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

J Dash, Z A E Waller, Gheorghe D Pantos, S Balasubramanian

Research output: Contribution to journalArticlepeer-review

59 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)4571-4581
Number of pages11
JournalChemistry - A European Journal
Volume17
Issue number16
DOIs
Publication statusPublished - Apr 2011

Keywords

  • acetylene
  • molecular recognition
  • G-quadruplexes
  • amides
  • click chemistry

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