Dinuclear ruthenium(II) complexes that induce and stabilise G-quadruplex DNA

Area of Science:

• Coordination Chemistry
• Biophysical Chemistry
• Molecular Biology

Background:

• Telomeric G-quadruplex DNA structures are crucial in cellular processes.
• Targeting G-quadruplexes offers potential therapeutic strategies for cancer.
• Developing selective DNA-binding agents is essential for therapeutic applications.

Purpose of the Study:

• To synthesize and characterize novel dinuclear ruthenium(II) complexes.
• To investigate the binding interactions of these complexes with telomeric G-quadruplex DNA.
• To evaluate the potential of these complexes as telomerase inhibitors and anticancer agents.

Main Methods:

• Synthesis and characterization of dinuclear ruthenium(II) complexes.
• Circular dichroism (CD) spectroscopy.
• Fluorescence resonance energy transfer (FRET) melting assays.
• Isothermal titration calorimetry (ITC).
• Molecular modelling.
• Telomerase inhibition assays.
• Cellular proliferation assays (HeLa cells).

Main Results:

• Complexes 1, 2, and 4 stabilized antiparallel telomeric G-quadruplex structures.
• Complexes 1 and 2 demonstrated strong binding affinity and selectivity for G-quadruplex over duplex DNA.
• A suitable π-π stacking plane is crucial for effective G-quadruplex interaction.
• Complex 1 exhibited potent inhibition of both telomerase activity and HeLa cell proliferation.

Conclusions:

• Dinuclear ruthenium(II) complexes can selectively bind and stabilize telomeric G-quadruplex DNA.
• Structural features, specifically π-π stacking, influence binding affinity and selectivity.
• Complex 1 is a highly promising candidate for further development as a telomerase inhibitor and anticancer therapeutic.