Diarylethynyl amides that recognize the parallel conformation of genomic promoter DNA G-quadruplexes.
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 (1)H 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.
Dash
Jyotirmayee
J
The University Chemical Laboratory, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK.
Shirude
Pravin S
PS
Hsu
Shang-Te Danny
ST
Balasubramanian
Shankar
S
D000577:Amides / Q000737:chemistry*; D002942:Circular Dichroism; D004247:DNA / Q000737:chemistry* / Q000235:genetics*; D054856:G-Quadruplexes; D016678:Genome / Q000235:genetics*; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D009691:Nucleic Acid Denaturation; D011401:Promoter Regions, Genetic / Q000235:genetics*; D020349:Surface Plasmon Resonance; D017186:Titrimetry
D000577:Amides; D008024:Ligands; D004247:DNA