Specifically targeting mixed-type dimeric G-quadruplexes using berberine dimers.

Area of Science:

• Medicinal Chemistry
• Biochemistry
• Molecular Biology

Background:

• Human telomeric DNA forms G-quadruplex structures, including dimeric G2T1, which are implicated in cancer.
• Berberine derivatives are explored for their potential as anticancer agents targeting DNA structures.

Purpose of the Study:

• To synthesize and evaluate polyether-tethered berberine dimers for binding affinity and selectivity towards human telomeric G2T1.
• To investigate the role of polyether linkers in modulating G-quadruplex DNA interactions.
• To assess the potential of these compounds as anticancer agents targeting specific DNA structures.

Main Methods:

• Synthesis of three polyether-tethered berberine dimers (1a-c).
• Binding affinity and selectivity studies using techniques like fluorescence spectroscopy and isothermal titration calorimetry.
• Thermal stabilization assays to evaluate DNA structural changes.
• Spectroscopic methods (e.g., NMR, CD) to elucidate binding modes.

Main Results:

• Compound 1a exhibited the highest binding affinity (Ka > 10^8 M^-1) and significant selectivity for mixed-type G2T1 over other G-quadruplexes.
• Compound 1a induced quadruplex formation and enhanced thermal stability of mixed-type G2T1.
• Binding interactions of compound 1a with G2T1 were proposed to involve end-stacking and external binding modes.

Conclusions:

• Polyether linker length is crucial for regulating binding affinity and selectivity towards mixed-type G2T1.
• Compound 1a demonstrates potential as a selective G-quadruplex binder for targeting specific genomic regions.
• These findings provide a basis for designing novel multimeric G-quadruplex binders with therapeutic potential, particularly as anticancer agents.