Interaction of polycationic Ni(II)-salophen complexes with G-quadruplex DNA

Area of Science:

• Coordination Chemistry
• Supramolecular Chemistry
• Biophysical Chemistry

Background:

• G-quadruplex DNA structures are crucial in telomere maintenance and cancer.
• Small molecules that selectively interact with G-quadruplex DNA are valuable therapeutic agents.
• Nickel(II) salophen complexes offer a versatile scaffold for developing such agents.

Purpose of the Study:

• To synthesize and characterize novel Ni(II) salophen complexes with varying alkyl-imidazolium side chains.
• To investigate the binding affinity and selectivity of these complexes towards G-quadruplex DNA.
• To evaluate the potential of these complexes as inhibitors of telomerase activity.

Main Methods:

• Synthesis and crystal structure determination of Ni(II) salophen complexes.
• Fluorescence resonance energy transfer (FRET) melting assays to assess DNA stabilization.
• Surface plasmon resonance (SPR) to quantify binding constants (KD).
• Computational studies for structural interaction analysis.
• Telomeric repeat amplification protocol (TRAP) assays to measure telomerase inhibition.

Main Results:

• Nine Ni(II) salophen complexes with 1-3 carbon side chains were synthesized.
• Complexes selectively stabilized G-quadruplex DNA over duplex DNA.
• High binding affinity (0.1–1 μM KD) for G-quadruplexes and selectivity over duplex DNA (>2 μM KD) were observed.
• Complexes with more and shorter side chains exhibited the highest binding constants.
• Computational studies revealed stacking of the aromatic core and insertion of cationic side chains into G-quadruplex grooves.
• Significant inhibition of telomerase activity (IC50 as low as 700 nM) was demonstrated, with no significant polymerase inhibition.

Conclusions:

• The synthesized Ni(II) salophen complexes exhibit high selectivity and affinity for G-quadruplex DNA.
• The structural features of the complexes dictate their binding interactions with G-quadruplex DNA.
• These complexes effectively inhibit telomerase activity, presenting a promising avenue for anticancer drug development.