A Water‐Soluble Tetraazaperopyrene Dye as Strong G‐Quadruplex DNA Binder. Issue 18 (21st March 2016)

• Record Type: Journal Article
• Authors: Hahn, Lena; Buurma, Niklaas J.; Gade, Lutz H.
• Is Part Of: Chemistry. Volume 22:Issue 18(2016)
• Page Start: 6314
• Page End: 6322
• Publication Date: 2016-03-21
• Subjects: DNA -- docking studies -- dyes/pigments -- G-quadruplexes; Chemistry -- Periodicals; 540
• DOI: 10.1002/chem.201504934
• Languages: English
• ISSNs: 0947-6539

Abstract

Abstract: The interactions of the water‐soluble tetraazaperopyrene dye1 with ct‐DNA, duplex‐[(dAdT)12 ⋅ (dAdT)12 ], duplex‐[(dGdC)12 ⋅ (dGdC)12 ] as well as with two G‐quadruplex‐forming sequences, namely the human telomeric 22AG and the promotor sequence c‐myc, were investigated by means of UV/visible and fluorescence spectroscopy, isothermal titration calorimetry (ITC) and molecular docking studies. Dye1 exhibits a high affinity for G‐quadruplex structures over duplex DNA structures. Furthermore, the ligand shows promising G‐quadruplex discrimination, with an affinity towards c‐myc of 2×10 7 m −1 (i.e., K d =50 nm ), which is higher than for 22AG (4×10 6 m −1 ). The ITC data reveal that compound1 interacts with c‐myc in a stoichiometric ratio of 1:1 but also indicate the presence of two identical lower affinity secondary binding sites per quadruplex. In 22AG, there are two high affinity binding sites per quadruplex, that is, one on each side, with a further four weaker binding sites. For both quadruplex structures, the high affinity interactions between compound1 and the quadruplex‐forming nucleic acid structures are weakly endothermic. Molecular docking studies suggest an end‐stacking binding mode for compound1 interacting with quadruplex structures, and a higher affinity for the parallel conformation of c‐myc than for the mixed‐hybrid conformation of 22AG. In addition, docking studies also suggest that the reduced affinity for duplex DNA structures is due to the non‐viability of an intercalative binding mode. Abstract : TAPPing nucleic acids : A water‐soluble tetraazaperopyrene dye exhibits remarkable selectivity for G‐quadruplex structures over duplex DNA structures as was shown by UV/visible and fluorescence spectroscopies, isothermal titration calorimetry (ITC) and molecular docking studies (see figure).