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


Reference:

Dash, J., Waller, Z. A. E., Pantos, G. D. and Balasubramanian, S., 2011. Synthesis and binding studies of novel diethynyl-pyridine amides with genomic promoter DNA G-quadruplexes. Chemistry - A European Journal, 17 (16), pp. 4571-4581.

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Official URL:

http://dx.doi.org/10.1002/chem.201003157

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 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 Forster 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 diaryl-ethynyl amides (J. Am. Chem. Soc. 2008, 130, 15950-15956). 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.

Details

Item Type Articles
CreatorsDash, J., Waller, Z. A. E., Pantos, G. D. and Balasubramanian, S.
DOI10.1002/chem.201003157
Uncontrolled Keywordsacetylene, molecular recognition, g-quadruplexes, amides, click chemistry
DepartmentsFaculty of Science > Chemistry
RefereedYes
StatusPublished
ID Code23896

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