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Synthesis and Binding Studies of Novel Diethynyl‐Pyridine Amides with Genomic Promoter DNA G‐Quadruplexes
Author(s) -
Dash Jyotirmayee,
Waller Zoë A. E.,
Pantoş G. Dan,
Balasubramanian Shankar
Publication year - 2011
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201003157
Subject(s) - chemistry , intramolecular force , pyridine , g quadruplex , förster resonance energy transfer , click chemistry , dna , stereochemistry , binding selectivity , surface plasmon resonance , combinatorial chemistry , fluorescence , nanotechnology , biochemistry , materials science , medicinal chemistry , physics , quantum mechanics , nanoparticle
Herein, we report the design, synthesis and biophysical evaluation of novel 1,2,3‐triazole‐linked diethynyl‐pyridine amides and trisubstituted diethynyl‐pyridine amides as promising G‐quadruplex binding ligands. We have used a Cu I ‐catalysed azide–alkyne cycloaddition click reaction to prepare the 1,2,3‐triazole‐linked diethynyl‐pyridine amides. The G‐quadruplex DNA binding properties of the ligands have been examined by using a Förster resonance energy transfer (FRET) melting assay and surface plasmon resonance (SPR) experiments. The investigated compounds are conformationally flexible, having free rotation around the triple bond, and exhibit enhanced G‐quadruplex binding stabilisation and specificity between intramolecular promoter G‐quadruplex DNA motifs compared to the first generation of diarylethynyl amides ( J. Am. Chem. Soc. 2008 , 130 , 15 950–15 956). The ligands show versatility in molecular recognition and promising G‐quadruplex discrimination with 2–50‐fold selectivity exhibited between different intramolecular promoter G‐quadruplexes. Circular dichroism (CD) spectroscopic analysis suggested that at higher concentration these ligands disrupt the c‐kit2 G‐quadruplex structure. The studies validate the design concept of the 1,3‐diethynyl‐pyridine‐based scaffold and demonstrate that these ligands exhibit not only significant selectivity over duplex DNA but also variation in G‐quadruplex interaction properties based on small chemical changes in the scaffold, leading to unprecedented differential recognition of different DNA G‐quadruplex sequences.