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.
Synthesis and In vitro Evaluation of novel 5‐nitroIndole Derivatives as c‐Myc G‐Quadruplex Binders with Anticancer Activities
