Selective Binding and Redox-Activity on Parallel G-Quadruplexes by Pegylated Naphthalene Diimide-Copper Complexes

Area of Science:

• Supramolecular Chemistry
• Chemical Biology
• Medicinal Chemistry

Background:

• G-quadruplexes (G4s) are crucial regulatory structures with emerging roles in diseases like COVID-19.
• Naphthalene diimides (NDIs) are effective G4 ligands, but some can irreversibly cleave G4s.
• NDI-Cu-DETA demonstrates G4 cleavage activity, highlighting the potential of metal-NDI complexes.

Purpose of the Study:

• To develop novel copper(II)-NDI complexes for selective targeting of parallel G4s.
• To investigate the binding affinity, specificity, and G4 stabilization capabilities of new functionalized NDIs.
• To assess the potential of these complexes in G4 cleavage via redox-catalyzed activity.

Main Methods:

• Synthesis of two novel Cu(II)-NDI complexes (HP2Cu and PE2Cu) with 2-(2-aminoethoxy)ethanol side-chains.
• Determination of copper coordination and binding constants using competition titrations.
• Analysis of G4 stabilization and ROS-induced cleavage of telomeric RNA-G4s.

Main Results:

• Both HP2Cu and PE2Cu exhibit high binding affinity and specificity for parallel RNA-G4s.
• The new complexes effectively stabilize the parallel G4 topology.
• ROS-induced cleavage activity was observed, indicating potential for G4 destructuring.

Conclusions:

• The novel Cu(II)-NDI complexes, HP2Cu and PE2Cu, show significant promise for selective interaction with parallel G4s.
• These compounds can stabilize and cleave G4 structures, offering a foundation for developing new antiviral or therapeutic agents.
• The functionalization strategy provides a pathway for designing targeted G4-interactive ligands.