A Water‐Soluble Tetraazaperopyrene Dye as Strong G‐Quadruplex DNA Binder

Abstract

The interactions of the water‐soluble tetraazaperopyrene dye 1 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. Dye 1 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 2×107 m −1 (i.e., K d=50 nm), which is higher than for 22AG (4×106 m −1). The ITC data reveal that compound 1 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 compound 1 and the quadruplex‐forming nucleic acid structures are weakly endothermic. Molecular docking studies suggest an end‐stacking binding mode for compound 1 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.

Investigation of the interactions between methylene blue and intramolecular G-quadruplexes: an explicit distinction in electrochemical behavior

“…In all cases, the binding strength is weaker than that caused by some large aromatic molecules, such as the tetraazaperopyrene molecule, which has extended flat aromatic structure and can bind with the parallel G-quadruplex conformation of c-myc via end-stacking. 34 These ITC data supports the electrochemical results well and suggest that MB interacts with intramolecular G-quadruplexes is not similar with large π surface molecules.…”

“…First, MB dilution was studied and we observed an exothermic process with non-constant heats of dilution ( Figure 5A), which suggested stepwise self-aggregation. 33,34 Data fitting using IC-ITC 35,36 gave an equilibrium constant Kagg of 1.4×10 3 M -1 and an enthalpy change for agg egatio ΔHagg of -15.8 kcal·mol -1 for this process (as shown in Figure 5B; fittings and evaluation of error margins for the parameters were recorded in Figure S6). In the binding titrations, MB was injected stepwise into solutions of G-quadruplexes with different conformations and the resulting enthalpograms are shown in Figure 6.…”

Amino‐Acid‐Derived Naphthalenediimides as Versatile G‐Quadruplex Binders

“…Owing to the unique topology of each G‐quadruplex structure, the prospect of generating highly selective and effective molecules towards the stabilisation of G‐rich DNA over dsDNA is promising, but challenging . A relatively large number of small ligands, such as Telomestatin, Quarfloxin, porphyrinoids, amido‐anthraquinones, quindoline, and acridine derivatives, that interact with these higher‐order structures have been developed, several of which have entered clinical trials . Figure illustrates the various G‐quadruplex binding modes adopted by small ligands; an example not included in this Figure, which stands out as a unique binding mode, is the threading and stacking interaction, whereby a polyaromatic moiety that bears an alkyl triamine group replaces the alkaline cations and stacks on the top G‐tetrad .…”

The Thiophene “Sigma‐Hole” as a Concept for Preorganized, Specific Recognition of G⋅C Base Pairs in the DNA Minor Groove

“…The compounds should have, for example, appropriate curvature to fit the convex shape of the minor groove . Although not essential, cationic groups have been attached at one or both ends of the new compounds reported herein to aid solubility and increase the electrostatic interaction with the negatively charged DNA backbone . Amidine cationic groups, which have been quite successful for targeting DNA, provide a hydrogen‐bond‐donating, planar surface for optimizing interactions with A ⋅ T bps as flanking sites of G ⋅ C bps .…”