DPPZ-Naphthalimide Conjugates as G-Quadruplex DNA Targeting Scaffolds: Design, Synthesis and Biomolecular Interaction...

Area of Science:

• Medicinal Chemistry
• Molecular Biology
• Biochemistry

Background:

• Guanine-rich DNA can form G-quadruplex (G4) structures, crucial in telomeres and oncogenes.
• G4 structures are attractive anticancer targets; small molecules stabilizing them can inhibit telomerase and oncogene expression.

Purpose of the Study:

• To synthesize and evaluate DPPZ-anhydride-conjugated ligands and their quaternized derivatives for DNA recognition.
• To investigate the impact of π-extension, bromine substitution, and cationic modification on G4 DNA binding selectivity and affinity.

Main Methods:

• Synthesis of DPPZ-anhydride ligands (1, 2) and quaternized derivatives (1-q, 2-q).
• Characterization using NMR and spectroscopic methods.
• Evaluation of DNA-binding properties toward duplex (ds-DNA) and G-quadruplex (G4-DNA) using UV-Vis, FID assays, and competitive dialysis.

Main Results:

• Quaternization significantly enhanced binding constants and reduced DC50 values, especially for G4-DNA.
• Bromine substitution increased affinity but not topology selectivity.
• Compound 1-q demonstrated the best balance of affinity and G4 selectivity, outperforming other derivatives in BSA binding.

Conclusions:

• Strategic π-conjugation and electrostatic reinforcement effectively create topology-selective DNA-binding ligands.
• The developed ligands, particularly 1-q, show promise as anticancer agents targeting G4 DNA structures.