Title:Trizbenzim, Cu-Trizbenzim and Zn-Trizbenzim as G-Quadruplex Inducing and Stabilizing Compounds on Human Telomeric Sequence and their Anticancer Properties
Volume: 21
Issue: 17
Author(s): Duraisamy Renuga, Palanisamy U. Maheswari*, Kadhar M.M. Sheriffa Begum and Dharmar Prabaharan
Affiliation:
- Department of Chemical Engineering, National Institute of Technology, Tiruchirappalli – 620015, Tamilnadu,India
Keywords:
Triazine, benzimidazole, G quadruplex, MOE docking, antiparallel, CD studies.
Abstract:
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 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 and some backbone interactions on the strand. The FID assay using
thiazole orange intercalator 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 Zntrizbenzim
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 alkali metal ions.
