Water-Soluble Heptacyclic Oligo-Heteroaryls Targeting G‑Quadruplex DNA via Groove-Binding Interactions

Area of Science:

• Medicinal Chemistry
• Chemical Biology
• Nucleic Acid Chemistry

Background:

• G-quadruplexes (G4s) are noncanonical nucleic acid structures vital for regulating biological processes.
• G4s are attractive therapeutic targets due to their roles in gene regulation and disease.

Purpose of the Study:

• To design, synthesize, and evaluate a new family of water-soluble heptacyclic oligo-heteroaryl ligands for G4 recognition.
• To investigate the impact of structural modifications (central atoms, pendant groups) on G4 binding affinity and selectivity.

Main Methods:

• Modular and convergent synthesis enabling late-stage functionalization.
• Biophysical evaluation including aqueous solubility and G4 stabilization assays.
• Molecular docking calculations to elucidate binding modes.

Main Results:

• The novel ligands exhibit high aqueous solubility and selectively stabilize G4 structures, particularly the parallel LTR-IV motif.
• Ligands primarily interact with G4s via groove-binding.
• No significant differences in binding profiles were observed between nitrogen- and carbon-substituted analogues.

Conclusions:

• A versatile class of G4 binders with favorable solubility and tunable structures has been identified.
• These ligands provide a promising foundation for developing functionalized derivatives for chemical biology and therapeutic applications targeting G-quadruplexes.