Cooperative Hydrogen Bonding in Glyco–Oligoamides: DNA Minor Groove Binders in Aqueous Media

Abstract

A strategy to create cooperative hydrogen‐bonding centers by using strong and directional intramolecular hydrogen‐bonding motifs that can survive in aqueous media is presented. In particular, glyco–oligoamides, a family of DNA minor groove binders, with cooperative and non‐cooperative hydrogen‐bonding donor centers in the carbohydrate residues have been designed, synthesized, and studied by means of NMR spectroscopy and molecular modeling methods. Indeed, two different sugar moieties, namely, β‐D‐Man‐Py‐γ‐Py‐Ind (1; Ind=indole, Man=mannose, Py=pyrrole) and β‐D‐Tal‐Py‐γ‐Py‐Ind (2; Tal=talose), were chosen according to our design. These sugar molecules should present one‐ or two‐directional intramolecular hydrogen bonds. The challenge has been to study the conformation of the glyco–oligoamides at low temperature in physiological media by detecting the exchangeable protons (amide NH and OH resonances) by means of NMR spectroscopic analysis. In addition, two more glyco–oligoamides with non‐cooperative hydrogen‐bonding centers, that is, β‐D‐Glc‐Py‐γ‐Py‐Ind (3; Glc=glucose), β‐D‐Gal‐Py‐γ‐Py‐Ind (4; Gal=galactose), and the model compounds β‐D‐Man‐Py‐NHAc (5) and β‐D‐Tal‐Py‐NHAc (6) were synthesized and studied for comparison. We have demonstrated the existence of directional intramolecular hydrogen bonds in 1 and 2 in aqueous media. The unexpected differences in terms of stabilization of the intramolecular hydrogen bonds in 1 and 2 relative to 5 and 6 promoted us to evaluate the influence of CH—π interactions on the establishment of intramolecular hydrogen bonds by using computational methods. Initial binding studies of 1 and 2 with calf‐thymus DNA and poly(dA‐dT)2 by NMR spectroscopic analysis and molecular dynamics simulations were also carried out. Both new sugar–oligoamides are bound in the minor groove of DNA, thus keeping a stable hairpin structure, as in the free state, in which both intramolecular hydrogen‐bonding and CH—π interactions are present.

Association of symmetrical alkane diols with pyridine: DFT/GIAO calculation of 1H NMR chemical shifts

“…In the more limited context of physical organic chemistry, it is often associated with hydrogen bonding, each hydrogen bond in a chain of linked hydrogen bonds (two or more) being stronger than it would be in the absence of the others. Because of the importance of carbohydrates in molecular recognition, crystallization, self‐assembly, cryoprotection etc., largely controlled by the OH groups, cooperativity continues to be a subject of considerable interest . The proximity of several OH groups favours intramolecular hydrogen bonding and cooperativity, although it is not always clear whether these features are the cause or simply the opportunistic consequence of conformational preferences .…”

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

“…[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. This conclusion was based on the nOes observed at 5°C, especially those between the protons of both of the pyrrole units and those between the carbohydrate and the indole residues (in red in Figure S18 in the Supporting Information).…”

“…[6] As illustrated in Figure 1, we have previously reported on the survival of an intramolecular NH···2-OH bond in water for the glyco-oligoamide β-dMan-Py-γ-Py-Ind (1). [7] This directional intramolecular hydrogen bond might allow 2-OH to behave as a cooperative donor in an intermolecular process. In the work presented in this paper, we have explored the use of hydrogenbonding cooperativity for carbohydrate-DNA recognition.…”

Recent Advances in NMR Studies of Carbohydrates

“…5). Work published by Peñalver et al [94] and Blázquez-Sánchez et al [95] described the use of a neutral glycol-conjugate (β-Gal-Py-γ-Py-Ind) to determine sugar-DNA interactions. The NMR spectrum assignment of the glyco-oligoamide/oligonucleotide 1:1 complex was based on the standard 2D NMR methodology employing TOCSY and NOESY experiments.…”