Carbohydrate-Based DNA Ligands:  Sugar−Oligoamides as a Tool to Study Carbohydrate−Nucleic Acid Interactions

Abstract

Sugar-oligoamides have been designed and synthesized as structurally simple carbohydrate-based ligands to study carbohydrate-DNA interactions. The general design of the ligands 1-3 has been done as to favor the bound conformation of Distamycin-type gamma-linked covalent dimers which is a hairpin conformation. Indeed, NMR analysis of the sugar-oligoamides in the free state has indicated the presence of a percentage of a hairpin conformation in aqueous solution. The DNA binding activity of compounds 1-3 was confirmed by calf thymus DNA (ct-DNA) NMR titration. Interestingly, the binding of the different sugar-oligoamides seems to be modulated by the sugar configuration. Semiquantitative structural information about the DNA ligand complexes has been derived from NMR data. A competition experiment with Netropsin suggested that the sugar-oligoamide 3 bind to DNA in the minor groove. The NMR titrations of 1-3 with poly(dA-dT) and poly(dG-dC) suggested preferential binding to the ATAT sequence. TR-NOE NMR experiments for the sugar-oligoamide 3-ct-DNA complex both in D(2)O and H(2)O have confirmed the complex formation and given information on the conformation of the ligand in the bound state. The data confirmed that the sugar-oligoamide ligand is a hairpin in the bound state. Even more relevant to our goal, structural information on the conformation around the N-glycosidic linkage has been accessed. Thus, the sugar asymmetric centers pointing to the NH-amide and N-methyl rims of the molecule have been characterized.

Free energy surfaces for the interaction of D-glucose with planar aromatic groups in aqueous solution

“…This binding motif for carbohydrate binding sites is sufficiently widespread as to suggest a special affinity between sugar rings and these aromatic side chains. 10,11 There are relatively few studies investigating carbohydrate-aromatic interactions in isolation. Fernández-Alonzo et al 12 used NMR to demonstrate that monosaccharides ͑methyl ␤-galactoside͒ and aromatic rings ͑benzene͒ do indeed form complexes in solution and used ab initio calculations to quantify the interaction energies to around 12 kJ/ mol ͑in vacuum͒.…”

A Neutral DNA Sequence‐Selective Vector for Interaction Studies: Fluorescence Binding Experiments Directed Towards a Carbohydrate‐DNA Carrier

“…We therefore selected the indole fluorophore maximum emission wavelength (λ = 410 nm) in order to follow the changes in the fluorescence emission intensity in the quantum yield measurements and DNA titration studies. [62] In an earlier work from our group, [49] the hairpin conformations of sugar-oligoamides 4, 6 and 7 in aqueous solution were characterized by NMR spectroscopy. [63] Here, we have used fluorescence quantum yield values to ensure the presence of similar free state conformations for ligands 1-8 and thus to correlate the differences in the measured binding energies with the changes in the shape of the structural elements (Scheme 2).…”

“…[57,58] The sugar-oligoamides 4, 6 and 7 were therefore synthesized. [49] An nOe study suggested that the sugar-oligoamides each present a noticeable percentage of hairpin conformation in the free state, while TR-NOESY data also suggested hairpin structures in the bound state. Additionally, a qualitative study of the binding with ct-DNA by NMR showed specific interaction, while a competition experiment with netropsin suggested that the designed ligands are minor groove binders.…”

“…More recently, we described [49] the first results of this new strategy. The design of the sugar-oligoamide derivative involved taking into account that the bound conformation of distamycin-type γ-linked covalent dimers, as described by Wemmer et al, [50] is a hairpin conformation.…”

D‐ and L‐Mannose‐Containing glyco‐­Oligoamides Show Distinct Recognition Properties When Interacting with DNA

“…We have previously characterized a hairpin structure for free glyco-oligoamides with equatorial 2-OH groups. [10,15] Following an analogous protocol, compound 1 (β-d-Man) was shown to have a hairpin-like conformation, with its α face pointing towards the indole ring. [7] The NMR spectroscopic data for 2 and 3 in the free state ( Figure S18 in the Supporting Information) also indicated the presence of a major hairpin structure.…”