Groove binding mediated structural modulation and DNA cleavage by quinoline appended chalcone derivative

Himank Kumar; Vinod Devaraji; Rangaraj Prasath; Manojkumar Jadhao; Ritika Joshi; Purushothaman Bhavana; Sujit Kumar Ghosh

doi:10.1016/j.saa.2015.07.010

Groove binding mediated structural modulation and DNA cleavage by quinoline appended chalcone derivative

Spectrochim Acta A Mol Biomol Spectrosc. 2015:151:605-15. doi: 10.1016/j.saa.2015.07.010. Epub 2015 Jul 3.

Authors

Himank Kumar¹, Vinod Devaraji², Rangaraj Prasath³, Manojkumar Jadhao¹, Ritika Joshi¹, Purushothaman Bhavana³, Sujit Kumar Ghosh⁴

Affiliations

¹ Department of Chemistry, Visvesvaraya National Institute of Technology, Nagpur, Maharashtra 440010, India.
² Department of Pharmaceutical Chemistry, College of Pharmacy, Madras Medical College, Chennai 600003, India.
³ Department of Chemistry, BITS-Pilani, K.K. Birla Goa Campus, Zuarinagar, Goa 403726, India.
⁴ Department of Chemistry, Visvesvaraya National Institute of Technology, Nagpur, Maharashtra 440010, India. Electronic address: skghosh@chm.vnit.ac.in.

PMID: 26163783
DOI: 10.1016/j.saa.2015.07.010

Abstract

The present study embodies the detail DNA binding interaction of a potential bioactive quinoline appended chalcone derivative (E)-3-(anthracen-10-yl)-1-(6,8-dibromo-2-methylquinolin-3-yl)prop-2-en-1-one (ADMQ) with calf thymus DNA (ctDNA) and its consequences by UV-Vis absorption, steady state fluorescence spectroscopy, fluorescence anisotropy, circular dichromism, helix melting, agarose gel electrophoresis, molecular docking, Induced Fit Docking (IFD) and molecular dynamics (MD) simulation. The UV-Vis absorption and fluorescence study reveal that the molecule undergoes considerable interaction with the nucleic acid. The control KI quenching experiment shows the lesser accessibility of ADMQ molecule to the ionic quencher (I(-)) in presence of ctDNA as compared to the bulk aqueous phase. Insignificant change in helix melting temperature as well as in circular dichromism (CD) spectra points toward non-covalent groove binding interaction. The moderate rotational confinement of this chalcone derivative (anisotropy=0.106) trapped in the nucleic acid environment, the comparative displacement assay with well-known minor groove binder Hoechst 33258 and intercalator Ethidium Bromide establishes the minor groove binding interactions of the probe molecule. Molecular docking, IFD and MD simulation reveal that the DNA undergoes prominent morphological changes in terms of helix unwinding and bending to accommodate ADMQ in a crescent shape at an angle of 110° in a sequence specific manner. During interaction, ADMQ rigidifies and bends the sugar phosphate backbone of the nucleic acid and thereby shortens its overall length by 3.02Å. Agarose gel electrophoresis experiment with plasmid pBR 322 reveals that the groove binded ADMQ result in a concentration dependent cleavage of plasmid DNA into its supercoiled and nicked circular form. The consolidated spectroscopic research described herein provides quantitative insight into the interaction of a heterocyclic chalcone derivative with relevant target nucleic acid, which may be useful for the future research on chalcone based therapeutic agents.

Keywords: ADMQ; Anisotropy; Circular dichromism; Fluorescence quenching; Groove binding; Helix melting.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Anthracenes / chemistry*
Anthracenes / metabolism*
Cattle
Circular Dichroism
DNA / chemistry*
DNA / metabolism*
DNA Cleavage*
Fluorescence Polarization
Models, Molecular
Molecular Docking Simulation*
Nucleic Acid Conformation
Quinolines / chemistry*
Quinolines / metabolism*
Spectrometry, Fluorescence
Thermodynamics

Substances

3-(anthracen-10-yl)-1-(6,8-dibromo-2-methylquinolin-3-yl)prop-2-en-1-one
Anthracenes
Quinolines
DNA
calf thymus DNA