Synthesis and binding studies of novel diethynyl-pyridine amides with genomic promoter DNA G-quadruplexes

Dash, Jyotirmayee, Waller, Zoe A. E., Pantoş, G. Dan and Balasubramanian, Shankar (2011) Synthesis and binding studies of novel diethynyl-pyridine amides with genomic promoter DNA G-quadruplexes. Chemistry - A European Journal, 17 (16). 4571–4581. ISSN 0947-6539

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Abstract

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 CuI-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.

Item Type:	Article
Faculty \ School:	Faculty of Science > School of Pharmacy
UEA Research Groups:	Faculty of Science > Research Groups > Chemical Biology and Medicinal Chemistry (former - to 2021) Faculty of Science > Research Groups > Medicinal Chemistry (former - to 2017)
Depositing User:	Rachel Smith
Date Deposited:	17 Mar 2011 16:07
Last Modified:	27 Jul 2023 07:07
URI:	https://ueaeprints.uea.ac.uk/id/eprint/26563
DOI:	10.1002/chem.201003157

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