Stabilization and Structural Alteration of the G-Quadruplex DNA Made from the Human Telomeric Repeat Mediated by Troger's Base Based Novel Benzimidazole Derivatives

Paul, Ananya and Maji, Basudeb and Misra, Santosh K and Jain, Akash K and Muniyappa, K and Bhattacharya, Santanu (2012) Stabilization and Structural Alteration of the G-Quadruplex DNA Made from the Human Telomeric Repeat Mediated by Troger's Base Based Novel Benzimidazole Derivatives. In: JOURNAL OF MEDICINAL CHEMISTRY, 55 (17). pp. 7460-7471.

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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 Troger's base skeleton with the G-quadruplex DNA (G4DNA). These Troger'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.

Item Type:	Journal Article
Publication:	JOURNAL OF MEDICINAL CHEMISTRY
Publisher:	AMER CHEMICAL SOC
Additional Information:	Copyright for this article belongs to AMER CHEMICAL SOC, WASHINGTON
Department/Centre:	Division of Biological Sciences > Biochemistry Division of Chemical Sciences > Organic Chemistry
Date Deposited:	15 Dec 2012 05:01
Last Modified:	15 Dec 2012 05:01
URI:	http://eprints.iisc.ac.in/id/eprint/45561

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