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Selective G-quadruplex DNA Stabilizing Agents Based on Bisquinolinium and Bispyridinium Derivatives of 1,8-Naphthyridine

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Title Selective G-quadruplex DNA Stabilizing Agents Based on Bisquinolinium and Bispyridinium Derivatives of 1,8-Naphthyridine
 
Creator DHAMODHARAN, V
HARIKRISHNA, S
JAGADEESWARAN, C
HALDER, K
PRADEEPKUMAR, PI
 
Subject HUMAN TELOMERIC SEQUENCE
RNA G-QUADRUPLEX
INTRAMOLECULAR G-QUADRUPLEX
SMALL-MOLECULE
STRUCTURAL POLYMORPHISM
DISPLACEMENT ASSAY
CHROMOSOME ENDS
FREE-ENERGIES
STRANDED-DNA
TUMOR-CELLS
 
Description Various biologically relevant G-quadruplex DNA structures offer a platform for therapeutic intervention for altering the gene expression or by halting the function of proteins associated with telomeres. One of the prominent strategies to explore the therapeutic potential of quadruplex DNA structures is by stabilizing them with small molecule ligands. Here we report the synthesis of bisquinolinium and bispyridinium derivatives of 1,8-naphthyridine and their interaction with human telomeric DNA and promoter G-quadruplex forming DNAs. The interactions of ligands with quadruplex forming DNAs were studied by various biophysical, biochemical, and computational methods. Results indicated that bisquinolinium ligands bind tightly and selectively to quadruplex DNAs at low ligand concentration (similar to 0.2-0.4 mu M). Furthermore, thermal melting studies revealed that ligands imparted higher stabilization for quadruplex DNA (an increase in the T-m of up to 21 degrees C for human telomeric G-quadruplex DNA and >25 degrees C for promoter G-quadruplex DNAs) than duplex DNA (Delta T-m < 1.6 degrees C). Molecular dynamics simulations revealed that the end-stacking binding mode was favored for ligands with low binding free energy. Taken together, the results indicate that the naphthyridine-based ligands with quinolinium and pyridinium side chains form a promising class of quadruplex DNA stabilizing agents having high selectivity for quadruplex DNA structures over duplex DNA structures.
 
Publisher AMER CHEMICAL SOC
 
Date 2014-10-16T14:29:10Z
2014-10-16T14:29:10Z
2012
 
Type Article
 
Identifier JOURNAL OF ORGANIC CHEMISTRY, 77(1)229-242
http://dx.doi.org/10.1021/jo201816g
http://dspace.library.iitb.ac.in/jspui/handle/100/15786
 
Language en