Synthesis and Binding Studies of Novel Diethynyl-Pyridine Amides with Genomic Promoter DNA G-Quadruplexes

Authors

  • Dr. Jyotirmayee Dash,

    Corresponding author
    1. Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW (UK), Fax: (+44) 1223-336-913
    2. Department of Chemical Sciences, Indian Institute of Science Education and Research-Kolkata, Mohanpur Campus, Mohanpur 7412 52, Nadia, West Bengal (India), Fax: (+91) 33-25873020
    • Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW (UK), Fax: (+44) 1223-336-913
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  • Dr. Zoë A. E. Waller,

    1. Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW (UK), Fax: (+44) 1223-336-913
    2. School of Pharmacy, University of East Anglia, Norwich, NR4 7TJ (UK)
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  • Dr. G. Dan Pantoş,

    1. Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW (UK), Fax: (+44) 1223-336-913
    2. Department of Chemistry, University of Bath, Bath, BA2 7AY (UK)
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  • Prof. Dr. Shankar Balasubramanian

    Corresponding author
    1. Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW (UK), Fax: (+44) 1223-336-913
    2. Cancer Research UK, Cambridge Research Institute, Li Ka Shing Center, Cambridge, CB2 0RE (UK)
    3. School of Clinical Medicine, University of Cambridge, Cambridge, CB2 0SP (UK)
    • Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW (UK), Fax: (+44) 1223-336-913
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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.

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