Substituted Naphthalenediimide Compounds Bind Selectively to Two Human Quadruplex Structures with Parallel Topology.

Area of Science:

• Medicinal Chemistry
• Biochemistry
• Molecular Biology

Background:

• Quadruplex structures, including DNA and RNA forms, are crucial in biological processes.
• Naphthalenediimide derivatives are investigated for their potential to interact with nucleic acids.

Purpose of the Study:

• To investigate the interactions of naphthalenediimide derivatives with various quadruplex targets.
• To evaluate the binding affinity and structural preferences of these compounds for quadruplexes.

Main Methods:

• Thermal melting studies to assess stabilization.
• Surface plasmon resonance and fluorescence spectroscopy for binding kinetics.
• Circular dichroism (CD) spectroscopy for structural analysis.
• Qualitative molecular modeling to predict complex topologies.

Main Results:

• Naphthalenediimide derivatives demonstrated strong stabilization of quadruplexes (hTERT, human telomeric DNA, and TERRA).
• Compounds exhibited weak stabilization of duplex DNA, indicating selectivity.
• Nanomolar equilibrium dissociation constants were determined for quadruplex binding.
• CD spectra and SPR data suggested a preference for parallel quadruplex folds by two derivatives, confirmed by modeling.

Conclusions:

• Naphthalenediimide derivatives are potent binders and stabilizers of DNA and RNA quadruplexes.
• The compounds show selectivity towards quadruplex structures over duplex DNA.
• A preference for parallel quadruplex topologies was observed, providing insights for drug design.