Helical aromatic oligoamide foldamers as selective G-quadruplex ligands.

Area of Science:

• Medicinal Chemistry
• Supramolecular Chemistry
• Chemical Biology

Background:

• G-quadruplex (G4) structures are non-canonical DNA secondary structures implicated in various biological processes.
• Developing selective ligands for G4 structures is crucial for therapeutic applications.
• Aromatic oligoamide helical foldamers offer a modular scaffold for designing G4 binders.

Purpose of the Study:

• To investigate the G-quadruplex (G4) binding selectivity of short aromatic oligoamide helical foldamers.
• To explore the influence of foldamer composition (quinoline and pyridine units) on G4 binding.
• To understand the structural basis for G4 recognition and selectivity.

Main Methods:

• Synthesis of quinoline (Q) and pyridine (P) containing oligoamide foldamers.
• G-quadruplex binding assays to determine stoichiometry and selectivity.
• Crystal structure analysis of foldamer-G4 complexes.
• Solution Nuclear Magnetic Resonance (NMR) spectroscopy to confirm binding interactions.

Main Results:

• Foldamers exhibit 1:1 and 2:1 binding stoichiometries with G4 structures.
• Preferred binding to parallel G4 structures, particularly with accessible external G-quartets.
• Crystal structure reveals π-stacking interactions between quinoline units and G-quartets.
• NMR confirms foldamer targeting of G4 ends.
• Selective targeting of G4 variants with loop mutations.
• Conformational selectivity is influenced by foldamer size and pyridine flexibility.

Conclusions:

• Mixed quinoline-pyridine foldamers are effective and selective G4 ligands.
• The modular scaffold allows for tuning affinity and selectivity.
• These foldamers represent a promising class of molecules for G4-targeting applications.