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Updated: Jun 13, 2026
Single-Molecule Fluorescence Visualization of DNA Polymerase Dynamics at G-Quadruplexes
Published on: April 4, 2025
Structure-based design of platinum(II) complexes as c-myc oncogene down-regulators and luminescent probes for
Ping Wang1, Chung-Hang Leung, Dik-Lung Ma
1Department of Chemistry and Open Laboratory of Chemical Biology of the Institute of Molecular Technology for Drug Discovery and Synthesis, The University of Hong Kong, Pokfulam Road, Hong Kong, PR China.
Abstract:
A series of platinum(II) complexes with tridentate ligands was synthesized and their interactions with G-quadruplex DNA within the c-myc gene promoter were evaluated. Complex 1, which has a flat planar 2,6-bis(benzimidazol-2-yl)pyridine (bzimpy) scaffold, was found to stabilize the c-myc G-quadruplex structure in a cell-free system. An in silico G-quadruplex DNA model has been constructed for structure-based virtual screening to develop new Pt(II)-based complexes with superior inhibitory activities. By using complex 1 as the initial structure for hit-to-lead optimization, bzimpy and related 2,6-bis(pyrazol-3-yl)pyridine (dPzPy) scaffolds containing amine side-chains emerge as the top candidates. Six of the top-scoring complexes were synthesized and their interactions with c-myc G-quadruplex DNA have been investigated. The results revealed that all of the complexes have the ability to stabilize the c-myc G-quadruplex. Complex 3 a ([Pt(II)L2R](+); L2=2,6-bis[1-(3-piperidinepropyl)-1H-enzo[d]imidazol-2-yl]pyridine, R=Cl) displayed the strongest inhibition in a cell-free system (IC(50)=2.2 microM) and was 3.3-fold more potent than that of 1. Complexes 3 a and 4 a ([Pt(II)L3R](+); L3=2,6-bis[1-(3-morpholinopropyl)-1H-pyrazol-3-yl]pyridine, R=Cl) were found to effectively inhibit c-myc gene expression in human hepatocarcinoma cells with IC(50) values of approximately 17 microM, whereas initial hit 1 displayed no significant effect on gene expression at concentrations up to 50 microM. Complexes 3 a and 4 a have a strong preference for G-quadruplex DNA over duplex DNA, as revealed by competition dialysis experiments and absorption titration; 3 a and 4 a bind G-quadruplex DNA with binding constants (K) of approximately 10(6)-10(7) dm(3) mol(-1), which are at least an order of magnitude higher than the K values for duplex DNA. NMR spectroscopic titration experiments and molecular modeling showed that 4 a binds c-myc G-quadruplex DNA through an external end-stacking mode at the 3'-terminal face of the G-quadruplex. Intriguingly, binding of c-myc G-quadruplex DNA by 3 b is accompanied by an increase of up to 38-fold in photoluminescence intensity at lambda(max)=622 nm.
Insights
New platinum(II) complexes targeting the c-myc G-quadruplex show promise for cancer therapy. Complex 3a demonstrated potent inhibition of c-myc gene expression in cancer cells, stabilizing the G-quadruplex structure with high selectivity.
Area of Science:
- Medicinal Chemistry
- Bioinorganic Chemistry
- Molecular Biology
Background:
- G-quadruplex DNA structures, such as those in the c-myc gene promoter, are potential therapeutic targets for cancer.
- Platinum(II) complexes are explored for their ability to interact with and stabilize these structures.
Purpose of the Study:
- To synthesize and evaluate novel platinum(II) complexes for their interaction with the c-myc G-quadruplex.
- To develop structure-based virtual screening methods for identifying potent G-quadruplex-binding agents.
- To assess the efficacy of these complexes in inhibiting c-myc gene expression in cancer cells.
Main Methods:
- Synthesis of platinum(II) complexes with tridentate ligands (bzimpy and dPzPy scaffolds).
- In silico modeling and virtual screening for structure-based drug design.
- In vitro assays (cell-free systems, competition dialysis, absorption titration) to evaluate DNA binding and G-quadruplex stabilization.
- In vivo studies using human hepatocarcinoma cells to assess gene expression inhibition.
- NMR spectroscopy for binding mode analysis.
Main Results:
- Complex 1 stabilized the c-myc G-quadruplex in cell-free systems.
- Virtual screening identified optimized bzimpy and dPzPy scaffolds.
- Complex 3a showed the strongest inhibition in cell-free systems (IC50=2.2 microM), 3.3-fold more potent than Complex 1.
- Complexes 3a and 4a effectively inhibited c-myc gene expression in cancer cells (IC50 approx. 17 microM).
- Complexes 3a and 4a exhibited high selectivity for G-quadruplex DNA over duplex DNA (binding constants K ~10^6-10^7 dm^3 mol^-1).
- Complex 4a binds via external end-stacking to the 3'-terminal face of the c-myc G-quadruplex.
- Complex 3b binding enhanced G-quadruplex photoluminescence by up to 38-fold.
Conclusions:
- Novel platinum(II) complexes, particularly 3a and 4a, effectively stabilize the c-myc G-quadruplex and inhibit its expression in cancer cells.
- These complexes display high selectivity for G-quadruplex DNA, suggesting potential as targeted anticancer agents.
- Structure-based design and virtual screening are valuable tools for developing potent G-quadruplex-interacting compounds.
