ePrints@IIScePrints@IISc Home | About | Browse | Latest Additions | Advanced Search | Contact | Help

Symmetrical Bisbenzimidazoles with Benzenediyl Spacer: The Role of the Shape of the Ligand on the Stabilization and Structural Alterations in Telomeric G-Quadruplex DNA and Telomerase Inhibition

Bhattacharya, Santanu and Chaudhuri, Padmaparna and Jain, Akash K and Paul, Ananya (2010) Symmetrical Bisbenzimidazoles with Benzenediyl Spacer: The Role of the Shape of the Ligand on the Stabilization and Structural Alterations in Telomeric G-Quadruplex DNA and Telomerase Inhibition. In: Bioconjugate Chemistry, 21 (7). pp. 1148-1159.

[img] PDF
synthesis.pdf - Published Version
Restricted to Registered users only

Download (2405Kb) | Request a copy
Official URL: http://pubs.acs.org/doi/abs/10.1021/bc9003298

Abstract

The extremities of chromosomes end in a G-rich single-stranded overhang that has been implicated in the onset of the replicate senescence. The repeated sequence forming a G-overhang is able to adopt a four-stranded DNA structure called G-quadruplex, which is a poor substrate for the enzyme telomerase. Small molecule based ligands that selectively stabilize the telomeric G-quadruplex DNA, induce telomere shortening eventually leading to cell death. Herein, we have investigated the G-quadruplex DNA interaction with two isomeric bisbenzimidazole-based compounds that differ in terms of shape (V-shaped angular vs linear).While the linear isomer induced some stabilization of the intramolecular G-quadruplex structure generated in the presence of Na+ the other, having V-shaped central planar core, caused a dramatic structural alteration of the latter, above a threshold concentration. This transition was evident from the pronounced changes observed in the circular dichroism spectra and from the get mobility shift assa involving the G-quadruples DNA. Notably, this angular isomer could also induce the G-quadruplex formation in the absence of any added cation. The ligand-quadruples complexes were investigated by computational molecular modeling, providing further information on structure-activity relationships. Finally, TRAP (telomerase repeat amplification protocol) experiments demonstrated that the angular isomer is selective toward the inhibition of telomerase activity.

Item Type: Journal Article
Additional Information: Copyright of this article belongs to American Chemical Society.
Department/Centre: Division of Chemical Sciences > Organic Chemistry
Date Deposited: 11 Aug 2010 07:59
Last Modified: 19 Sep 2010 06:13
URI: http://eprints.iisc.ernet.in/id/eprint/31226

Actions (login required)

View Item View Item