title: Stabilization and structural alteration of the G-quadruplex DNA made from the human telomeric repeat mediated by Tröger's base based novel benzimidazole derivatives.
abstract: Ligand-induced stabilization of the G-quadruplex DNA structure derived from the single-stranded 3'-overhang of the telomeric DNA is an attractive strategy for the inhibition of the telomerase activity. The agents that can induce/stabilize a DNA sequence into a G-quadruplex structure are therefore potential anticancer drugs. Herein we present the first report of the interactions of two novel bisbenzimidazoles (TBBz1 and TBBz2) based on Tröger's base skeleton with the G-quadruplex DNA (G4DNA). These Tröger's base molecules stabilize the G4DNA derived from a human telomeric sequence. Evidence of their strong interaction with the G4DNA has been obtained from CD spectroscopy, thermal denaturation, and UV-vis titration studies. These ligands also possess significantly higher affinity toward the G4DNA over the duplex DNA. The above results obtained are in excellent agreement with the biological activity, measured in vitro using a modified TRAP assay. Furthermore, the ligands are selectively more cytotoxic toward the cancerous cells than the corresponding noncancerous cells. Computational studies suggested that the adaptive scaffold might allow these ligands to occupy not only the G-quartet planes but also the grooves of the G4DNA.
authors: Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, India.
authors: Ananya
authors: A
authors: Paul
authors: Basudeb
authors: B
authors: Maji
authors: Santosh K
authors: SK
authors: Misra
authors: Akash K
authors: AK
authors: Jain
authors: K
authors: K
authors: Muniyappa
authors: Santanu
authors: S
authors: Bhattacharya
mesh_terms: D000818:Animals; D001483:Base Sequence; D001562:Benzimidazoles / Q000737:chemistry*; D045744:Cell Line, Tumor; D002942:Circular Dichroism; D017931:DNA Primers; D054856:G-Quadruplexes; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008958:Models, Molecular; D041681:NIH 3T3 Cells; D009690:Nucleic Acid Conformation; D009691:Nucleic Acid Denaturation; D016133:Polymerase Chain Reaction; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013056:Spectrophotometry, Ultraviolet; D019098:Telomerase / Q000037:antagonists & inhibitors; D016615:Telomere
chemical_list: D001562:Benzimidazoles; D017931:DNA Primers; D019098:Telomerase