Stabilization of G-quadruplex DNA and antitumor activity by different structures of nickel (II) complexes

• Ni(II) complexes have the capability of binding to stabilize G-quadruplex.
• Ni(II) complexes can be considered as a new class of highly selective G-quadruplex.
• Complex NPH showed a greater ability to induce the stability of G-quadruplex DNA.
• Complexes NBH and NPH possessed the greatest inhibitory selectivity against cancer cell lines and display application potential as anticancer agents.

In the present investigation, four nickel (II) complexes [Ni(bpy)3]2 + NB, [Ni(phen)3]2 + NP, [Ni(bpy)2(p-ipip)]2 + NBH and [Ni(phen)2(p-ipip)]2 + NPH were synthesized and characterized by electrospray ionization-mass spectrometry, where phen is 1,10-phenanthroline, bpy is 2,2′-bipyridine and p-ipip is 2-(4-indole)-imidazo[4,5f][1,10] phenanthroline. The interactions of human telomeric G-quadruplex DNA with these designed complexes were evaluated by CD spectroscopy, fluorescence resonance energy transfer (FRET) melting assay and FRET competitive binding experiment. The experimental evidence indicated that all complexes could strongly bind to and effectively stabilize the telomeric G-quadruplex DNA. Complex NPH was a better G-quadruplex binder than other complexes. Furthermore, polymerase chain reaction (PCR)-stop assay, gel mobility shift assay and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay demonstrated that complex NPH not only can stabilize dimers forms of the G-quadruplex at low concentrations but also high inhibitory selectivity against cancer cells. The results suggest that complex NPH may be a potential telomerase inhibitor for cancer chemotherapy.

The scheme is the illustration of the Ni(II) complex NPH which is able to induce the HTG21 DNA into a mixed-type or hybrid G-quadruple and dependently stabilize the G-quadruplex.Figure optionsDownload as PowerPoint slide