4.8 Article

Diarylethynyl Amides That Recognize the Parallel Conformation of Genomic Promoter DNA G-Quadruplexes

Journal

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
Volume 130, Issue 47, Pages 15950-15956

Publisher

AMER CHEMICAL SOC
DOI: 10.1021/ja8046552

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Funding

  1. BBSRC
  2. Cancer Research UK
  3. European Commission (Marie Curie Incoming Postdoctoral Fellowship
  4. Netherlands Ramsay Memorial Fellowship
  5. Human Frontier Science Program Long-term Fellowship [LT00798/2005]
  6. Biotechnology and Biological Sciences Research Council [BB/C51444X/1] Funding Source: researchfish

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We report bis-phenylethynyl amide derivatives as a potent G-quadruplex binding small molecule scaffold. The amide derivatives were efficiently prepared in 3 steps by employing Sonogashira coupling, ester hydrolysis and a chemoselective amide coupling. Ligand-quadruplex recognition has been evaluated using a fluorescence resonance energy transfer (FRET) melting assay, surface plasmon resonance (SPR), circular dichroism (CD) and H-1 nuclear magnetic resonance (NMR) spectroscopy. While most of the G-quadruplex ligands reported so far comprise a planar, aromatic core designed to stack on the terminal tetrads of a G-quadruplex, these compounds are neither polycyclic, nor macrocyclic and have free rotation around the triple bond enabling conformational flexibility. Such molecules show very good binding affinity, excellent quadruplex:duplex selectivity and also promising discrimination between intramolecular promoter quadruplexes. Our results indicate that the recognition of the c-kit2 quadruplex by these ligands is achieved through groove binding, which favors the formation of a parallel conformation.

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