TrizbenzIm, Cu-Trizbenzim and Zn-Trizbenzim as G-Quadruplex Inducing and Stabilizing Compounds on Human Telomeric Sequence and their Anticancer Properties

Background: The benzimidazole and their derivatives have rich biological relevance with respect to available natural amino acids and their role in protein folding and quaternary conformations. Thus the ligand trizbenzIm and their Cu(II) and Zn(II) metal complexes were prepared to induce G-quadruplex conformation even under no salt conditions with remarkable anticancer activities. Methods: The ligand N,N’,N’’-Tris-(1H-benzoimidazol-2-ylmethyl)-[1,3,5]triazine-2,4,6-triamine (trizbenzIm) and its Cu and Zn complexes (Cu-trizbenzIm, Zn-trizbenzIm) were synthesized and characterized by IR, NMR and MALDI-TOF techniques. The pure ligand and its complexes were interacted with human telomere DNA sequence d(TTAGGG), HTelo8and HTelo20and the interactions were followed by circular dichroism spectroscopy, FID assay and molecular docking techniques.The compounds were tested for anticancer activity towards selected cell lines. Results: All the three compounds stabilized the HTelo8 and HTelo20 in parallel and antiparallel G-quadruplex conformations with salt conditions. Under no salt conditions, the compounds induce and stabilize the G-quadruplex conformation in antiparallel topology, selectively. The pure ligand, Cu-trizbenzIm and Zn-trizbenzIm were involved in partial or classical intercalation together with some backbone interactions on the strand. The FID assay using thiazole orange intercalator clearly supports the proposed intercalation mode of binding for the three compounds, especially for the pure ligand and the Cu-complex. The MOE docking experiments using X-ray and NMR derived G-quadruplex models with the title compounds extensively support the G-quadruplex induction and stabilization of the telomere sequence by these compounds. The guanines bases involved in the G-tetrad formation interact well with the triazine and the benzimidazole part of the ligand through strong π-π interactions. The primary mode of binding is described as end stacking and intercalation of the compounds to the G-quadruplex structures. The Cu-trizbenzIm exhibited more anticancer property in comparison to the pure ligand and the Zn-trizbenzIm complex. The IC50 values were in the nanomolar range from 50 to 150nM in concentration. Conclusion: This novel self-induction of G-quadruplex is novel without the presence of any alkali metal ions.