drug design.
• These findings provide valuable insights into the development of novel G4-interactive small molecules for diverse applications.