DNA G-quadruplex (G4) structures have attracted much attention due to their ability to regulate gene expression and the potential role of cancer intervention. The formation of DNA G-quadruplexes requires monovalent cations (Na+ and K+), which can be facilitated by small molecules known as G4 ligands. Phenanthroline is a type of G4 ligand scaffold that forms metal complexes with a large aromatic surface suitable for stacking with G-quartets. In the present work, we evaluated a series of 5-substituted 1,10-phenanthroline-based nickel complexes binding to telomeric G-quadruplex DNA. Results from several biophysical methods including ESI-MS, CD thermal denaturation, CD titration, and FID assay suggested that the side chains at the 5 position of 1,10-phenanthroline were crucial for G-quadruplex recognition. Arylsulfanyl groups were the best side chains regarding binding affinity and selectivity towards G-quadruplex DNA. Several G-quadruplex binding Phen-Ni complexes inhibited telomerase activity in vitro and exhibited cytotoxicity against three cancer cell lines. Our results here provide a guidance of utilizing 5- substituted phenanthroline derivatives to design novel G4 ligands.

Evaluation of 5-substituted 1,10-phenanthroline and nickel complexes as G4 ligands and telomerase inhibitors

254th National Meeting (2017)

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